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Volume 48, Supplement 4, July 2010 ISSN 0278-6915<br />
<strong>Food</strong> <strong>and</strong><br />
<strong>Chemical</strong><br />
<strong>Toxicology</strong><br />
Editors<br />
J F Borzelleca<br />
A R Boobis<br />
A Safety Assessment of Saturated Branched Chain<br />
Alcohols when used as <strong>Fragrance</strong> Ingredients
FOOD AND CHEMICAL TOXICOLOGY<br />
Founding Editor<br />
The late Leon Golberg<br />
Editors<br />
JOSEPH<br />
F. BORZELLECA<br />
Department of Pharmacology <strong>and</strong><br />
<strong>Toxicology</strong>, Medical College of Virginia,<br />
Richmond, VA 23298-0613, USA<br />
ALAN<br />
R. BOOBIS<br />
Section of Experimental Medicine <strong>and</strong> <strong>Toxicology</strong>,<br />
Division of Medicine, Imperial College, Hammersmith Campus,<br />
Ducane Road, London W12 0NN, UK<br />
JOHN<br />
CHRISTIAN<br />
LARSEN<br />
National <strong>Food</strong> <strong>Institute</strong>, Technical University of Denmark,<br />
19 Mørkhøj Bygade, DK-2860 Søborg, Denmark<br />
BRYAN<br />
DELANEY<br />
Senior <strong>Research</strong> Scientist – <strong>Toxicology</strong>, Pioneer Hi-Bred International,<br />
2450 SE Oak Tree Court Ankeny, IA 50021-7102, USA<br />
GARY<br />
WILLIAMS<br />
Department of Pathology, New York Medical College, Basic Science<br />
Building, Room 413, Valhalla, NY 10595, USA<br />
SAMUEL<br />
M. COHEN<br />
Department of Pathology <strong>and</strong> Microbiology, University of Nebraska<br />
Medical Center, 983135 Nebraska Medical Center,<br />
Omaha, NE 68198-3135<br />
P. BALDRICK, UK<br />
J. K. CHIPMAN, UK<br />
T. F. X. COLLINS, USA<br />
Y. P. DRAGAN, USA<br />
L. O. DRAGSTED, Denmark<br />
L. FERGUSON<br />
S. J. S. FLORA, India<br />
ERGUSON, New Zeal<strong>and</strong><br />
H. R. GLATT, Germany<br />
W. H. GLINSMANN<br />
LINSMANN, USA<br />
Y. HASHIMOTO, Japan<br />
A. W. HAYES, USA<br />
Y. HUA, China<br />
S. KACEW<br />
ACEW, Canada<br />
Review Editor<br />
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M. BARLOW<br />
Harrington House, 8 Harrington Road,<br />
Brighton, East Sussex BN1 6RE, UK<br />
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NASMÜLLER, Austria<br />
B. LAKE, UK<br />
R. W. LANE, USA<br />
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D. McGREGOR, France<br />
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IVONNE<br />
RIETJENS<br />
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J. BRUSICK<br />
Brusick Consultancy, 123 Moody Creek Road, VA 23024, Bumpass,<br />
Virginia, USA<br />
MICHAEL<br />
W. PARIZA<br />
Department of <strong>Food</strong> Microbiology <strong>and</strong> <strong>Toxicology</strong>, University of<br />
Wisconsin at Madison, 176 Microbial Sciences Building,<br />
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A. VISCONTI, Italy<br />
X. WANG<br />
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ERHAGEN, The Netherl<strong>and</strong>s<br />
ANG, People’s Republic of China<br />
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A Safety Assessment of Saturated Branched Chain<br />
Alcohols when used as <strong>Fragrance</strong> Ingredients
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46<br />
Contents lists available at ScienceDirect<br />
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong><br />
journal homepage: www.elsevier.com/locate/foodchemtox<br />
Review<br />
A safety assessment of branched chain saturated alcohols when used<br />
as fragrance ingredients q<br />
D. Belsito a , D. Bickers b , M. Bruze c , P. Calow d , H. Greim e , J.M. Hanifin f , A.E. Rogers g , J.H. Saurat h ,<br />
I.G. Sipes i , H. Tagami j , The RIFM Expert Panel<br />
a University of Missouri (Kansas City), c/o American Dermatology Associates, LLC, 6333 Long Avenue, Third Floor, Shawnee, KS 66216, USA<br />
b Columbia University Medical Center, Department of Dermatology, 161 Fort Washington Ave., New York, NY 10032, USA<br />
c Malmo University Hospital, Department of Occupational <strong>and</strong> Environmental Dermatology, Sodra Forstadsgatan 101, Entrance 47, Malmo SE-20502, Sweden<br />
d Roskilde University, Department of Environmental, Social <strong>and</strong> Spatial Change, Isafjordvej 66, Roskilde, Denmark<br />
e Technical University of Munich, <strong>Institute</strong> <strong>for</strong> <strong>Toxicology</strong> <strong>and</strong> Environmental Hygiene, Hohenbachernstrasse 15-17, Freising-Weihenstephan D-85354, Germany<br />
f Oregon Health Sciences University, Department of Dermatology L468, 3181 SW Sam Jackson Park Rd., Portl<strong>and</strong>, OR 97201-3098, USA<br />
g Boston University School of Medicine, Department of Pathology <strong>and</strong> Laboratory Medicine, 715 Albany Street, L-804, Boston, MA 02118-2526, USA<br />
h Dermatotoxicology Swiss Centre <strong>for</strong> Applied Human <strong>Toxicology</strong>, University Medical Center, Rue Michel Servet, 1211 Genève 4, Switzerl<strong>and</strong><br />
i Department of Pharmacology, University of Arizona, College of Medicine, 1501 North Campbell Avenue, P.O. Box 245050, Tucson, AZ 85724-5050, USA<br />
j 3-27-1 Kaigamori, Aoba-ku, Sendai 981-0942, Japan<br />
article<br />
info<br />
abstract<br />
Keywords:<br />
Review<br />
Safety<br />
<strong>Fragrance</strong> ingredients<br />
Branched chain saturated alcohols<br />
The Branched Chain Saturated Alcohol (BCSA) group of fragrance ingredients was evaluated <strong>for</strong> safety. In<br />
humans, no evidence of skin irritation was found at concentrations of 2–10%. Undiluted, 11 materials<br />
evaluated caused moderate to severe eye irritation. As current end product use levels are between<br />
0.001% <strong>and</strong> 1.7%, eye irritation is not a concern. The materials have no or low sensitizing potential. For<br />
individuals who are already sensitized, an elicitation reaction is possible. Due to lack of UVA/UVB<br />
light-absorbing structures, <strong>and</strong> review of phototoxic/photoallergy data, the BCSA are not expected to elicit<br />
phototoxicity or photoallergy. The 15 materials tested have a low order of acute toxicity. Following<br />
repeated application, seven BCSA tested were of low systemic toxicity. Studies per<strong>for</strong>med on eight BCSA<br />
<strong>and</strong> three metabolites show no in vivo or in vitro genotoxicity. A valid carcinogenicity study showed that<br />
2-ethyl-1-hexanol is a weak inducer of liver tumors in female mice, however, the relevance of this effect<br />
<strong>and</strong> mode of action to humans is still a matter of debate. The Panel is of the opinion that there are no<br />
safety concerns regarding BCSA under the present levels of use <strong>and</strong> exposure.<br />
Ó 2010 Elsevier Ltd. All rights reserved.<br />
Contents<br />
1. Introduction .......................................................................................................... S2<br />
2. <strong>Chemical</strong> identity, regulatory status, <strong>and</strong> exposure . ......................................................................... S2<br />
2.1. Rationale <strong>for</strong> grouping branched chain saturated alcohols together . ..................................................... S2<br />
2.2. Occurrence <strong>and</strong> use. . . . . ........................................................................................ S7<br />
2.3. Estimated consumer exposure . . . . . . . . . . . . ........................................................................ S7<br />
3. Metabolism .......................................................................................................... S8<br />
3.1. Primary alcohols . . . . . . . ........................................................................................ S8<br />
3.2. Secondary alcohols . . . ............................................................................................ S8<br />
3.3. Tertiary alcohols ................................................................................................. S8<br />
4. Pharmacokinetics. . .................................................................................................... S8<br />
4.1. Dermal route of exposure ........................................................................................ S8<br />
4.2. Oral route of exposure . . ........................................................................................ S8<br />
q All correspondence should be addressed to: A.M. Api, RIFM, 50 Tice Blvd, Woodcliff Lake, NJ 07677, USA. Tel.: +1 201 689 8089; fax: +1 201 689 8090. E-mail address:<br />
amapi@rifm.org.<br />
0278-6915/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.<br />
doi:10.1016/j.fct.2010.05.046
S2<br />
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46<br />
4.3. Respiratory route of exposure . ..................................................................................... S9<br />
4.4. Parenteral route of exposure ...................................................................................... S9<br />
5. Toxicological studies .................................................................................................. S9<br />
5.1. Acute toxicity .................................................................................................. S9<br />
5.2. Repeated dose toxicity ........................................................................................... S9<br />
5.2.1. Dermal studies ........................................................................................... S9<br />
5.2.2. Oral studies . . . . . . . . . . . ................................................................................. S10<br />
5.2.3. Inhalation studies . . . . . . ................................................................................. S11<br />
5.3. Mutagenicity <strong>and</strong> genotoxicity . . . . . . . . . .......................................................................... S13<br />
5.3.1. In vitro mutagenicity studies. . . . . . . . . . . . . . ................................................................. S13<br />
5.3.2. In vivo studies . . . . . . . . . ................................................................................. S18<br />
5.4. Carcinogenicity . . ............................................................................................. S18<br />
5.4.1. Cell trans<strong>for</strong>mation assays . . . . . . . . . . . . . . . ................................................................. S18<br />
5.4.2. Carcinogenicity studies . . ................................................................................. S18<br />
5.5. Reproductive <strong>and</strong> developmental toxicity .......................................................................... S20<br />
5.5.1. Fertility . . . . . . . . . . . . . . . ................................................................................. S20<br />
5.5.2. Developmental toxicity . . ................................................................................. S20<br />
5.6. Skin irritation . . . ............................................................................................. S32<br />
5.6.1. Human studies . . . . . . . . . ................................................................................. S32<br />
5.6.2. Animal studies . . . . . . . . . ................................................................................. S32<br />
5.7. Mucous membrane irritation . . . . . . . . . . .......................................................................... S32<br />
5.7.1. Sensory irritation . . . . . . . ................................................................................. S32<br />
5.7.2. Eye irritation . . . . . . . . . . ................................................................................. S33<br />
5.8. Skin sensitization ............................................................................................. S33<br />
5.8.1. Human studies . . . . . . . . . ................................................................................. S33<br />
5.8.2. Animal studies . . . . . . . . . ................................................................................. S33<br />
5.9. Phototoxicity <strong>and</strong> photoallergenicity . . . . .......................................................................... S33<br />
5.10. Miscellaneous studies .......................................................................................... S36<br />
6. Conclusion . . ........................................................................................................ S36<br />
Conflict of interest statement. . . ........................................................................................ S41<br />
References . . ........................................................................................................ S42<br />
1. Introduction<br />
In 2006 complete literature searches were conducted on the<br />
branched chain saturated alcohol group of fragrance ingredients.<br />
This document provides a risk assessment of these materials as fragrance<br />
ingredients <strong>and</strong> is a critical evaluation of the pertinent data.<br />
The scientific evaluation focuses on dermal exposure, which is considered<br />
to be the primary route <strong>for</strong> fragrance materials. Where relevant,<br />
toxicity, metabolism <strong>and</strong> biological fate data from other<br />
exposures have been considered.<br />
The current <strong>for</strong>mat includes a group summary evaluation paper<br />
<strong>and</strong> individual <strong>Fragrance</strong> Material Reviews on discrete chemicals.<br />
The group summary is an evaluation of relevant data<br />
selected from the large bibliography of studies <strong>and</strong> reports on<br />
the individual chemicals. The selected data were deemed to be<br />
relevant based on the currency of protocols, quality of the data,<br />
statistical significance <strong>and</strong> appropriate exposure. These are identified<br />
in tabular <strong>for</strong>m in the group summary. Details that are<br />
provided in the tables are not always discussed in the text of<br />
the group summary. The <strong>Fragrance</strong> Material Reviews contain a<br />
comprehensive summary of all published reports including complete<br />
bibliographies (McGinty et al., 2010a,b,c,d,e,f,g,h,i,j,k,l,m,n,<br />
o,p,q).<br />
2. <strong>Chemical</strong> identity, regulatory status, <strong>and</strong> exposure<br />
2.1. Rationale <strong>for</strong> grouping branched chain saturated alcohols together<br />
The group consists of 12 primary, 5 secondary <strong>and</strong> 3 tertiary<br />
alcohols. Of these materials, three have been previously reviewed<br />
in RIFM’s Safety Assessment on Terpene Alcohols (Belsito et al.,<br />
2008). The names <strong>and</strong> structures of the materials reviewed are<br />
shown in Table 1. 1 In addition, several noncyclic branched chain<br />
alcohols used as examples here have been reviewed in other recent<br />
RIFM publications. In<strong>for</strong>mation on previously reviewed substances<br />
of this group is not presented again unless it is new or required to<br />
evaluate remaining fragrance ingredients. The common characteristic<br />
structural elements of the alcohols with saturated branched chain<br />
are one hydroxyl group per molecule, a C 4 –C 12 carbon chain with<br />
one or several methyl side chains. Two members of the group, 2-<br />
ethyl-1-butanol <strong>and</strong> 2-ethyl-1-hexanol, contain an ethyl side chain.<br />
One member contains a methoxy group. Metabolism studies are<br />
lacking <strong>for</strong> this compound, however, a methoxy group is enzymatically<br />
not readily cleaved <strong>and</strong> if it were so, another primary alcohol<br />
group would be <strong>for</strong>med.<br />
As the database <strong>for</strong> the alcohols under review is limited, additional<br />
data <strong>for</strong> some metabolites of these alcohols have been used.<br />
It was demonstrated that 4-methyl-2-pentanol, a group member, is<br />
metabolized to 4-methyl-2-pentanone <strong>and</strong> 4-hydroxy-4-methyl-2-<br />
pentanone is a metabolite of both substances (Gingell et al.,<br />
2003). It can also be expected that 2,6-dimethyl-4-heptanol is<br />
metabolized to 2,6-dimethylheptan-4-one. There<strong>for</strong>e, studies on<br />
pharmacokinetics, metabolism, genotoxicity <strong>and</strong> systemic toxicity<br />
of 4-methyl-2-pentanone, 4-hydroxy-4-methyl-2-pentanone <strong>and</strong> 2,6-<br />
dimethylheptan-4-one have been added to the database. These<br />
materials are not used as fragrance ingredients. Due to their structural<br />
similarity, these alcohols also share common metabolic pathways<br />
(see below). As metabolism is crucial <strong>for</strong> pharmacokinetics<br />
<strong>and</strong> toxicity, these alcohols or their metabolites are expected to<br />
have the same primary target organs (liver, kidney, <strong>and</strong> blood) as<br />
was shown <strong>for</strong> 2-ethyl-1-hexanol, isoamyl alcohol, isotridecan-1-<br />
1 Isooctan-1-ol, isononyl alcohol, isodecyl alcohol <strong>and</strong> Isotridecan-1-ol (isomeric<br />
mixture) are generic names <strong>for</strong> mixtures of isomers of primary branched alcohols<br />
with an average C-number of 8, 9, 10, or 13, respectively.
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46 S3<br />
Table 1<br />
Material identification, summary of volume of use, <strong>and</strong> dermal exposure.<br />
Material Synonyms Structure Worldwide metric Dermal systemic exposure<br />
tons (annual) a in cosmetic products (mg/<br />
kg/day)<br />
Maximum skin<br />
level (%) b<br />
Subgroup: primary<br />
3,7-Dimethyl-1-octanol c<br />
C10H22O<br />
CAS# 106-21-8 Dihydrocitronellol 100–1000 0.0005 d 0.02<br />
Henry’s Law: 0.0000547 atm m 3 /mol 25 °C 1-Octanol, 3,7-dimethyl-<br />
LogK ow : 3.9 at 35 °C Pelargol<br />
Molecular weight: 158.29 Tetrahydrogeraniol<br />
Vapor pressure: 0.06 mm Hg 20 °C<br />
Water solubility: 175.4 mg/l at 25 °C<br />
2-Ethyl-1-butanol<br />
C 6 H 14 O<br />
CAS# 97-95-0 1-Butanol,2-ethyl-
S4<br />
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46<br />
Table 1 (continued)<br />
Material Synonyms Structure Worldwide metric Dermal systemic exposure<br />
tons (annual) a in cosmetic products (mg/<br />
kg/day)<br />
Maximum skin<br />
level (%) b<br />
Isooctan-1-ol<br />
C 8 H 18 O<br />
CAS# 26952-21-6 Isooctanol
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46 S5<br />
Subgroup: secondary<br />
2,6-Dimethyl-4-heptanol<br />
C9H20O<br />
CAS# 108-82-7 Diisobutylcarbinol 10–100 0.0005 d 0.02<br />
Henry’s Law: 0.0000412 atm m 3 /mol 25 °C 4-Heptanol,2,6-dimethyl-<br />
LogK ow 3.08 calc 2,6-Dimethylheptan-4-ol<br />
Molecular weight: 144.26<br />
Vapor pressure: 0.0624 mm Hg 25 °C<br />
Water solubility: 613.8 mg/l at 25 °C<br />
3,7-Dimethyl-7-methoxyoctan-2-ol<br />
C 11 H 24 O 2<br />
CAS# 41890-92-0 7-Methoxy-3,7-dimethyloctan-2-ol 1–10 0.09 1.3<br />
Henry’s Law: 0.000000404 atm m 3 /mol 25 °C 2-Octanol,7-methoxy-3,7-dimethyl-<br />
LogK ow : 2.76 calc Osirol<br />
Molecular weight: 188.31 Osyrol<br />
Vapor pressure: 0.0119 mm Hg 25 °C<br />
Water solubility: 707.1 mg/l at 25 °C<br />
6,8-Dimethylnonan-2-ol<br />
C 11 H 24 O<br />
CAS# 70214-77-6 2-Nonanol,6,8-dimethyl- 1–10 0.001 0.009<br />
LogKow: 4.06 calc Nonadyl<br />
Molecular weight: 172.12<br />
Vapor pressure: 0.000115 mm Hg 25 °C<br />
4-Methyl-2-pentanol<br />
C 6 H 14 O<br />
CAS# 108-11-2 Isobutyl methyl carbinol 0.01–0.1 0.0005 d 0.02<br />
Henry’s Law: 0.0000176 atm m 3 /mol 25 °C Methyl isobutyl carbinol<br />
LogKow: 1.68 calc MIC<br />
Molecular weight: 102.18 2-Pentanol,4-methyl-<br />
Vapor pressure: 3.7 mm Hg 20 °C 4-Methylpentan-2-ol<br />
Water solubility: 13,800 mg/l at 25 °C<br />
3,4,5,6,6-Pentamethylheptan-2-ol<br />
C 12 H 26 O<br />
CAS# 87118-95-4 2-Heptanol,3,4,5,6,6-pentamethyl- 10–100 0.14 1.7<br />
LogKow: 4.36 calc Koavol DH<br />
Molecular weight: 186.39<br />
Vapor pressure: 0.0000000461 mm Hg 25 °C<br />
Subgroup: tertiary<br />
2,6-Dimethyl-2-heptanol<br />
C 9 H 20 O<br />
CAS# 13254-34-7 Dimetol 10–100 0.0614 1.4<br />
Henry’s Law: 0.0000412 atm m 3 /mol 25 °C Freesiol<br />
LogK ow 3.0 at 45 °C 2-Heptanol,2-6-dimethyl-<br />
Molecular weight: 144.26 Lolitol<br />
Vapor pressure: 0.2 mm Hg 20 °C 2,6-Dimethylheptan-2-ol<br />
Water solubility: 572 mg/l at 25 °C<br />
(continued on next page)
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Table 1 (continued)<br />
Material Synonyms Structure Worldwide metric Dermal systemic exposure<br />
tons (annual) a in cosmetic products (mg/<br />
kg/day)<br />
Maximum skin<br />
level (%) b<br />
3,6-Dimethyl-3-octanol<br />
C 10 H 22 O<br />
CAS# 151-19-9 3-Octanol,3,6-dimethyl- 0.1–1 0.0005 d 0.02<br />
Henry’s Law: 0.0000547 atm m 3 /mol 25 °C 3,6-Dimethyloctan-3-ol<br />
LogK ow : 3.6 calc<br />
Molecular weight: 158.29<br />
Vapor pressure: 0.0651 mm Hg 25 °C<br />
Water solubility: 188.9 mg/l at 25 °C<br />
Tetrahydrolinalool c<br />
C 10 H 22 O<br />
CAS# 78-69-3 2,6-Dimethyl-6-octanol >1000 0.0005 d 0.02<br />
Henry’s Law: 0.0000547 atm m 3 /mol 25 C 3,7-Dimethyloctan-3-ol<br />
LogKow: 3.6 at 45 °C 3-Octanol, 3,7-dimethyl-<br />
Molecular weight: 158.29<br />
Vapor pressure: 0.0713 mm Hg 25 °C<br />
Water solubility: 188.9 mg/l at 25 °C<br />
Tetrahydromyrcenol c<br />
C10H22O<br />
CAS# 18479-57-7 2,6-Dimethyloctan-2-ol 100–1000 0.06 0.7<br />
Henry’s Law: 0.0000547 atm m 3 /mol 25 C 2,6-Dimethyl-2-octanol<br />
LogK ow : 3.6 calc 2-Octanol, 2,6-dimethyl<br />
Molecular weight: 158.29<br />
Vapor pressure: 0.05 mm Hg 20 °C<br />
Water solubility: 188.9 mg/l at 25 °C<br />
a 2007 Volume of use survey.<br />
b Skin levels were based on the assumption that the fragrance mixture is used at 20% in a consumer product.<br />
c<br />
d<br />
Materials have been previously reviewed by in RIFM’s Safety Assessment of Terpene Alcohols.<br />
A default value of 0.02% was used to calculate dermal systemic exposure.
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46 S7<br />
ol (isomeric mixture), 3,5,5-trimethyl-1-hexanol, 2,6-dimethylheptan-4-one,<br />
4-hydroxy-4-methyl-2-pentanone, 4-methyl-2-pentanol,<br />
<strong>and</strong> 4-methyl-2-pentanone.<br />
Data <strong>for</strong> 2-ethyl-1-hexanol, 2-ethylbutanol, 4-methyl-2-pentanol,<br />
isoamyl alcohol, 2-methylbutanol <strong>and</strong> 4-methyl-2-pentanone<br />
show that the alcohols share common metabolic pathways. The<br />
major pathways of metabolism <strong>and</strong> fate are:<br />
– conjugation of the alcohol group with glucuronic acid;<br />
– oxidation of the alcohol group;<br />
– side-chain oxidation yielding polar metabolites, which may be<br />
conjugated <strong>and</strong> excreted – or further oxidized to an aldehyde,<br />
a carboxylic acid, <strong>and</strong> to CO 2 ;<br />
– excretion of the unchanged parent compound.<br />
In most cases, metabolism yields innocuous metabolites. Intermediary<br />
reactive products of oxidation of primary alcohols are<br />
aldehydes, which are toxic <strong>and</strong> possibly genotoxic, although no relevant<br />
genotoxicity was shown with the primary alcohols tested.<br />
The alcohols under review are summarized in Table 1. CAS No.<br />
<strong>and</strong> synonyms <strong>for</strong> the alcohols considered in this review are shown<br />
in Table 1. The structural <strong>for</strong>mulas are provided in Table 1.<br />
2.2. Occurrence <strong>and</strong> use<br />
The alcohols under review are used as fragrance ingredients.<br />
They may be found in fragrances used in decorative cosmetics, fine<br />
fragrances, shampoos, toilet soaps, <strong>and</strong> other toiletries as well as in<br />
non-cosmetic products such as household cleaners <strong>and</strong> detergents.<br />
This report summarizes <strong>and</strong> synthesizes animal <strong>and</strong> human data,<br />
including studies by various routes of exposure, <strong>and</strong> emphasizes<br />
the risk assessment <strong>for</strong> use as fragrance ingredients. The scientific<br />
evaluation focuses on dermal exposure, which is considered the<br />
primary exposure route <strong>for</strong> fragrance materials. Where relevant<br />
the metabolism, toxicity, <strong>and</strong> biological fate data of other routes<br />
of exposure have also been considered.<br />
The selected data from published <strong>and</strong> unpublished reports were<br />
deemed relevant based on the nature of the protocols, quality of<br />
the data, <strong>and</strong> appropriate exposure. These data are presented in<br />
tabular <strong>for</strong>m.<br />
Some of the alcohols assessed in this report have been evaluated<br />
<strong>and</strong> approved <strong>for</strong> use as flavor ingredients in foodstuffs. In the United<br />
States, 2-ethyl-1-hexanol, isoamyl alcohol, <strong>and</strong> 3-methyl-1-<br />
pentanol have been approved <strong>for</strong> use as food additives or in food<br />
contact materials by the <strong>Food</strong> <strong>and</strong> Drug Administration (FDA). In<br />
addition, 2,6-dimethyl-4-heptanol, 2-methylbutanol, <strong>and</strong> 3,5,5-trimethyl-1-hexanol<br />
are listed as food additives (FDA, 2007).<br />
The International Joint FAO/WHO Expert Committee on <strong>Food</strong><br />
Additives (JECFA) has evaluated alicyclic ketones, secondary alcohols<br />
<strong>and</strong> related esters including 2,6-dimethyl-4-heptanol from<br />
the group under review <strong>and</strong> its metabolite 2,6-dimethylheptan-4-<br />
one (JECFA, 1999). JECFA also evaluated aliphatic, branched chain<br />
saturated <strong>and</strong> unsaturated alcohols, aldehydes, acids, <strong>and</strong> related<br />
esters including 2-methylbutanol (JECFA, 2004). These materials<br />
were judged by this Committee not to present a safety concern<br />
at the current estimated intake levels.<br />
The annual worldwide use of the individual alcohols reviewed<br />
herein varies greatly <strong>and</strong> ranges from 10 metric tons are 2,6-dimethyl-2-heptanol,<br />
2,6-dimethyl-4-heptanol, isotricedan-1-ol,<br />
<strong>and</strong> 3,4,5,6,6-pentamethylheptan-2-ol (IFRA, 2007; Table 1).<br />
2.3. Estimated consumer exposure<br />
Exposure data have been provided by the fragrance industry.<br />
Potential consumer exposure to fragrance materials occurs<br />
through the dermal <strong>and</strong> inhalation routes of exposure. Worst-case<br />
scenario calculations indicate that depositions on the surface of the<br />
skin following use of cosmetics represents the major route of exposure<br />
to fragrance ingredients when conservative estimates <strong>for</strong><br />
evaporation, rinsing <strong>and</strong> other <strong>for</strong>ms of product removal are employed<br />
(Cadby et al., 2002). There<strong>for</strong>e, the dermal route was the<br />
major route in assessing the safety of these compounds.<br />
The fragrance industry has developed three types of approaches<br />
to estimate potential exposure <strong>for</strong> consumers to fragrance materials.<br />
All three types of exposure are summarized in Table 1. The first is volume<br />
of use. The total worldwide volume of use <strong>for</strong> fragrance materials<br />
in the branched chain saturated alcohols ranges from 1000 metric tons per year (IFRA, 2004). The reported volume is<br />
<strong>for</strong> the fragrance ingredient as used in fragrance compounds (mixtures)<br />
in all finished consumer product categories. The volume of<br />
use is determined by IFRA approximately every 4 years through a<br />
comprehensive survey of IFRA <strong>and</strong> RIFM member companies. As such<br />
the volume of use data from this survey provides volume of use of<br />
fragrance ingredients <strong>for</strong> the majority of the fragrance industry.<br />
The second method estimates the potential percutaneous (total<br />
skin exposure) absorption from the entire body based on the use of<br />
multiple consumer personal care products containing the same fragrance<br />
ingredient. The dermal systemic exposure in cosmetic products<br />
is calculated based on the concentrations in 10 types of the<br />
most frequently used personal care <strong>and</strong> cosmetic products (antiperspirant,<br />
bath products, body lotion, eau de toilette, face cream,<br />
fragrance cream, hair spray, shampoo, shower gel, <strong>and</strong> toilet soap).<br />
The concentration of the fragrance ingredient in fine fragrances is<br />
obtained from examination of several thous<strong>and</strong> commercial <strong>for</strong>mulations.<br />
The upper 97.5 percentile concentration is calculated<br />
from the data obtained. This upper 97.5 percentile concentration<br />
is then used <strong>for</strong> all 10 consumer products. These concentrations<br />
are multiplied by the amount of product applied, the number of<br />
applications per day <strong>for</strong> each product type, <strong>and</strong> a ‘‘retention factor”<br />
(ranging from 0.001 to 1.0) to account <strong>for</strong> the length of time a<br />
product may remain on the skin <strong>and</strong>/or likelihood of the fragrance<br />
ingredient being removed by washing. The resultant calculation<br />
represents the total consumer exposure (mg/kg/day) (Cadby<br />
et al., 2002; Ford et al., 2000). In view of all of the above assumptions,<br />
the total calculated consumer exposure is conservative; it is<br />
unlikely that a consumer will consistently use a number of different<br />
consumer products which are all perfumed with the upper 97.5<br />
percentile level of the fragrance ingredient from a fine fragrance<br />
type of product (Cadby et al., 2002; Ford et al., 2000). The total consumer<br />
exposures to fragrance ingredients range from 0.0002 to<br />
0.11 mg/kg/body weight (bw)/day <strong>for</strong> the branched chain saturated<br />
alcohols fragrance ingredients in high-end users of cosmetic<br />
products containing these materials (see Table 1) (IFRA, 2004).<br />
The third method provides maximum skin levels. For consideration<br />
of potential sensitization, the exposure is calculated as the<br />
percent concentration of the fragrance ingredient applied to the<br />
skin based on the use of 20% of the fragrance mixture in the fine<br />
fragrance consumer product (IFRA, 2007). The maximum skin<br />
exposure levels of the branched chain saturated alcohol compounds<br />
that <strong>for</strong>m part of the <strong>for</strong>mulae of fine fragrances vary<br />
widely <strong>and</strong> have been report to range from 0.008% to 1.7%. The<br />
maximum skin exposure <strong>for</strong> branched chain saturated alcohols in<br />
fine fragrance products are listed in Table 1 (IFRA, 2007).<br />
In assessing safety, the calculated dermal systemic exposure in<br />
cosmetic products can then be compared to the indices of systemic<br />
toxicity such as NOAEL <strong>and</strong> LOAEL that are obtained from the repeat<br />
dose subchronic, chronic <strong>and</strong> reproductive toxicity studies<br />
to derive a margin of exposure (MOE). Systemic exposures (i.e.,<br />
the dose absorbed through the skin <strong>and</strong> available to the systemic<br />
circulation) were estimated based on dermal absorption rates.<br />
Where such data were lacking, as a conservative measure, dermal
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absorption was considered to be 100% (i.e., the maximum skin<br />
exposure value was considered as the estimate of systemic<br />
exposure).<br />
All exposure data were provided by the fragrance industry. Further<br />
explanation of how the data were obtained <strong>and</strong> of how exposures<br />
were determined has been previously reported by Cadby<br />
et al. (2002) <strong>and</strong> Ford et al. (2000).<br />
3. Metabolism<br />
3.1. Primary alcohols<br />
When 25 mmoles (2.55 g) of 2-ethyl-1-butanol were administered<br />
by gavage to rabbits, 40% of the dose was excreted in the urine<br />
as the glucuronide conjugate. The excretion of glucuronide was<br />
completed within 24 h (Kamil et al., 1953a). A rabbit was given<br />
3.1 ml (2.55 g) 2-ethyl-1-butanol <strong>and</strong> the 24-h urine was collected.<br />
2-Ethyl-1-butanol was excreted mainly as diethylacetylglucuronide<br />
<strong>and</strong> a minor amount of methyl n-propyl ketone was also<br />
found (Kamil et al., 1953b).<br />
Main metabolites of 2-ethyl-1-hexanol identified in the urine of<br />
rats after oral or dermal application were 2-ethylhexanoic acid, 5-<br />
hydroxy-2-ethylhexanoic acid, 5-keto-2-ethylhexanoic acid, 2-<br />
ethyl-1,6-hexanedioic acid <strong>and</strong> 6-hydroxy-2-ethylhexanoic acid,<br />
mainly as their glucuronides, <strong>and</strong> expired carbon dioxide. Potential<br />
metabolites not detected in each study were 2-ethylhexanoic acid,<br />
4- <strong>and</strong> 2-heptanone. One to three percent 2-ethyl-1-hexanol was<br />
excreted unchanged or as glucuronide. Metabolic saturation was<br />
seen with 500 mg/kg body weight applied (Kamil et al., 1953a,b).<br />
This metabolite pattern demonstrates the well-known metabolic<br />
pathways of primary alcohols: oxidation of the alcohol group <strong>and</strong><br />
oxidation of the side chain at various positions, glucuronidation<br />
of the oxidation products, <strong>and</strong> decarboxylation (Fig. 1; Albro,<br />
1975; Deisinger et al., 1993, 1994). Induction of metabolism was<br />
not seen with repeated oral dosing (Deisinger et al., 1994). In rabbits<br />
the glucuronide of 2-ethylhexanoic acid was identified as the<br />
main metabolite (87%) after oral application of 2-ethyl-1-hexanol<br />
(Kamil et al., 1953a,b). In vitro incubation with mammalian alcohol<br />
dehydrogenase resulted in a V max of 0.30 lmol/min/mg protein <strong>and</strong><br />
a K m value of 0.74 mM (Albro, 1975).<br />
Only about 9% of the administered dose was found in the <strong>for</strong>m<br />
of the glucuronide when isoamyl alcohol (3-methylbutanol) or 2-<br />
methylbutanol was given to rabbits. Other metabolites were not<br />
identified (Kamil et al., 1953a). Age-dependent glucuronidation<br />
activity was demonstrated in vitro in the olfactory mucosa of rats<br />
with isoamyl alcohol (Leclerc et al., 2002). The glucuronidation of<br />
isoamyl alcohol <strong>and</strong> other short-chained aliphatic alcohols was<br />
investigated in vitro with human liver microsomes. The V max value<br />
was 3.3 nmol/min/mg protein <strong>and</strong> the K m was determined as<br />
13.3 mM. The glucuronidation increased with chain length (C2–<br />
C5) of the alcohols studied (Jurowich et al., 2004).<br />
Oxidation to the aldehyde <strong>and</strong> glucuronidation was demonstrated<br />
<strong>for</strong> isoamyl alcohol <strong>and</strong> 2-methylbutanol with microsomes<br />
from rats pretreated with ethanol (Iwersen <strong>and</strong> Schmoldt, 1995).<br />
The rate of oxidative metabolism of isoamyl alcohol was about<br />
0.1 mmol/g liver in rat liver homogenate <strong>and</strong> about 0.05 mM/g perfused<br />
rat liver (Hedlund <strong>and</strong> Kiessling, 1969). The rate of oxidation<br />
of isoamyl alcohol by human skin alcohol dehydrogenase was<br />
183.3 nM/mg protein per minute (Wilkin <strong>and</strong> Stewart, 1987). The<br />
K m -values of isoamyl alcohol with alcohol dehydrogenase from human<br />
<strong>and</strong> horse liver were 0.07 <strong>and</strong> 0.08 mM, respectively (Pietruszko<br />
et al., 1973). After intraperitoneal application of 1000 mg<br />
isoamyl alcohol or 2-methylbutanol/kg body weight, the corresponding<br />
aldehydes could not be detected in expired air of rats<br />
(Haggard et al., 1945).<br />
3.2. Secondary alcohols<br />
After application of 4-methyl-2-pentanol (methyl isobutyl carbinol<br />
in Fig. 2) to rabbits 33.7% of the dose was excreted as the glucuronide<br />
(Kamil et al., 1953a). In mammals, the metabolism of<br />
secondary alcohols proceeds primarily through their respective ketones.<br />
4-Methyl-2-pentanol is metabolized to 4-methyl-2-pentanone<br />
(methyl isobutyl ketone in Fig. 2) <strong>and</strong> further to 4-hydroxy-4-<br />
methyl-2-pentanone in rats (Fig. 2; OECD/SIDS, 2007).<br />
Plasma levels of 4-methyl-2-pentanol, 4-methyl-2-pentanone,<br />
<strong>and</strong> 4-hydroxy-4-methyl-2-pentanone were determined up to 12 h<br />
after oral gavage administration of 5 mmol/kg of 4-methyl-2-pentanol<br />
or 4-methyl-2-pentanone to male rats. After dosing rats by gavage<br />
with 4-methyl-2-pentanol or 4-methyl-2-pentanone, the<br />
major material in the plasma <strong>for</strong> both compounds was 4-hydroxy-4-methyl-2-pentanone.<br />
No other metabolites were detected in<br />
the plasma. The extent of metabolism of 4-methyl-2-pentanol to<br />
4-methyl-2-pentanone was at least 73%. The reduction of 4-<br />
methyl-2-pentanone to 4-methyl-2-pentanol was insignificant<br />
(Gingell et al., 2003; Hirota, 1991a).<br />
Similar results were obtained with intraperitoneal application<br />
of 4-methyl-2-pentanol <strong>and</strong> 4-methyl-2-pentanone in mice. After<br />
intraperitoneal administration of 4-hydroxy-4-methyl-2-pentanone,<br />
neither 4-methyl-2-pentanol nor 4-methyl-2-pentanone could be<br />
detected in the blood <strong>and</strong> in the brain (Fig. 2; Granvil et al.,<br />
1994). This result shows that in rats <strong>and</strong> mice 4-methyl-2-pentanol<br />
is predominantly oxidized to 4-methyl-2-pentanone <strong>and</strong> both compounds<br />
share the same principal metabolite, namely 4-hydroxy-4-<br />
methyl-2-pentanone.<br />
In workers exposed to mixed solvents including 4-methyl-2-<br />
pentanone <strong>and</strong> 4-methyl-2-pentanol was identified by GC–MS in<br />
the urine. In a subject exposed to 42.3 ml pure 4-methyl-2-pentanone/m<br />
3 <strong>for</strong> 6 h, 0.42 mg 4-methyl-2-pentanol/g creatinine was excreted<br />
(Hirota, 1991b). This result confirms, that in humans as well,<br />
the reduction of 4-methyl-2-pentanone is insignificant (6 h 42 ml/<br />
m 3 4-methyl-2-pentanone corresponds to about 320 mg at 66%<br />
retention in the lung <strong>and</strong> a minute volume of 8 l).<br />
3.3. Tertiary alcohols<br />
Data on the tertiary alcohols under review are not available. A<br />
tertiary alcohol group cannot be oxidized. Tertiary alcohols are expected<br />
to be excreted either via conjugation or unchanged or undergo<br />
hydroxylation of the carbon chain, which in turn may give<br />
rise to a metabolite which can be easily excreted.<br />
4. Pharmacokinetics<br />
4.1. Dermal route of exposure<br />
In vitro absorption rates <strong>for</strong> 2-ethyl-1-hexanol were 0.22 ± 0.09<br />
<strong>and</strong> 0.038 ± 0.014 mg/cm 2 /h <strong>for</strong> rat <strong>and</strong> human skin, respectively,<br />
giving a rat/human ratio of 5.78. The permeability constants were<br />
2.59 ± 1.10 10 4 cm/h <strong>for</strong> rats <strong>and</strong> 4.54 ± 1.66 10 5 cm/h <strong>for</strong><br />
humans (Barber et al., 1992).<br />
The dermal absorption in the rat was determined to be 5.2% of a<br />
dose of 1000 mg 2-ethyl-1-hexanol/kg body weight applied <strong>for</strong> 6 h;<br />
the absorption rate was calculated to be 0.57 mg/cm 2 /h. The terminal<br />
half-life was calculated to be 77 h (Deisinger et al., 1994).<br />
4.2. Oral route of exposure<br />
In rats, oral administration of 2000 mg isoamyl alcohol/kg body<br />
weight led to a peak concentration of 170 mg/l blood 1 h later. The
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46 S9<br />
authors calculated an oxidation rate of 5 mg/kg body weight/h<br />
(Gaillard <strong>and</strong> Derache, 1965).<br />
After oral administration to rats, 69–75% of a dose of 500 mg<br />
14 C-labeled 2-ethyl-1-hexanol/kg body weight was excreted in<br />
the urine within 96 h. About 13–15% of the dose was excreted in<br />
the feces <strong>and</strong> about the same amount was exhaled. More than<br />
50% of the dose was excreted within 24 h (Deisinger et al., 1993,<br />
1994).<br />
Plasma levels of 4-methyl-2-pentanol, 4-methyl-2-pentanone,<br />
<strong>and</strong> 4-hydroxy-4-methyl-2-pentanone were determined up to 12 h<br />
after oral gavage administration of 5 mmol/kg of 4-methyl-2-pentanol<br />
or 4-methyl-2-pentanone to male rats. The major material in<br />
the plasma <strong>for</strong> both compounds was 4-hydroxy-4-methyl-2-pentanone,<br />
with similar areas under the curve (AUCs) <strong>and</strong> C max at 9 h<br />
after dosing <strong>for</strong> both 4-methyl-2-pentanol <strong>and</strong> 4-methyl-2-pentanone.<br />
4-Methyl-2-pentanone plasma levels <strong>and</strong> AUC were also similar<br />
after 4-methyl-2-pentanone or 4-methyl-2-pentanol<br />
administration. 4-Methyl-2-pentanol AUC was only about 6% of<br />
the total material in the blood following 4-methyl-2-pentanol<br />
administration, <strong>and</strong> insignificant after 4-methyl-2-pentanone<br />
administration (Gingell et al., 2003).<br />
4.3. Respiratory route of exposure<br />
Respiratory uptake of isoamyl alcohol was investigated in four<br />
healthy volunteers. Air concentration was 25–200 ppm <strong>and</strong> exposure<br />
duration was 10 min. The mean uptake <strong>for</strong> the last 5 min of<br />
exposure was 63% <strong>and</strong> the mean respiratory rate was 15.3 min 1<br />
(Kumagai et al., 1998).<br />
4.4. Parenteral route of exposure<br />
After intravenous administration to rats, about 74% of a dose of<br />
1mg 14 C-labeled 2-ethyl-1-hexanol/kg body weight was excreted<br />
in the urine within 96 h. About 4% of the dose was excreted in<br />
the feces <strong>and</strong> 23% was exhaled. More than 50% of the dose was excreted<br />
within 8 h. The terminal half-life was estimated to be 60 h<br />
(Deisinger et al., 1993, 1994).<br />
The concentration of isoamyl alcohol in blood declined within<br />
5 h to non-detectable levels after intraperitoneal administration<br />
of 1000 mg isoamyl alcohol/kg body weight. Similar values were<br />
found <strong>for</strong> 2-methylbutanol administered at the same dose. An<br />
elimination half-life was not calculated. For isoamyl alcohol <strong>and</strong><br />
2-methylbutanol, 1.2% <strong>and</strong> 7.6%, respectively, were excreted via urine<br />
<strong>and</strong> expired air. Compared to other amyl alcohols tested by the<br />
authors, primary alcohols were eliminated from the blood more<br />
quickly than secondary <strong>and</strong> tertiary alcohols (Haggard et al., 1945).<br />
5. Toxicological studies<br />
5.1. Acute toxicity<br />
Fig. 1. Metabolism of 2-ethyl-1-hexanol in the rat (from Albro, 1975). Metabolites<br />
marked with asterisks were detected.<br />
Acute dermal toxicity studies have been per<strong>for</strong>med with six primary,<br />
three secondary, <strong>and</strong> three tertiary alcohols, all but one in<br />
rabbits. The dermal LD 50 values in rabbits <strong>and</strong> the one in rats are<br />
in the range of 1000–>5000 mg/kg body weight. In summary all<br />
the compounds are of low acute toxicity by the dermal route (Table<br />
2-1).<br />
Eight primary alcohols, four secondary, <strong>and</strong> three tertiary alcohols<br />
have been tested <strong>for</strong> oral acute toxicity. The oral LD 50 values in<br />
rats, mice, <strong>and</strong> rabbits are in the range of 1000–>5000 mg/kg body<br />
weight, <strong>and</strong> there<strong>for</strong>e, all the compounds exhibit a low toxicity<br />
when administered via the oral route (Table 2-2).<br />
Lethargy was the most often reported clinical sign after oral or<br />
dermal administration, diarrhea <strong>and</strong> ataxia after oral administration,<br />
<strong>and</strong> irritation of the skin after dermal administration. Signs<br />
of gastrointestinal irritation were noted at necropsy in acute oral<br />
toxicity tests.<br />
In inhalation tests with five primary <strong>and</strong> two secondary alcohols,<br />
no mortality was observed in rats exposed to air saturated<br />
with alcohol vapor at room temperature <strong>for</strong> as long as 8 h. LC 50 values<br />
were not determined. Local ocular <strong>and</strong> upper respiratory tract<br />
irritation was seen with 2-ethyl-1-hexanol. However, 4-methyl-2-<br />
pentanol exposure at 2000 ml/m 3 <strong>for</strong> 8 h resulted in death at<br />
14 days of 5/6 rats, <strong>and</strong> exposure to saturated air at 20 °C resulted<br />
in anesthesia at 4 h <strong>and</strong> death of 6/10 mice after 10 h.<br />
Acute toxicity data obtained from studies with other than oral<br />
or dermal exposure are summarized in Table 2-3.<br />
5.2. Repeated dose toxicity<br />
The evaluation of repeated dose systemic toxicity is based on<br />
several oral studies with mainly primary alcohols <strong>and</strong> only one secondary<br />
alcohol. The metabolic pathways with all the materials in<br />
this group yield innocuous metabolites. The database could be<br />
strengthened by an evaluation of the systemic toxicity of a secondary<br />
<strong>and</strong> tertiary alcohol. Other studies can be found in Section 5.10.<br />
5.2.1. Dermal studies<br />
Dermal studies with branched chain saturated alcohols are<br />
summarized in Table 3-1.<br />
5.2.1.1. Primary alcohols. Over a period of 12 days, rats were treated<br />
with undiluted 2-ethyl-1-hexanol (2 ml/kg body weight/day, about<br />
1600 mg/kg body weight/day) on their shaved backs. At necropsy,<br />
the treated animals had decreased absolute <strong>and</strong> relative thymus<br />
weights, liver granulomas, bronchiectasis in the lung, renal tubular<br />
epithelial necrosis in the kidneys, edema in heart <strong>and</strong> testes, decreased<br />
spermatogenesis, <strong>and</strong> an increase in lipids in adrenals were<br />
found on day 17. These effects were reversed on day 30 (Schmidt<br />
et al., 1973).<br />
2-Ethyl-1-hexanol was applied topically under occlusion to<br />
Fischer 344 rats <strong>for</strong> 5 days, followed by 2 days untreated, 4 days
S10<br />
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46<br />
Fig. 2. Metabolism of 4-methyl-2-pentanol in the rat <strong>and</strong> mouse (OECD/SIDS,<br />
2007).<br />
treated with 0, 500, or 1000 mg/kg body weight/day. Treatmentrelated<br />
clinical signs of toxicity were restricted to the skin at the<br />
treatment site <strong>and</strong> included exfoliation (minimal severity) at both<br />
doses <strong>and</strong> transient erythema at the high dose. Serum triglycerides<br />
were increased in females at both doses. In high-dose females,<br />
peripheral blood lymphocytes <strong>and</strong> absolute spleen weight were reduced<br />
(RIFM, 1988; Weaver et al., 1989).<br />
Albino rabbits (2/sex/dose) were treated by dermal occluded<br />
application with 0, 400, or 2000 mg/kg body weight/day of isooctanol<br />
(alcohols C7–9, branched CAS No. 68526-83-0) <strong>for</strong> 12 days<br />
with 10 applications, lasting 18–24 h each. Control animals received<br />
isopropyl alcohol. No relevant changes in appearance,<br />
behavior, body weight, hematology, <strong>and</strong> urinalysis were noted in<br />
treated animals. Necropsy <strong>and</strong> microscopic evaluation demonstrated<br />
no treatment-related findings. Moderate to severe skin irritation<br />
at the application site was noted in treated animals with<br />
necrosis in high-dose animals. The systemic NOAEL was<br />
2000 mg/kg body weight/day (Esso, 1961a, as cited in ExxonMobil<br />
<strong>Chemical</strong> Company, 2001a).<br />
5.2.1.2. Secondary alcohols. New Zeal<strong>and</strong> White rabbits (5/sex/dose)<br />
were treated topically by occlusive application of 0 or 1000 mg/kg<br />
body weight/day of 3,4,5,6,6-pentamethylheptan-2-ol <strong>for</strong> 28 consecutive<br />
days at the same site according to OECD test guideline<br />
(TG) 410. Severe skin irritation was induced in rabbits receiving<br />
1000 mg/kg body weight/day of 3,4,5,6,6-pentamethylheptan-2-<br />
ol. However, no alterations in general health, hematology, biochemistry,<br />
major organ weights, or histopathology were observed.<br />
For systemic effects the NOAEL was 1000 mg/kg body weight/day<br />
(RIFM, 1985c).<br />
5.2.1.3. Tertiary alcohols. No studies are available <strong>for</strong> the members<br />
of this subgroup.<br />
5.2.2. Oral studies<br />
Oral toxicity studies with branched chain saturated alcohols are<br />
summarized in Table 3-2.<br />
5.2.2.1. Primary alcohols. Three repeated dose oral toxicity studies<br />
were done with isoamyl alcohol. In a 90-day study according to<br />
OECD TG 408, isoamyl alcohol was administered in the drinking<br />
water in concentrations of 0, 1000 ppm (about 80 mg/kg/d),<br />
4000 ppm (about 340 mg/kg/d), <strong>and</strong> 16,000 ppm (about 1250 mg/<br />
kg/d). The NOAEL of isoamyl alcohol was concluded to be<br />
4000 ppm in males (340 mg/kg/d) by the authors because the increase<br />
of erythrocyte counts at this dose fell within the historical<br />
control range. The NOAEL <strong>for</strong> females was 16,000 ppm (1250 mg/<br />
kg/d) because the increase in prothrombin time was only seen in females<br />
<strong>and</strong> fell within the historical control range (Schilling et al.,<br />
1997). Isoamyl alcohol was tested in a 17-week toxicity study with<br />
Ash/CSE rats. The test substance was administered by gavage to 15<br />
male <strong>and</strong> 15 female rats per group at dose levels of 0 (vehicle), 150,<br />
500, or 1000 mg/kg body weight/day in corn oil. Observations<br />
included mortality, behavior, body weight, food <strong>and</strong> water consumption,<br />
hematology, serum analysis, urinalysis, renal concentration,<br />
organ weights, <strong>and</strong> gross pathology; microscopic pathology<br />
of 25 organs or tissues on control <strong>and</strong> top dose only. The only observed<br />
effect was a statistically significant reduced body weight<br />
in males at the highest dose level; food intake was reduced, but<br />
not statistically. The NOAEL was 500 mg/kg body weight/day <strong>for</strong><br />
males <strong>and</strong> 1000 mg/kg body weight/day <strong>for</strong> females (Carpanini<br />
<strong>and</strong> Gaunt, 1973). Finally, isoamyl alcohol was administered to<br />
male <strong>and</strong> female Wistar rats as a 2% solution in drinking water<br />
(about 2000 mg/kg body weight/day) <strong>for</strong> 56 weeks. No treatmentrelated<br />
effects on body weight, liver weight, ADH, GOT, GPT<br />
activity, <strong>and</strong> protein content of the liver were found. Histological<br />
examinations of the livers, hearts, spleens, kidneys, <strong>and</strong> lungs did<br />
not show any significant abnormalities (Johannsen <strong>and</strong> Purchase,<br />
1969).<br />
Several studies in mice (gavage, RIFM, 1992a,b) <strong>and</strong> rats (gavage,<br />
RIFM, 1988; Weaver et al., 1989), given 2-ethyl-1-hexanol<br />
by gavage or drinking water (RIFM, 1988; Weaver et al., 1989),<br />
or feed (RIFM, 1992c) <strong>for</strong> periods of 9–11 days yielded NOAELs in<br />
the range of 100–150 mg/kg body weight/day. Doses of 330 mg/<br />
kg body weight/day <strong>and</strong> higher resulted in CNS depression, lacrimation,<br />
decreased food consumption, <strong>and</strong> body weights. 2-Ethyl-<br />
1-hexanol was administered by gavage to F344 rats <strong>and</strong> B6C3F1<br />
mice of both sexes as an aqueous solution (0, 25, 125, 250, or<br />
500 mg/kg body weight/day) <strong>for</strong> 13 weeks. Histopathology was<br />
undertaken on tissues recommended in US EPA guidelines. The<br />
NOAEL was 125 mg/kg body weight/day <strong>for</strong> rats <strong>and</strong> mice (Astill<br />
et al., 1996a). In a carcinogenicity study (see Section 5.4) 2-ethyl-<br />
1-hexanol was given to male <strong>and</strong> female rats <strong>and</strong> mice by gavage<br />
5 times a week in 0.005% aqueous Cremophor EL (rats: 0 (water),<br />
0 (vehicle), 50, 150, or 500 mg/kg body weight/day, 2 months;<br />
mice: 0 (water), 0 (vehicle), 50, 200, or 750 mg/kg body weight/<br />
day, 18 months). The NOAEL <strong>for</strong> systemic toxicity <strong>for</strong> mice was<br />
200 mg/kg body weight/day. In rats, the NOAEL <strong>for</strong> systemic toxicity<br />
was 50 mg/kg body weight/day (Astill et al., 1996b).<br />
An oral study according to OECD TG 422 (combined repeated<br />
dose <strong>and</strong> reproductive/developmental toxicity screening test) was<br />
conducted with 3,5,5-trimethyl-1-hexanol. Twelve SD (Crj:CD) rats<br />
per sex <strong>and</strong> dose group were gavaged with 0 (vehicle: olive oil), 12,<br />
60, or 300 mg/kg body weight/day. Exposure duration in males was<br />
46 days <strong>and</strong> in females from day 14 be<strong>for</strong>e mating to day 3 of lactation.<br />
Males of all dose groups showed alpha-2u-globulin nephropathy.<br />
In males <strong>and</strong> females dosed with 60 or 300 mg/kg body weight/<br />
day, systemic effects were seen, including reduced body weight <strong>and</strong><br />
food consumption. On the basis of these findings, the NOAEL <strong>for</strong> repeated<br />
dose toxicity was 12 mg/kg body weight/day <strong>for</strong> male <strong>and</strong><br />
female rats (MHW, Japan, 1997b as cited in OECD/SIDS, 2003).<br />
In a 90-day study according to OECD TG 408 isotridecanol(iso<br />
alcohols C11–14, C13 rich, CAS No. 68526-86-3) was administered<br />
orogastrically (gavage) to Sprague–Dawley rats in doses of 0, 100,<br />
500, or 1000 mg/kg body weight/day. No effects were observed<br />
only at the lowest dose. The NOAEL <strong>for</strong> systemic toxicity was
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46 S11<br />
100 mg/kg body weight/day (Exxon Biomedical Sciences Inc., 1986<br />
as cited in ExxonMobil <strong>Chemical</strong> Company, 2001b).<br />
5.2.2.2. Secondary alcohols. A combined repeated dose <strong>and</strong> reproductive/developmental<br />
screening study according to OECD TG<br />
422 is available with 4-hydroxy-4-methyl-2-pentanone,a metabolite<br />
of 4-methyl-2-pentanol. Ten rats per sex <strong>and</strong> group were dosed by<br />
gavage with 0, 30, 100, 300, or 1000 mg 4-hydroxy-4-methyl-2-<br />
pentanone/kg body weight/day in distilled water. Males were<br />
dosed <strong>for</strong> 44 days <strong>and</strong> females from day 14 be<strong>for</strong>e mating to day<br />
3 of lactation (approximately <strong>for</strong> 45 days). No effects were noted<br />
at 30 mg/kg body weight/day. Males treated with at least<br />
100 mg/kg body weight/day showed male rat-specific alpha-2unephropathy.<br />
At both 300 <strong>and</strong> 1000 mg/kg body weight/day, deleterious<br />
effects were observed, including dilatation of the distal tubules<br />
<strong>and</strong> fatty degeneration of the proximal tubular epithelium in<br />
kidneys in females (300 mg/kg body weight/day) (MHW, Japan<br />
1997, as cited in OECD/SIDS, 2007). The NOAEL was 100 mg/kg<br />
body weight/day due to kidney effects in females at 300 mg/kg<br />
body weight/day. The kidney effects in males at 100 mg/kg body<br />
weight are not relevant <strong>for</strong> humans.<br />
2,6-Dimethyl-4-heptanol was tested in a 13-week toxicity<br />
study in rats. Male <strong>and</strong> female animals were fed a diet containing<br />
the test substance mixed with five parts of microcrystalline cellulose<br />
(16/sex/group). The daily intake of the test material was<br />
11 mg/kg body weight/day <strong>for</strong> males <strong>and</strong> females. Female rats<br />
showed a statistically significantly lower ( 12.1%) body weight<br />
gain <strong>and</strong> reduced food efficiency. The authors concluded that the<br />
reduction in body weight gain was most probably of no toxicological<br />
significance since the reduction was not associated with other<br />
toxicologically significant differences between test <strong>and</strong> control animals<br />
(Posternak <strong>and</strong> Vodoz, 1975). Because only the range of body<br />
weights at the start of the study is given, it is unclear whether the<br />
animals were adequately r<strong>and</strong>omized to control <strong>and</strong> test groups<br />
based on body weight. Only one dose was tested, there<strong>for</strong>e, it cannot<br />
be judged whether the body weight gain reduction is a substance-induced<br />
effect. A NOAEL <strong>for</strong> this study <strong>for</strong> the females<br />
cannot be deduced because of the reduction in body weight gain.<br />
For males the NOAEL is 11 mg/kg body weight/day.<br />
5.2.2.3. Tertiary alcohols. No data available.<br />
5.2.3. Inhalation studies<br />
Inhalation studies with branched chain saturated alcohols are<br />
summarized in Table 3-3.<br />
5.2.3.1. Primary alcohols. Male <strong>and</strong> female Wistar rats (10/group/<br />
sex) were exposed 6 h daily on 5 days per week <strong>for</strong> 90 days to 2-<br />
ethyl-1-hexanol (purity 99.9%) in concentrations of 15, 40, or<br />
120 ml/m 3 (highest vapor concentration at room temperature).<br />
Neither local nor systemic effects were found. The NOAEL is<br />
120 ml/m 3 (Klimisch et al., 1998).<br />
Three female Alderly-Park rats exposed in whole body exposure<br />
chambers <strong>for</strong> 13 six-hour exposure periods to saturated vapor of a<br />
mixture of branched chain alcohols designated isooctan-1-ol<br />
(180 ml/m 3 ) showed no adverse effects (Gage, 1970).<br />
5.2.3.2. Secondary alcohols. A 9-day study in rats (10/sex/group, 5 h/<br />
day, 5 days/week) exposed to 98, 300, or 905 ml/m 3 2,6-dimethylheptan-4-one<br />
demonstrated increased liver weights from 300 ml/<br />
m 3 as well as alpha-2u-globulin accumulation in the kidneys of<br />
males (Dodd et al., 1987). Considering the increased liver weights<br />
as a sign of enzyme induction, the NOAEL is 98 ml/m 3 .<br />
In a 6-week inhalation study with 2,6-dimethylheptan-4-one,<br />
groups of 30 rats (15/sex) were exposed to 0, 125, 252, 534, 925,<br />
or 1654 ml/m 3 of 2,6-dimethylheptan-4-one, 7 h/day, 5 days/week<br />
<strong>for</strong> 6 weeks. Liver <strong>and</strong> kidney weights were increased at 252 ml/<br />
m 3 in females. At 925 ml/m 3 ‘‘increased incidence of minor pathological<br />
change” was reported. At 1654 ml/m 3 all females died during<br />
the first exposure whereas 12/15 males survived all exposures<br />
at this concentration. Among surviving males at 1654 ml/m 3 there<br />
were no major histopathological changes; ‘‘cloudy swelling” in the<br />
liver <strong>and</strong> the convoluted tubules in the kidneys <strong>and</strong> lung congestion<br />
were observed in some surviving males (Carpenter et al.,<br />
Table 2-1<br />
Acute dermal toxicity studies.<br />
Material Species No./dose LD 50 mg/kg body weight b References<br />
Subgroup: primary<br />
2-Ethyl-1-butanol Rabbit 4 1260 (95% C.I. 850–1870) Smyth et al. (1954)<br />
Rabbit n.f.i. 2000 Draize et al. (1944)<br />
2-Ethyl-1-hexanol Rabbit 10 >5000 RIFM (1977a)<br />
Rabbit 4 (males) 2380 (95% C.I. 1700–3340) Smyth et al. (1969)<br />
Rabbit 4 >2600 Scala <strong>and</strong> Burtis (1973)<br />
Isoamyl alcohol Rabbit 10 >5000 RIFM (1976a)<br />
Rabbit 6 4000 RIFM (1979c)<br />
Rabbit 4 (males) 3970 (95% C.I. 2930–5370) Smyth et al. (1969)<br />
Isotridecan-1-ol (isomeric mixture) Rabbit 4 (males) 7070 Smyth et al. (1962)<br />
Rabbit 4 >2600 Scala <strong>and</strong> Burtis (1973)<br />
2-Methylbutanol Rabbit 4 (males) 3540 Smyth et al. (1962)<br />
Rabbit n.f.i. 3540 RIFM (1979b)<br />
3,5,5-Trimethyl-1-hexanol Rabbit 10 >5000 RIFM (1977a)<br />
Subgroup: secondary<br />
2,6-Dimethyl-4-heptanol Rabbit 20 (males) 4591 (95% C.I. 2036–10,383) Smyth et al. (1949)<br />
4-Methyl-2-pentanol Rabbit 5 3560 (2720–4760) Smyth et al. (1951)<br />
3,4,5,6,6-Pentamethylheptan-2-ol Rat 10 (5/sex) >2000 RIFM (1985a)<br />
Subgroup: tertiary<br />
2,6-Dimethyl-2-heptanol Rabbit 10 >5000 RIFM (1976a)<br />
3,6-Dimethyl-3-octanol a Rabbit 8 >5000 RIFM (1973a)<br />
3-Methyloctan-3-ol a Rabbit 10 >5000 RIFM (1978c)<br />
n.f.i.: no further in<strong>for</strong>mation.<br />
a No relevant use was reported.<br />
b Units have been converted to make easier comparisons; original units are in the <strong>Fragrance</strong> Material Reviews.
S12<br />
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46<br />
1953). Considering the increased liver weights as a sign of enzyme<br />
induction at 250 ml/m 3 , the NOAEL is 125 ml/m 3 .<br />
Wistar rats were whole body exposed to 0, 211, 825, or 3700 mg<br />
4-methyl-2 pentanol/m 3 (0, 50.5, 198, or 886 ml/m 3 ) (purity > 98%)<br />
6 h per day <strong>and</strong> 5 days per week <strong>for</strong> 6 weeks, 12 animals per sex<br />
<strong>and</strong> group. In females of all concentration groups <strong>and</strong> in males<br />
treated with 198 ml/m 3 or more, increased levels of ketone bodies<br />
in urine were noted. At the highest concentration, absolute kidney<br />
weights increased in males <strong>and</strong> proteinuria was detected; an increase<br />
in serum alkaline phosphatase in females was observed.<br />
There were no exposure-related histopathological effects in the<br />
kidneys or other organs. The increases in ketone bodies, kidney<br />
weight, <strong>and</strong> alkaline phosphatase were not considered adverse toxicological<br />
effects. There<strong>for</strong>e, the NOAEL was assessed to be<br />
3700 mg/m 3 (886 ml/m 3 ) by OECD/SIDs (Blair, 1982 as cited in<br />
OECD/SIDS, 2007). However, since the increase in alkaline phosphatase<br />
in high-concentration females was significantly elevated<br />
the NOAEL is judged to be 198 ml/m 3 .<br />
A 14-week inhalation study (equivalent to OECD TG 413) was<br />
per<strong>for</strong>med with the metabolite of 4-methyl-2-pentanol <strong>and</strong><br />
Table 2-2<br />
Acute oral toxicity studies.<br />
Material Species No./dose LD 50 mg/kg body weight b References<br />
Subgroup: primary<br />
2-Ethyl-1-butanol Rat 5 1850 (95% C.I. 1520–2240) Smyth et al. (1954)<br />
Rat n.f.i. 1850 Nishimura et al. (1994) <strong>and</strong> Bar <strong>and</strong><br />
Griepentrog (1967)<br />
Rabbit n.f.i. 1200 Draize et al. (1944)<br />
2-Ethyl-1-hexanol Rat n.f.i. 2049 Nishimura et al. (1994)<br />
Rat 5 2460 (1820–3330) Smyth et al. (1969)<br />
Rat 5-15 3200 Hodge (1943)<br />
Rat males, n.f.i. 7100 (95% C.I. 5500–9199) Shaffer et al. (1945)<br />
Rat 36 total 3290 (95% C.I. 2870–3790) Schmidt et al. (1973)<br />
Rat n.f.i. 3290 (95% C.I. 2870–3790) Bar <strong>and</strong> Griepentrog (1967) <strong>and</strong> Dave <strong>and</strong><br />
Lidman (1978)<br />
Rat 5 3730 Scala <strong>and</strong> Burtis (1973)<br />
Isoamyl alcohol Mouse 4 (2/sex) >2000 (pre-screen <strong>for</strong> micronucleus RIFM (2008)<br />
test)<br />
Rat 5 males 7100 (4820–10400) Smyth et al. (1969)<br />
Rat 4/sex males: 1300 (95% C.I. 670–2410) Purchase (1969)<br />
females: 4000 (95% C.I. 2450–6170)<br />
Rat n.f.i. 4360 Golovinskaia (1976)<br />
Rat n.f.i. 1300 Nishimura et al. (1994)<br />
Rat n.f.i. >5000 RIFM (1979c)<br />
Rabbit 10–35 3438 Munch (1972)<br />
Isodecyl alcohol Rat n.f.i. 6500 Nishimura et al. (1994)<br />
Isotridecan-1-ol (isomeric mixture) Rat 5 males 17,200 Smyth et al. (1962); Nishimura et al. (1994)<br />
Rat 5 4750 (ca) Scala <strong>and</strong> Burtis (1973)<br />
Rat 3 2000 RIFM (2002a)<br />
Rat n.f.i. >2000 (50% branched, 50% linear ECB (1995) as cited in Greim (2000)<br />
<strong>for</strong>m)<br />
Mouse n.f.i. 6500 RIFM (1963a)<br />
Mouse n.f.i. 7257 (mixture of branched saturated<br />
primary isomers, purity > 99.7%)<br />
ECB (1995) <strong>and</strong> Hoechst (1961a) as cited in<br />
Greim (2000)<br />
2-Methylbutanol Rat 5 males 4920 (95% C.I. 3750–6460) Smyth et al. (1962)<br />
Rat n.f.i. 1000 Nishimura et al. (1994)<br />
Rat n.f.i. 4010 Rowe <strong>and</strong> McCollister (1982)<br />
Rat 10 (5/sex) 4170 RIFM (1979b)<br />
Rat 10 (5/sex) >5000 RIFM (1985e)<br />
3-Methyl-1-pentanol Mouse 10 >2000 RIFM (1982a)<br />
3,5,5-Trimethyl-1-hexanol Rat 10 2300 (95% C.I. 1700–3100) RIFM (1977a)<br />
Rat n.f.i. >2000 MHW, Japan (1997a) as cited in OECD/SIDS<br />
(2003)<br />
Subgroup: secondary<br />
2,6-Dimethyl-4-heptanol Rat 20 males (5/dose) 3560 (95% C.I. 1430–8860) Smyth et al. (1949)<br />
Rat 32 total (16/sex) 4350 Posternak <strong>and</strong> Vodoz (1975)<br />
Rat 5–11 6500 McOmie <strong>and</strong> Anderson (1949)<br />
Mouse 6–14 5000 (95% C.I. 2500–7500) McOmie <strong>and</strong> Anderson (1949)<br />
3,7-Dimethyl-7-methoxyoctan-2-ol Rat 5/sex 5000 RIFM (1976a)<br />
4-Methyl-2-pentanol Rat n.f.i. 2950 Bar <strong>and</strong> Griepentrog (1967)<br />
Rat n.f.i. 2590 Nishimura et al. (1994)<br />
Rat 5 2590 (2260–2970) Smyth et al. (1951)<br />
3,4,5,6,6-Pentamethylheptan-2-ol Rat 10 (5/sex) 5845 (95% C.I. 5360–6375) RIFM (1984a)<br />
Subgroup: tertiary<br />
2,6-Dimethyl-2-heptanol Rat 10 >5000 RIFM (1976a)<br />
Rat n.f.i. 6800 RIFM (1979a)<br />
3,6-Dimethyl-3-octanol a Rat 10 >5000 RIFM (1973a)<br />
3-Methyloctan-3-ol a Rat 10 3400 (95% C.I: 2500–4700) RIFM (1978c)<br />
n.f.i.: no further in<strong>for</strong>mation.<br />
a No relevant use was reported.<br />
b Units have been converted to make easier comparisons; original units are in the <strong>Fragrance</strong> Material Reviews.
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46 S13<br />
4-methyl-2-pentanone. Male <strong>and</strong> female rats <strong>and</strong> mice (14 per species/sex/group)<br />
were exposed to 0, 50, 250, or 1000 ml 4-methyl-2-<br />
pentanone/m 3 (0, 204, 1020, or 4090 mg/m 3 ) 6 h per day <strong>and</strong> 5 days<br />
per week. Slight, but statistically significant, increases in absolute<br />
<strong>and</strong> relative liver weight were observed in males of both species at<br />
the highest concentration. As there were no histopathological<br />
changes in the livers observed, the changes were considered to be<br />
of no toxicological relevance. Male rats demonstrated alpha-2uglobulin<br />
ephropathy. The NOAEL was considered to be 1000 ml/m 3<br />
(4090 mg/m 3 ) <strong>for</strong> both species (Phillips et al., 1987).<br />
In a two-generation study with rats with 4-methyl-2-pentanone clinical<br />
signs in the <strong>for</strong>m of CNS depression were noted during exposures of<br />
adults to 1000 <strong>and</strong> 2000 ml/m 3 . The systemic NOAEL was 500 ml/m 3 in<br />
this study. Signs of irritation were not reported (Nemec et al., 2004).<br />
5.2.3.3. Tertiary alcohols. No data available.<br />
5.3. Mutagenicity <strong>and</strong> genotoxicity<br />
5.3.1. In vitro mutagenicity studies<br />
The available studies are summarized in Table 4-1.<br />
5.3.1.1. Indicator studies. In a study of the cytotoxic <strong>and</strong> genotoxic<br />
effects of a number of alcohols <strong>and</strong> ketones, 2-methylbutanol<br />
Table 2-3<br />
Acute inhalation <strong>and</strong> miscellaneous toxicity studies in animals.<br />
Material Dose route Species No./dose LD 50 <strong>and</strong>/or clinical signs References<br />
Subgroup: primary<br />
2-Ethyl-1-butanol<br />
Inhalation, exposure to<br />
Rat 6 Maximum time <strong>for</strong> no death: 8 h Smyth et al. (1954)<br />
concentrated vapors<br />
2-Ethyl-1-hexanol<br />
Inhalation, exposure to<br />
Rat 6 Maximum time <strong>for</strong> no death: 8 h Smyth et al. (1969)<br />
concentrated vapors<br />
Whole body exposure <strong>for</strong> 6 h to Rat, mouse, 10/species<br />
No mortality, irritation of eyes, Scala <strong>and</strong> Burtis (1973)<br />
air bubbled through 2-ethyl-1-<br />
hexanol to yield a nominal<br />
chamber concentration of<br />
227 ml/m 3 guinea pig<br />
nose, throat, <strong>and</strong> respiratory<br />
passages, blinking, lacrimation,<br />
preening, nasal discharge,<br />
salivation, gasping, <strong>and</strong> chewing<br />
movements<br />
Intraperitoneal Rat 5–15 LD 50 650 mg/kg body weight Hodge (1943)<br />
Intraperitoneal Rat 5/sex LD 50 500–1000 mg/kg body Dave <strong>and</strong> Lidman (1978)<br />
weight<br />
Intraperitoneal Mouse 5–15 LD 50 780 mg/kg body weight Hodge (1943)<br />
Isoamyl alcohol i.v. Mouse Not reported LD 50 2.64 mmol/kg body weight<br />
(233 mg/kg body weight)<br />
Chvapil et al. (1962)<br />
Isotridecan-1-ol<br />
(isomeric mixture)<br />
Inhalation, exposure to air<br />
saturated with alcohol vapor at<br />
room temperature <strong>for</strong> 8 h<br />
Inhalation to 12 ml/m 3<br />
(saturation concentration at<br />
30 °C) <strong>for</strong> 6 h<br />
Rat 6 rats/14 days No effects RIFM (1963c) <strong>and</strong> Smyth<br />
et al. (1962)<br />
Rat, mouse,<br />
guinea pig<br />
10/species No effects Scala <strong>and</strong> Burtis (1973)<br />
Intraperitoneal Mouse n.f.i. LD 50 600 mg/kg body weight RIFM (1963b)<br />
2-Methylbutanol Intraperitoneal Rat n.f.i. 1000 mg/kg body weight: Haggard et al. (1945)<br />
sedation, irritation of the<br />
peritoneum <strong>and</strong> injury of the<br />
lungs; 2000 mg/kg body weight:<br />
respiratory arrest <strong>and</strong> death<br />
Intraperitoneal Mouse 10 (5/sex) LD 50 between 200 <strong>and</strong><br />
RIFM (1979b)<br />
700 mg/kg body weight<br />
Inhalation, saturated<br />
Rat n.f.i. No mortality, escape behavior, RIFM (1979b)<br />
atmosphere at 20 °C (calculated:<br />
10,050 mg/m 3 bzw. 2744 ml/m 3 )<br />
<strong>for</strong> 7 h<br />
intermittent respiration<br />
Inhalation, saturated vapor <strong>for</strong><br />
8h<br />
Rat 6 No mortality Rowe <strong>and</strong> McCollister<br />
(1982)<br />
3-Methyl-1-pentanol Intraperitoneal Mouse 10 LD 50 > 250 mg/kg body weight;<br />
P2000 mg/kg body weight:<br />
10/10 animals died within<br />
30 min (respiratory depression)<br />
RIFM (1982a)<br />
Subgroup: secondary<br />
2,6-Dimethyl-4-heptanol<br />
Inhalation, exposure to<br />
substantially saturated vapor or<br />
cooled mist (400 ml/m 3 ) <strong>for</strong> 8 h<br />
Inhalation, exposure to a<br />
saturated vapor–air mixture <strong>for</strong><br />
12 h<br />
Rat 12 No mortality Smyth et al. (1949)<br />
Mouse 10 2.0 mg/l: no mortality McOmie <strong>and</strong> Anderson<br />
(1949)<br />
4-Methyl-2-pentanol Inhalation <strong>for</strong> 8 h at 2000 ppm Rat 6 5/6 animals died within 14 days Carpenter et al. (1949) <strong>and</strong><br />
Smyth et al. (1951)<br />
Inhalation exposure to a<br />
saturated vapor–air at 20 °C <strong>for</strong><br />
4–15 h<br />
Mouse 10 Somnolence <strong>and</strong> anesthesia<br />
Mortality at 10 h (6/10) <strong>and</strong> 15 h<br />
(8/10)<br />
McOmie <strong>and</strong> Anderson<br />
(1949)<br />
3,4,5,6,6-<br />
Pentamethylheptan-2-ol<br />
n.f.i.: no further in<strong>for</strong>mation.<br />
Intraperitoneal injection at doses<br />
of 50, 166, 500, 750, 1000, 1250,<br />
1666, <strong>and</strong> 3000 mg/kg body<br />
weight<br />
Mouse 2 One death at 1250 mg/kg<br />
Clinical signs observed <strong>for</strong> all<br />
mice above 1000 mg/kg<br />
RIFM (1985d)
S14<br />
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46<br />
Table 3-1<br />
Repeated dose toxicity studies – dermal.<br />
Material Method Dose Species (No./dose) Results References<br />
Subgroup: primary<br />
2-Ethyl-1-hexanol Single application/day on<br />
the shaved back <strong>for</strong> 12 days<br />
Isooctanol (alcohols C7–C9<br />
branched CAS No.<br />
68526-83-0)<br />
5 days occlusive treatment,<br />
2 days untreated, 4 days<br />
treated<br />
Occlusive, 18–24 h <strong>for</strong><br />
12 days (10 treatments)<br />
2 ml/kg body weight/<br />
day (1600 mg/kg body<br />
weight/day)<br />
0, 500, or 1000 mg/kg<br />
body weight/day<br />
0 (isopropyl alcohol),<br />
400, 2000 mg/kg body<br />
weight/day<br />
Rat (10) Absolute <strong>and</strong> relative thymus weights decreased, liver<br />
granulomas, bronchiectasis in the lung, renal tubular<br />
epithelial necroses, edematous heart <strong>and</strong> testes <strong>and</strong><br />
decreased spermatogenesis<br />
Fischer 344 rat (10/sex) P500 mg/kg body weight/day: exfoliation (minimal<br />
severity), spleen weight decreased; serum triglycerides<br />
increased (females);<br />
1000 mg/kg body weight: transient erythema (days 4–7)<br />
(graded as barely perceptible), decreased absolute<br />
spleen weight, lymphocytes decreased<br />
Rabbit (Albino) (2/sex) Systemic NOAEL: 2000 mg/kg body weight/day 400 mg/<br />
kg body weight/day: moderate to severe irritation,<br />
fissure, coriaceous skin<br />
2000 mg/kg body weight/day:necrosis of the skin<br />
Schmidt et al. (1973)<br />
RIFM (1988); Weaver et al. (1989)<br />
Esso <strong>Research</strong> <strong>and</strong> Engineering Company<br />
(1961) as cited in ExxonMobil <strong>Chemical</strong><br />
Company (2001a)<br />
Subgroup: secondary<br />
3,4,5,6,6-<br />
Pentamethylheptan-2-ol<br />
Dermal (occlusive), 6 h/day<br />
<strong>for</strong> 28 days (OECD TG 410)<br />
Dermal (occlusive), 6 h/day<br />
<strong>for</strong> 28 days<br />
0 (water), 1000 mg/kg<br />
body weight/day<br />
30, 100, 300, <strong>and</strong><br />
1000 mg/kg/day<br />
Rabbit (New Zeal<strong>and</strong><br />
White) (5/sex)<br />
Rabbit (New Zeal<strong>and</strong><br />
White) (10/sex)<br />
Systemic NOAEL: 1000 mg/kg body weight/day<br />
1000 mg/kg body weight/day: (f), severe dermal<br />
reactions: well defined severe erythema <strong>and</strong> edema,<br />
histopathology of the skin: acanthotic <strong>and</strong> focal<br />
ulcerative changes of epidermis, associated<br />
inflammation, hyperkeratosis, scab <strong>for</strong>mation<br />
Systemic NOAEL: 1000 mg/kg body weight/day Slight to<br />
moderate dermal irritation; severe irritation at high (300<br />
<strong>and</strong> 1000 mg/kg/day) doses; reversible after 8 days<br />
RIFM (1985c)<br />
RIFM (1986b)<br />
Abbreviations see Table 3-3.
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46 S15<br />
Table 3-2<br />
Repeated dose toxicity studies – oral.<br />
Material Method Dose Species (No./dose) Results References<br />
Subgroup: primary<br />
2-Ethyl-1-hexanol Gavage, 5 days/week,<br />
22 days<br />
Gavage, 9 treatments in<br />
11 days<br />
0, 330, 660, 930 mg/kg body<br />
weight in sunflower oil,<br />
controls 10 ml oil/kg body<br />
weight<br />
0, 100, 330, 1000, 1500 mg/<br />
kg body weight/day, test<br />
substance undiluted<br />
Drinking water, 9 days 0, 308 ppm (half-saturated)<br />
<strong>and</strong> 636 ppm (saturated):<br />
61.1 <strong>and</strong> 151.1 mg/kg body<br />
weight/day <strong>for</strong> males <strong>and</strong><br />
73.4 <strong>and</strong> 173.5 mg/kg body<br />
weight/day <strong>for</strong> females.<br />
Gavage, 9 doses in 11 d 0, 100, 330, 1000, or<br />
1500 mg/kg body weight/<br />
day, in propylene glycol<br />
Gavage, 9 doses in 11 d 0, 100, 330, 1000, or<br />
1500 mg/kg body weight/<br />
day, in an aqueous emulsion<br />
in Cremophor EL<br />
Diet, 11 days 500, 980, 1430, or 2590 mg/<br />
kg/day (males) 540, 1060,<br />
1580, or 2820 mg/kg/day<br />
(females)<br />
Rat (10) 930 mg/kg: body weight on day 17 decreased, mortality:<br />
1/10<br />
Fischer 344 rat<br />
(10/sex)<br />
Fischer 344 rat<br />
(10/sex)<br />
B6C3F1 mice<br />
(10/sex)<br />
B6C3F1 mice<br />
(10/sex)<br />
Systemic NOAEL 100 mg/kg body weight/day<br />
330 mg/kg body weight/day: hypoactivity, ataxia,<br />
prostration, delayed righting reflex, muscle twitch,<br />
lacrimation, <strong>and</strong> urine-stained fur. <strong>Food</strong> consumption <strong>and</strong><br />
body weights decreased (males), thymic atrophy <strong>and</strong><br />
lymphoid cell degeneration in the thymus;<br />
1000 mg/kg body weight/day: food consumption <strong>and</strong> body<br />
weights decreased (females), total peripheral blood<br />
leukocytes <strong>and</strong> lymphocytes, spleen weight decreased<br />
(females), absolute <strong>and</strong> relative liver weight increased<br />
without histopathological findings, absolute <strong>and</strong> relative<br />
stomach weight increased with hyperkeratosis, mucosal<br />
hyperplasia, edema, exocytosis, <strong>and</strong> gastritis;<br />
1500 mg/kg body weight/day: total peripheral blood<br />
leukocytes <strong>and</strong> lymphocytes, spleen weight decreased<br />
(males), absolute <strong>and</strong> relative testes weights decreased, no<br />
histopathological findings in testes or kidneys at any dose<br />
Schmidt et al. (1973)<br />
RIFM (1988); Weaver et al.<br />
(1989)<br />
No adverse effects RIFM (1988); Weaver et al.<br />
(1989)<br />
Systemic NOAEL 100 mg/kg body weight/day<br />
330 mg/kg body weight/day: relative liver <strong>and</strong> stomach<br />
weights (male) increased;<br />
1000 mg/kg body weight/day: relative liver <strong>and</strong> stomach<br />
weights (female) increased; 2/20 deaths;<br />
1500 mg/kg body weight/day: ataxia, lethargy, piloerection,<br />
dyspnea, hypothermy, abdominal or lateral position <strong>and</strong> loss<br />
of consciousness, reduction in food consumption (males),<br />
relative testes weight decreased; clinical chemistry <strong>and</strong><br />
hematology no substance-related changes. No<br />
histopathological examinations; 10/20 deaths<br />
Systemic NOAEL 100 mg/kg body weight/day<br />
300 mg/kg body weight/day: acanthosis with hyperkeratosis<br />
in the <strong>for</strong>estomach;<br />
P1000 mg/kg body weight/day: relative liver (males) <strong>and</strong><br />
stomach weights (female) increased, hypertrophy of<br />
hepatocytes; 1/20 deaths;<br />
1500 mg/kg body weight/day: ataxia, lethargy, piloerection,<br />
abdominal or lateral position <strong>and</strong> loss of consciousness;<br />
clinical chemistry <strong>and</strong> hematology, no substance-related<br />
changes; 5/20 deaths.<br />
F344 rat (10/sex) NOAEL < 500 (m) or 540 (f) mg/kg bodyweight/day<br />
P500 (m) or 540 (f) mg /kg/d: relative stomach weights<br />
increased females (f); triglycerides <strong>and</strong> alanine<br />
aminotransferase decreased, males (m); feed consumption<br />
significantly decreased (m)<br />
RIFM (1992a)<br />
RIFM (1992b)<br />
RIFM (1992c)<br />
(continued on next page)
S16<br />
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46<br />
Table 3-2 (continued)<br />
Material Method Dose Species (No./dose) Results References<br />
Gavage, 5 days/week,<br />
13 weeks<br />
Gavage, 24 months,<br />
5 days/week<br />
3 weeks, oral<br />
administration<br />
Gavage, 18 months,<br />
5 days/week<br />
Isoamyl alcohol Drinking water<br />
3 months<br />
Gavage, daily <strong>for</strong><br />
17 weeks<br />
Drinking water,<br />
56 weeks<br />
Neurotoxicity: Whole<br />
body exposures with a<br />
30 min habituation <strong>and</strong><br />
4 h exposure<br />
Neurotoxicity: Whole<br />
body exposure with a<br />
30 min habituation <strong>and</strong><br />
2 h exposure<br />
0, 25, 125, 250 or 500 mg/kg<br />
body weight/day<br />
0 (water), 0 (vehicle), 50,<br />
150, 500 mg/kg/body<br />
weight/day in 0.005%<br />
Cremophor EL<br />
F344 rat, B6C3F1<br />
mice (10/sex)<br />
P980 (m) or 1060 (f) mg/kg/d: absolute <strong>and</strong> relative liver<br />
weights increased (m,f); feed consumption decreased (m,f);<br />
water consumption significantly decreased (f); triglyceride<br />
<strong>and</strong> alanine aminotransferase decreased (m);<br />
P1430 (m) or 1580 (f) mg/kg/d: food consumption reduced<br />
(m,f), hypertrophy of hepatocytes; body weight significantly<br />
reduced (m); water consumption significantly reduced (m,f);<br />
triglyceride <strong>and</strong> alanine aminotransferase decreased (males);<br />
2590 (m) or 2820 (f) mg/kg/d: absolute <strong>and</strong> relative liver<br />
weights increased (m,f);body weight decreased (m,f); feed<br />
consumption decreased (m,f), water consumption<br />
significantly decreased (m,f); triglyceride <strong>and</strong> alanine<br />
aminotransferase decreased (m,f)<br />
NOAEL: 125 mg/kg body weight/day, rats <strong>and</strong> mice<br />
P250 mg/kg body weight/day: relative liver, kidney (rats,<br />
both sexes) <strong>and</strong> stomach weights (female rats) increase, fat<br />
deposits in the liver cells (male rats) decrease, relative liver<br />
<strong>and</strong> stomach weights (male mice) increased;<br />
500 mg/kg body weight/day: acanthosis of the <strong>for</strong>estomach<br />
(female mice); peroxisome proliferation (marker: cyanideinsensitive<br />
palmitoyl CoA oxidase) (rats, both sexes) increase<br />
F344 rats (50/sex) Systemic NOAEL: 50 mg/kg body weight/day<br />
P150 mg/kg body weight/day: body weight gain decreased,<br />
poor clinical state, labored breathing, piloerection or urinestained<br />
genital region<br />
Astill et al. (1996a)<br />
Astill et al. (1996b)<br />
833 mg/kg n.f.i. Rat (n = 5) Statistical increase (p < .05) in liver was observed Yamada (1974)<br />
0 (water), 0 (vehicle), 50,<br />
200, 750 mg/kg body<br />
weight/day in 0.005%<br />
Cremophor EL<br />
0, 1000, 4000, 16,000 mg/l<br />
drinking water<br />
(purity > 98.6%); estimated<br />
to be: 0, 80, 320, 1280 mg/<br />
kg body weight/day<br />
0 (vehicle), 150, 500,<br />
1000 mg/kg body weight/<br />
day, in corn oil<br />
0, 2% (2000 mg/kg body<br />
weight/day)<br />
3–4 exposures to the<br />
various solvent<br />
concentrations (between<br />
25% <strong>and</strong> 75%)<br />
3–4 exposures to various<br />
solvent concentrations<br />
(between 25% <strong>and</strong> 75%)<br />
B6C3F1 mice<br />
(50/sex)<br />
Systemic NOAEL: 200 mg/kg body weight/day<br />
750 mg/kg body weight/day: increased mortality, body<br />
weight gains decreased, food consumption decreased, fatty<br />
liver, hyperplasia of the <strong>for</strong>estomach epithelium<br />
Wistar rat (10/sex) NOAEL females = 1280 mg/kg body weight/day<br />
NOAEL males = 320 mg/kg body weight/day<br />
1280 mg/kg body weight (males): erythrocyte value<br />
increased; mean corpuscular volume (MCV) decreased; mean<br />
corpuscular hemoglobin (MCH) decreased<br />
320 <strong>and</strong> 1280 mg/kg/day (females): increased prothrombin<br />
time<br />
Ash/CSE rat<br />
(15/sex)<br />
additional 5<br />
animals examined<br />
after 3 <strong>and</strong><br />
6 weeks,<br />
respectively<br />
NOAEL females = 1000 mg/kg body weight/day NOAEL<br />
males = 500 mg/kg body weight/day<br />
1000 mg/kg body weight/day: males: body weight gain<br />
decrease<br />
Astill et al. (1996b)<br />
Schilling et al. (1997) RIFM<br />
(1991b)<br />
Carpanini <strong>and</strong> Gaunt (1973)<br />
Wistar rat (20/sex) No significant effects Johannsen <strong>and</strong> Purchase<br />
(1969)<br />
Male albino SPF<br />
rats 16 (4/group)<br />
Female mice of the<br />
H strain 32<br />
(4/group)<br />
The concentration that evoked a 30% depression in the<br />
recorded activity was determined to be 1700 ppm<br />
The concentration that evoked a 30% depression in the<br />
recorded activity was determined to be 950 ppm<br />
Frantik et al. (1994)<br />
Frantik et al. (1994)
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46 S17<br />
Isotridecanol (Alcohols,<br />
C11–14 iso, C13<br />
rich, CAS No. 68526-<br />
86-3)<br />
3,5,5-Trimethyl-1-<br />
hexanol<br />
Subgroup: secondary<br />
2,6-Dimethyl-4-<br />
heptanol<br />
4-Hydroxy-4-methyl-2-<br />
pentanone<br />
Abbreviations see Table 3-3.<br />
Gavage, 7 days/week,<br />
<strong>for</strong> 14 weeks, OECD TG<br />
408<br />
0 (distilled water), 100, 500,<br />
1000 mg/kg body weight/<br />
day<br />
Sprague–Dawley<br />
rat (20/sex)<br />
Gavage, males: 14 days 144 mg/kg body weight/day Alderly-Park<br />
Wistar rat<br />
Gavage, males:<br />
46 days, females: from<br />
14 days be<strong>for</strong>e mating<br />
to day 3 of lactation,<br />
OECD TG 422<br />
0, 12, 60, 300 mg/kg body<br />
weight/day in olive oil<br />
SD (Crj:CD) rat<br />
(12/sex)<br />
NOAEL: 100 mg/kg body weight/day<br />
P500 mg/kg body weight/day: food consumption decreased<br />
(m), body weight decreased (m), mean platelet counts<br />
increased (f), glucose decreased (f), liver weight increased (m,<br />
f),<br />
1000 mg/kg body weight/day: glucose decreased (m),<br />
cholesterol decreased (f), rel. brain <strong>and</strong> testes weight<br />
increased (m), rel. adrenal weight increased (f)<br />
Increase in the relative liver weight<br />
No difference from controls in body weight, clinical, or<br />
histopathological signs. Peroxisome proliferation,<br />
hypocholesterolemia, <strong>and</strong> hypoglyceridaemia were not<br />
evident<br />
NOAEL systemic toxicity males <strong>and</strong> females: 12 mg/kg body<br />
weight/day<br />
P12 mg/kg body weight/day: renal hyaline droplets,<br />
eosinophilic bodies (m)<br />
P60 mg/kg body weight/day: relative liver <strong>and</strong> kidney<br />
weight increase (m,f), renal epithelial fatty change (f);<br />
implantation index decreased (f)<br />
300 mg/kg body weight/day: 1 f died, 3 f killed (weakness);<br />
body weights increase (m), food consumption increased (m),<br />
body weights decreased (f), food consumption decrease (f);<br />
total litter loss in 2 dams<br />
Diet, 13 weeks 0, 11 (f), 11 (m) mg/kg body<br />
weight/day mixed with<br />
microcrystalline cellulose<br />
Gavage, males:<br />
44 days, females: from<br />
14 d be<strong>for</strong>e mating to<br />
day 3 of lactation<br />
(approx. 45 days),<br />
OECD TG 422<br />
0, 30, 100, 300, 1000 mg/kg<br />
body weight/day in water<br />
Rat (16/sex) No NOAEL (females) based on reductions of body weight gain<br />
systemic NOAEL (males): 11 mg/kg body weight;<br />
11.06 mg/kg body weight/day: (females) body weight gain<br />
<strong>and</strong> food efficiency (weight gained (g)/food consumed<br />
(g) 100, 10.8%) decrease (body weight gain 12.1%).<br />
Hematological <strong>and</strong> histological examinations without any<br />
Crj:CD(SD) rat<br />
(10/sex)<br />
significant differences between test <strong>and</strong> control rats<br />
NOAEL: 100 mg/kg body weight/day<br />
P100 mg/kg body weight/day: male alpha-2u-nephropathy<br />
P300 mg/kg body weight/day: locomotor activity <strong>and</strong><br />
stimulation response decrease (m,f); dilatation of the distal<br />
tubules <strong>and</strong> fatty degeneration of the proximal tubular<br />
epithelium in kidneys (f)<br />
P1000 mg/kg body weight/day: hepatocellular hypertrophy<br />
(m,f), altered blood parameters (increase: platelet counts,<br />
GOT, total protein, total cholesterol, total bilirubin, blood<br />
urea nitrogen, creatinine, calcium (m); decrease: glucose)<br />
(m), dilatation of distal tubules of kidneys (m), vacuolization<br />
of the zona fasciculata of the adrenals (m); body weight gain<br />
decrease (f), rel. liver weight increase (f)<br />
Exxon Biomedical Sciences<br />
Inc. (1986) as cited in<br />
ExxonMobil <strong>Chemical</strong><br />
Company (2001b)<br />
Rhodes et al. (1984)<br />
MHW, Japan (1997b) as<br />
cited in OECD/SIDS (2003)<br />
Posternak <strong>and</strong> Vodoz (1975)<br />
MHW, Japan (1997) as cited<br />
in OECD/SIDS (2007)
S18<br />
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<strong>and</strong> isoamyl alcohol were tested <strong>for</strong> their potency to induce DNA<br />
damage in V79 Chinese hamster fibroblasts, human lung carcinoma<br />
epithelial A549 cells <strong>and</strong> human peripheral blood cells with<br />
the alkaline comet assay. In V79 <strong>and</strong> A549 cells 2-methylbutanol<br />
<strong>and</strong> isoamyl alcohol showed DNA damage only at cytotoxic concentrations.<br />
The COMET assay could not be per<strong>for</strong>med in human<br />
peripheral blood cells due to extreme cytotoxicity (cells with completely<br />
fragmented DNA) (Kreja <strong>and</strong> Seidel, 2001, 2002).<br />
2-Methylbutanol <strong>and</strong> isoamyl alcohol gave negative results in a<br />
light absorption umu test <strong>and</strong> positive results in a luminescent<br />
umu test (Nakajima et al., 2006). These tests are based on the ability<br />
of DNA damaging agents to induce expression of the umu operon,<br />
which is responsible <strong>for</strong> chemical <strong>and</strong> radiation mutagenesis, in<br />
Escherichia coli. The positive result is not plausible in view of the<br />
other negative tests <strong>for</strong> genotoxicity (see below) <strong>and</strong> the overall<br />
negative results <strong>for</strong> branched chain saturated alcohols. 2-Ethyl-1-<br />
hexanol gave a negative <strong>and</strong> a positive result in two rec-assays<br />
(Saido et al., 2003; Tomita et al., 1982). The results of this test system<br />
are not considered <strong>for</strong> the evaluation of the genotoxicity of the<br />
alcohols under study because positive results were often assessed<br />
with substances, which were negative in other genotoxicity test<br />
systems. A test <strong>for</strong> induction of unscheduled DNA synthesis with<br />
2-ethyl-1-hexanol was negative in primary rat hepatocytes (Hodgson<br />
et al., 1982).<br />
4-Methyl-2-pentanone was negative in a vitro UDS test (no further<br />
in<strong>for</strong>mation; IPCS, 1990 as cited in OECD/SIDS, 2004).<br />
5.3.1.2. Mutation studies. The primary alcohols 3,5,5-trimethyl-1-<br />
hexanol, 2-ethyl-1-hexanol, isotridecan-1-ol (isomeric mixture),<br />
the secondary alcohols 4-methyl-2-pentanol, its metabolites 4-<br />
methyl-2-pentanone <strong>and</strong> 4-hydroxy-4-methyl-2-pentanone, 2,6-dimethyl-4-heptanol<br />
<strong>and</strong> its metabolite 2,6-dimethylheptan-4-one,<br />
as well as a mixture of the secondary alcohol 3,4,5,6,6-pentamethylheptan-2-ol<br />
(55–80%) <strong>and</strong> 3,4,5,6,6-pentamethylheptan-2-on<br />
(20-45%) were inactive in Ames tests. Urine from Sprague–Dawley<br />
rats dosed by oral gavage <strong>for</strong> 15 days with 1000 mg 2-ethyl-1-hexanol/kg<br />
body weight/day was found to be non-mutagenic in Salmonella<br />
typhimurium with <strong>and</strong> without addition of rat liver<br />
microsomes or beta-glucuronidase/arylsulfatase (DiVincenzo<br />
et al., 1983, 1985). 2-Ethyl-1-hexanol was mutagenic in S. typhimurium<br />
TA100 using the mutation to resistance to 8-azaguanine (Seed,<br />
1982). As this test was per<strong>for</strong>med only in one S. typhimurium strain<br />
<strong>and</strong> the other mutagenicity tests using reversion to histidine independence<br />
were negative, this result seems to be of limited<br />
relevance.<br />
The primary alcohols 2-methylbutanol, isoamyl alcohol, <strong>and</strong> 2-<br />
ethyl-1-hexanol were also inactive in mammalian cell systems<br />
(TK +/ mouse lymphoma mutagenicity assay in L5178Y cells or<br />
HPRT assay with Chinese hamster V79 fibroblast cells) (Kirby<br />
et al., 1983; Kreja <strong>and</strong> Seidel, 2002). For 4-methyl-2-pentanone, a<br />
mouse lymphoma test was considered equivocal (no further in<strong>for</strong>mation;<br />
IPCS, 1990 as cited in OECD/SIDS, 2004).<br />
A Saccharomyces cerevisiae mitotic gene conversion assay was<br />
negative <strong>for</strong> 2,6-dimethylheptan-4-one (OECD/SIDS, 2004).<br />
The secondary alcohol 4-methyl-2-pentanol tested <strong>for</strong> gene<br />
mutation in Saccharomyces cerevisiae gave negative results (Clare,<br />
1983 as cited in OECD/SIDS, 2007).<br />
5.3.1.3. Chromosome aberration studies. The primary alcohols 2-<br />
ethyl-1-hexanol <strong>and</strong> 3,5,5-trimethyl-1-hexanol as well as the secondary<br />
alcohol 4-methyl-2-pentanol <strong>and</strong> 2,6-dimethylheptan-4-<br />
one, did not induce chromosome aberrations in vitro when incubated<br />
with Chinese hamster ovary, Chinese hamster lung or rat liver<br />
cells (Brooks et al., 1985 as cited in OECD/SIDS, 2004; Brooks<br />
et al., 1988; Clare, 1983 as cited in OECD/SIDS, 2007; MHW, Japan,<br />
1997d as cited in OECD/SIDS, 2003; Phillips et al., 1982). 4-Hydroxy-4-methyl-2-pentanone,<br />
tested <strong>for</strong> chromosomal aberrations in<br />
Chinese hamster lung cells, revealed significantly increased polyploidy<br />
in the two highest doses (600 <strong>and</strong> 1200 lg/ml). In<strong>for</strong>mation<br />
as to whether this was done with or without S9 was not available.<br />
This test was considered negative because a trend test showed no<br />
dose-dependency (MHW, Japan, 1997 as cited in OECD/SIDS, 2007).<br />
5.3.1.4. Micronucleus studies. The primary alcohols 2-methylbutanol<br />
<strong>and</strong> isoamyl alcohol did not induce micronuclei in V79 Chinese<br />
hamster fibroblasts, with or without addition of hepatic S9 mix<br />
from Aroclor induced rats (Kreja <strong>and</strong> Seidel, 2002).<br />
5.3.2. In vivo studies<br />
The available studies are summarized in Table 4-2. No indication<br />
<strong>for</strong> a covalent binding of 2-ethyl-1-hexanol to liver DNA of rats<br />
<strong>and</strong> mice was noted (Albro et al., 1982; Däniken et al., 1984). 2-<br />
Ethyl-1-hexanol was not mutagenic in the dominant lethal test<br />
(Rushbrook et al., 1982; only as abstract) <strong>and</strong> not clastogenic in a<br />
bone marrow chromosome aberration test (Putman et al., 1983),<br />
although this result is not reliable because the doses used failed<br />
to induce toxicity. 2-Ethyl-1-hexanol (Astill et al., 1986; Barber<br />
et al., 1985; only as abstract, no in<strong>for</strong>mation on the method, <strong>and</strong><br />
validity cannot be assessed) <strong>and</strong> 3,4,5,6,6-pentamethylheptan-2-<br />
ol were not clastogenic in the mouse bone marrow micronucleus<br />
test (RIFM, 1985d). Isoamyl alcohol showed an increase in chromosomal<br />
aberrations in bone marrow cells of rats (Barilyak <strong>and</strong> Kozachuk,<br />
1988). The study is invalid as no in<strong>for</strong>mation is available if a<br />
positive control group was used, the definite dose was not mentioned<br />
(1/5 of LD 50 ), only one dose was tested, the control animals<br />
did not show any chromosomal aberrations, <strong>and</strong> the purity of the<br />
substance was not given. The authors also found chromosomal<br />
aberrations with propanol, which was not genotoxic in a variety<br />
of tests (Greim, 1996). An in vivo mouse micronucleus assay was<br />
conducted on isoamyl alcohol (RIFM, 2008) at doses of 500, 1000,<br />
<strong>and</strong> 2000 mg/kg there was no increase in the frequency of detected<br />
micronuclei. Isoamyl alcohol was determined to be non-mutagenic<br />
in the micronucleus assay.<br />
Additionally, 4-methyl-2-pentanone was negative in an in vivo<br />
micronucleus test (no further in<strong>for</strong>mation; IPCS, 1990 as cited in<br />
OECD/SIDS, 2004).<br />
5.4. Carcinogenicity<br />
The available carcinogenicity studies are summarized in Tables<br />
5-1.<br />
5.4.1. Cell trans<strong>for</strong>mation assays<br />
In a cell trans<strong>for</strong>mation study with mouse epidermis-derived<br />
JB6 cells 2-ethyl-1-hexanol did not promote JB6 cells to anchorage<br />
independence (Ward et al., 1986). A cell trans<strong>for</strong>mation assay with<br />
BALB 3T3 cells did not induce a significant number of trans<strong>for</strong>med<br />
foci (Barber et al., 1985; RIFM, 1983b).<br />
5.4.2. Carcinogenicity studies<br />
2-Ethyl-1-hexanol was given to male <strong>and</strong> female rats <strong>and</strong> mice<br />
by gavage 5 times a week in 0.005% aqueous Cremophor EL (rats: 0<br />
(water), 0 (vehicle), 50, 150, 500 mg/kg body weight/day,<br />
24 months; mice: 0 (water), 0 (vehicle), 50, 200, 750 mg/kg body<br />
weight/day, 18 months). The incidences of carcinomas <strong>and</strong> basophilic<br />
foci in the liver increased in female mice with the dose<br />
<strong>and</strong> attained statistical significance in the highest dose group compared<br />
with the vehicle control group but not with the water control<br />
group. The time-adjusted incidence of hepatocellular<br />
carcinomas in female mice (13.1%) was outside the normal range<br />
(0–2%), but in male mice (18.8%) was within the historical control<br />
range at the testing facility (0–22%). No adenomas were observed.
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46 S19<br />
Table 3-3<br />
Repeated dose toxicity studies – inhalation.<br />
Material Method Concentration Species (No./dose) Results References<br />
Subgroup: primary<br />
2-Ethyl-1-hexanol OECD TG 413 90 days,<br />
6 h/day, 5 days/week<br />
0, 15, 40, or 120 ml/m 3<br />
(highest vapour<br />
concentration at room<br />
temperature), purity: 99.9%<br />
Isooctanol 13 days, 6 h/day 180 ml/m 3 (highest vapour<br />
concentration at room<br />
temperature)<br />
Wistar rat (10/sex) Local <strong>and</strong> systemic NOAEL: 120 ml/m 3 Klimisch et al. (1998)<br />
Alderly-Park rat (3 f) No mortality, clinical signs, autopsy findings <strong>and</strong><br />
histopathological changes<br />
Gage (1970)<br />
Subgroup: secondary<br />
2,6-Dimethylheptan-4-one 2 weeks, 5 h/day,<br />
5 days/week<br />
6 weeks, 7 h/day,<br />
5 days/week<br />
4-Methyl-2-pentanone 14 weeks, 6 h/day,<br />
5 days/w (OECD TG<br />
413)<br />
14 weeks, 6 h/day,<br />
5 days/w (OECD TG<br />
413)<br />
0, 98, 300, 905 ml/m 3 Rats (10/sex) NOAEL: 98 ml/m 3<br />
0, 125, 252, 534, 925,<br />
Rat (15/sex) NOAEL: 125 ml/m 3<br />
1654 ml/m 3<br />
0, 50, 250, 1000 ml/m 3<br />
(0, 204, 1020, 4090 mg/m 3 )<br />
0, 50, 250, 1000 ml/m 3<br />
(0, 204, 1020, 4090 mg/m 3 )<br />
Fischer 344 rat (14/sex) NOAEL: 250 ml/m 3<br />
P 300 ml/m 3 : liver weight increased, alpha-2uglobulin<br />
accumulation in the kidneys (m)<br />
125 ml/m 3 : No adverse effects 252 ml/m 3 : Liver <strong>and</strong><br />
kidney weights increased (f)<br />
534 ml/m 3 : Liver <strong>and</strong> kidney weights increased<br />
(m + f)<br />
925 ml/m 3 : Liver <strong>and</strong> kidney weights increased<br />
(m + f)<br />
1654 ml/m 3 : Mortality in all females <strong>and</strong> 3/15<br />
males. Surviving males: body weight gain<br />
decreased <strong>and</strong> liver <strong>and</strong> kidney weights increased<br />
P250 ml/m 3 : hyaline droplets in proximal tubular<br />
cells (m)<br />
1000 ml/m 3 : abs. <strong>and</strong> rel. liver weight (slight but<br />
statistically significant) increase (m)<br />
B6C3F1 mouse (14/sex) NOAEL: 50 ml/m 3 1000 ml/m 3 : abs. <strong>and</strong> rel. liver<br />
weight (slight but statistically significant) increase<br />
(m)<br />
4-Methyl-2-pentanol 12 4-h-exposures 0, 20,000 mg/m 3 Mouse (9) Unclear description of effects, unclear extent of<br />
histopathology<br />
6 weeks, 6 h/day,<br />
5 days/w (OECD TG<br />
407)<br />
0, 50.5, 198, 886 ml/m 3<br />
(0, 211, 825, 3700 mg/m 3 )<br />
Wistar rat (12/sex) NOAEL: 198 ml/m 3<br />
P50.5 ml/m 3 : concentration of ketone bodies in<br />
urine increased (f)<br />
P198 ml/m 3 : concentration of ketone bodies in<br />
urine increased (m)<br />
886 ml/m 3 : abs. kidney weight increased (m),<br />
serum alkaline phosphatase increased (f)<br />
Dodd et al. (1987)<br />
Carpenter et al. (1953)<br />
Phillips et al. (1987)<br />
Phillips et al. (1987)<br />
McOmie <strong>and</strong> Anderson (1949)<br />
Blair (1982) as cited in OECD/<br />
SIDS (2007)<br />
ADH: alcohol dehydrogenase, BUN: blood urea nitrogen, GOT: glutamate oxalacetate transaminase (now renamed: AST aspartate aminotransferase), GPT: gutamate pyruvate transaminase (now renamed: ALT alanine aminotransferase),<br />
f: female, m: male, n.f.i.: no further in<strong>for</strong>mation, n.s.: not statistically significant, s.a.: see above, s.c.: subcutaneous.
S20<br />
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46<br />
The number of basophilic liver foci was increased in male mice in<br />
the mid dose group only. The authors considered the liver tumors<br />
in the mouse to be inconclusive because the incidence of hepatocarcinoma<br />
precursors did not significantly increase with the dose.<br />
Nevertheless, they concluded that 2-ethylhexanol is weakly or<br />
questionably carcinogenic <strong>for</strong> the female mouse. Under the conditions<br />
of this study 2-ethyl-1-hexanol was not oncogenic to rats.<br />
Doses of 150 <strong>and</strong> 500 mg/kg body weight/day led to reduced body<br />
weight gains <strong>and</strong> in some animals to lethargy <strong>and</strong> unkemptness<br />
which proves that the maximum tolerated dose was reached. At<br />
the end of the study the mortality was about 52% in the high-dose<br />
group females <strong>and</strong> about 28% in the other groups (Table 5-1; Astill<br />
et al., 1996b).<br />
5.5. Reproductive <strong>and</strong> developmental toxicity<br />
5.5.1. Fertility<br />
5.5.1.1. In vitro. 2-Ethyl-1-hexanol (200 lM <strong>for</strong> 24 h) had no effect<br />
on lactate <strong>and</strong> pyruvate production by Sertoli-cell-enriched cultures<br />
derived from 28-day old Sprague–Dawley rats, whereas<br />
phthalate monoesters known to cause testicular atrophy in vivo increased<br />
Sertoli cell lactate production <strong>and</strong> lactate/pyruvate ratio<br />
(Moss et al., 1988).<br />
In an in vitro model of rat seminiferous tubules 200 lM 2-ethyl-<br />
1-hexanol did not induce dissociation of germinal cells from Sertoli<br />
cells (Gangolli, 1982).<br />
Ethyl-1-hexanol (200 lM <strong>for</strong> 24 or 48 h) did not result in an increase<br />
of germ-cell detachment in rat testicular-cell cultures (Gray,<br />
1986; Gray <strong>and</strong> Beam<strong>and</strong>, 1984; Sjoberg et al., 1986).<br />
5.5.1.2. In vivo. In vivo studies of reproductive <strong>and</strong> developmental<br />
toxicity of the branched chain saturated alcohols are summarized<br />
in Tables 6-1 (dermal), 6-2 (oral), <strong>and</strong> 6-3 (inhalation).<br />
5.5.1.3. Dermal. Effects on the reproductive organs of rats treated<br />
dermally with 1000 mg 3,4,5,6,6-pentamethylheptan-2-ol/kg body<br />
weight/day <strong>for</strong> 28 days did not occur (see also Section 5.2.1; RIFM,<br />
1985c).<br />
5.5.1.4. Oral.<br />
5.5.1.4.1. Primary alcohols. 2-Ethyl-1-hexanol administered by<br />
gavage, 167 mg/kg body weight/day, had no effects on Sertoli cells<br />
<strong>and</strong> gonocytes of 3-day old CD Sprague–Dawley rats (4/group) (Li<br />
et al., 2000). Daily gavage doses of 2.7 mmol 2-ethyl-1-hexanol/<br />
kg (350 mg/kg body weight) of <strong>for</strong> 5 days did not induce testicular<br />
damage in 35-day old male Sprague–Dawley rats (Sjoberg et al.,<br />
1986).<br />
In a 90-day gavage systemic toxicity study no effects on reproductive<br />
organs of rats <strong>and</strong> mice were noted up to doses of 500 mg<br />
2-ethyl-1-hexanol/kg body weight/day (see Section 5.2.1.1, Astill<br />
et al., 1996a).<br />
In combined repeated dose <strong>and</strong> reproductive/developmental<br />
toxicity screening test (OECD TG 422) with gavage application<br />
of3,5,5-trimethyl-1-hexanol (see Section 5.2.1.1) no effects on fertility<br />
were observed in males. In females a dose dependent decrease<br />
in implantation index was noted in the 60 <strong>and</strong> 300 mg/kg<br />
group (MHW, Japan, 1997b as cited in OECD/SIDS, 2003). Based<br />
on these findings, the NOAELs <strong>for</strong> fertility were 12 mg/kg body<br />
weight/day <strong>for</strong> females <strong>and</strong> 300 mg/kg body weight/day <strong>for</strong> males.<br />
5.5.1.4.2. Secondary alcohols. In the combined repeated dose<br />
<strong>and</strong> reproductive/developmental toxicity screening test (OECD TG<br />
422) with gavage application of 4-hydroxy-4-methyl-2-pentanone<br />
(see Section 5.2.1.1), a metabolite of 4-methyl-2-pentanol, no statistically<br />
significant changes in any reproductive parameter at any<br />
dose were noted. According to the authors there was a tendency <strong>for</strong><br />
lower reproductive indices (fertility <strong>and</strong> implantations, no further<br />
in<strong>for</strong>mation) at the highest dose of 1000 mg/kg body weight/day.<br />
There<strong>for</strong>e the NOAEL <strong>for</strong> fertility was 300 mg/kg body weight/day<br />
(MHW, Japan, 1997 as cited in OECD/SIDS, 2007).<br />
2,6-Dimethyl-4-heptanol showed no effects on the reproductive<br />
organs of rats in a 13-week feeding study with the only tested dose<br />
of 11 mg/kg body weight/day (Posternak <strong>and</strong> Vodoz, 1975). Its<br />
metabolite 2,6-dimethylheptane-4-one given by gavage has been<br />
assessed in a reproduction/developmental toxicity screen (OECD<br />
TG 421) <strong>and</strong> did not lead to reproductive effects up to the highest<br />
tested dose of 1000 mg/kg body weight/day (Shell HSE, 1996 as cited<br />
in OECD/SIDS, 2004).<br />
5.5.1.4.3. Tertiary alcohols. No studies were available.<br />
5.5.1.5. Inhalation.<br />
5.5.1.5.1. Primary alcohols. In a 90-day inhalation study in rats,<br />
no effects on the reproductive organs were seen at concentrations<br />
up to 120 ml/m 3 2-ethyl-1-hexanol (Klimisch et al., 1998).<br />
5.5.1.5.2. Secondary alcohols. With 4-methyl-2-pentanone, the<br />
metabolite of 4-methyl-2-pentanol, a two-generation study per<strong>for</strong>med<br />
in Sprague–Dawley rats (30/sex/group) exposed to 0, 500,<br />
1000, or 2000 ml/m 3 (0, 2050, 4090, or 8180 mg/m 3 ), <strong>for</strong> 6 h per<br />
day, 7 days per week. Treatment started 70 days prior to mating<br />
<strong>for</strong> the F 0 <strong>and</strong> F 1 generations, continued to the end of the mating<br />
period <strong>for</strong> males <strong>and</strong> to day 20 of gestation <strong>for</strong> females. Treatment<br />
of females resumed at day 5 of lactation. Because of CNS depression<br />
in F 1 pups upon initiation of exposures on post-natal day 22<br />
<strong>and</strong> the death of one F 1 male pup from the 2000 ml/m 3 group,<br />
treatment was interrupted <strong>and</strong> continued on day 28. In males of<br />
all exposure groups alpha-2u-globulin nephropathy was observed.<br />
F 0 <strong>and</strong> F 1 adults of the mid <strong>and</strong> high exposure groups showed a<br />
sedative effect, which was reversible 1 h after exposure. Decreased<br />
body weight gain <strong>and</strong> slightly decreased food consumption during<br />
the first 2 weeks of exposure occurred only at the high concentration<br />
in both generations. There were no effects on reproductive <strong>and</strong><br />
developmental parameters, or on estrous cycle <strong>and</strong> sperm parameters.<br />
The NOAEL <strong>for</strong> systemic toxicity was established at 1000 ml/<br />
m 3 (4090 mg/m 3 ) due to slightly reduced body weight <strong>and</strong> feed<br />
consumption at 2000 ml/m 3 . The NOAEL <strong>for</strong> reproductive toxicity<br />
was 2000 ml/m 3 (8180 mg/m 3 ) (Nemec et al., 2004). In view of<br />
the clinical signs of CNS depression of adults during the exposures<br />
at 1000 <strong>and</strong> 2000 ml/m 3 the systemic parental NOAEL is 500 ml/<br />
m 3 .<br />
Histopathological examinations in the 6-week inhalation study<br />
with 4-methyl-2-pentanol (Blair, 1982 as cited in OECD/SIDS,<br />
2007) showed no adverse effects on the reproductive organs of<br />
male <strong>and</strong> female rats up to the highest concentration tested<br />
(886 ml/m 3 ). For further details see Section 5.2.1.2.<br />
5.5.1.5.3. Tertiary alcohols. No studies were available.<br />
5.5.2. Developmental toxicity<br />
5.5.2.1. Dermal. 2-Ethyl-1-hexanol (99.72% pure) was administered<br />
on the clipped dorsal skin by occlusive cover to F344 rats 6 h per<br />
day from gestation days 6–15 at doses of 0, 0.5, 1.0, 2.0, or<br />
3.0 ml/kg body weight/day (0, 420, 840, 1680, or 2520 mg/kg body<br />
weight/day) in a range-finding study (8/group). In the main study<br />
(25/group) doses of 0, 0.3, 1.0, <strong>and</strong> 3.0 ml/kg body weight/day (0,<br />
252, 840, or 2520 mg/kg body weight/day) were applied. Persistent<br />
exfoliation, crusting, <strong>and</strong> erythema on the application site were<br />
seen in both studies from 840 mg/kg body weight/day. Maternal<br />
weight gain was reduced at 1680 <strong>and</strong> 2520 mg/kg body weight/<br />
day. The NOAELs <strong>for</strong> maternal toxicity were 252 mg/kg body<br />
weight/day based on skin irritation <strong>and</strong> 840 mg/kg body weight/<br />
day based on systemic toxicity. The developmental NOAEL was<br />
the highest tested dose of 2520 mg/kg body weight/day (Fisher<br />
et al., 1989; Tyl et al., 1992).
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46 S21<br />
Table 4-1<br />
Mutagenicity <strong>and</strong> genotoxicity: in vitro studies.<br />
Material Test system Concentration Results References<br />
Subgroup: primary<br />
2-Ethyl-1-hexanol Rec-assay Bacillus subtilis H17, M45 500 lg/disk in DMSO Negative Tomita et al. (1982)<br />
Urine of 2-ethyl-1-hexanol<br />
treated rats (1000 mg/kg<br />
body weight <strong>for</strong> 15 days)<br />
Rec-assay Bacillus subtilis HA101, Rec-4 Diluted in DMSO to make the<br />
inhibition circle between I.D. 9 <strong>and</strong><br />
40 mm<br />
Ames assay with <strong>and</strong> without S9<br />
activation (preincubation method)<br />
Ames assay with <strong>and</strong> without S9<br />
activation (preincubation method)<br />
Ames assay with <strong>and</strong> without S9<br />
activation (preincubation method)<br />
Ames assay with <strong>and</strong> without S9<br />
activation (preincubation method)<br />
Ames assay with <strong>and</strong> without S9<br />
activation (method unspecified)<br />
Ames assay with <strong>and</strong> without S9<br />
activation (preincubation method)<br />
Ames assay with <strong>and</strong> without S9<br />
activation (preincubation method)<br />
L5178Y TK +/ mouse lymphoma<br />
mutagenicity assay<br />
S. typhimurium TA98, TA100, TA1537,<br />
TA1538, TA 1535, E. coli WP2uvrA<br />
S. typhimurium TA98, TA100, TA1535,<br />
TA1537<br />
S. typhimurium TA98, TA100, TA1535,<br />
TA1537<br />
S. typhimurium TA98, TA100, TA1535,<br />
TA1537, 1538, 2637<br />
1–1000 lg/plate in DMSO, growth<br />
inhibition P500 lg/plate<br />
Positive Saido et al. (2003)<br />
Not mutagenic Shimizu et al. (1985)<br />
3.3–333 lg/plate in DMSO Not mutagenic Zeiger et al. (1982)<br />
3.3–220 lg/plate in DMSO Not mutagenic Zeiger et al. (1985)<br />
100–2000 lg/plate in DMSO, tested<br />
up to cytotoxic concentrations<br />
Not mutagenic Agarwal et al. (1985)<br />
S. typhimurium (unspecified) n.f.i. Not mutagenic Barber et al. (1985)<br />
S. typhimurium TA98, TA100, TA1535,<br />
TA1537, 1538<br />
0.01–1.0 ll/plate in DMSO, cytotoxic<br />
concentration P1.0 ll/plate<br />
Not mutagenic Kirby et al. (1983)<br />
S. typhimurium TA98, TA100 0.1–10.0 lM, n.f.i. Not mutagenic Warren et al. (1982)<br />
L5178Y mouse lymphoma cells 0.013–1.0 ll/ml in DMSO, cytotoxic<br />
concentration P1.0 ll/ml<br />
Not mutagenic Kirby et al. (1983)<br />
8-Azaguanine resistance assay S. typhimurium TA100 0.5–1.5 lM, n.f.i. Mutagenic Seed (1982)<br />
Hodgson et al. (1982)<br />
UDS assay Primary rat hepatocytes cultures<br />
prepared from Fischer 344 rats<br />
Cells were treated simultaneously<br />
with test compound <strong>and</strong> tritiated<br />
thymidine <strong>for</strong> 1 h, n.f.i.<br />
Did not induce detectable levels of<br />
UDS<br />
Chromosomal aberration assay Chinese hamster ovary cells 1.5–2.8 mM Did not induce an increased<br />
frequency of chromosomal<br />
aberrations compared to the control;<br />
50% kill at 2.5 mM<br />
Ames assay with <strong>and</strong> without S9<br />
activation (st<strong>and</strong>ard plate assay)<br />
S. typhimurium TA98, TA100, TA1535,<br />
TA1537, TA 1538<br />
Isoamyl alcohol Comet assay Chinese hamster V79 fibroblast cells,<br />
human lung carcinoma epithelial cell<br />
line A549, <strong>and</strong> human peripheral<br />
blood cells (pB)<br />
Isotridecan-1-ol (isomeric<br />
mixture)<br />
Up to 2 ml undiluted urine, negative<br />
<strong>and</strong> positive controls: urine of<br />
untreated rats <strong>and</strong><br />
8-hydroxyquinoline<br />
umu test: Light absorption S. typhimurium TA1535/pSK1002 Concentrations in which growth<br />
inhibition 650% (n.f.i.)<br />
umu test: Luminiscent S. typhimurium TA1535/pTL210 concentrations in which growth<br />
inhibition 650% (n.f.i.)<br />
Micronucleus test with <strong>and</strong> without<br />
S9 activation<br />
HPRT test with <strong>and</strong> without S9<br />
activation<br />
Ames assay with <strong>and</strong> without S9<br />
activation<br />
Phillips et al. (1982)<br />
Not mutagenic DiVincenzo et al. (1985)<br />
0, 23, 46, 91 mM DNA damage at at cytotoxic<br />
concentrations (91 mM in V79 <strong>and</strong><br />
A549 cells), extremely cytotoxic in pB<br />
Kreja <strong>and</strong> Seidel (2001, 2002)<br />
(analyses not possible)<br />
Negative Nakajima et al. (2006)<br />
Positive<br />
Chinese hamster V79 fibroblast cells 0, 5, 9, 23 mM Not genotoxic Kreja <strong>and</strong> Seidel (2002)<br />
Chinese hamster V79 fibroblast cells Up to 51.5 mM (highest non-toxic<br />
concentration)<br />
S. typhimurium TA98, TA100, TA1535,<br />
TA1537<br />
Not mutagenic Kreja <strong>and</strong> Seidel (2002)<br />
20-5000 lg/plate no cytotoxicity Not mutagenic RIFM (1989)<br />
2-Methylbutanol umu test: Light absorption S. typhimurium TA1535/pSK1002 Concentrations in which growth Negative Nakajima et al. (2006)<br />
umu test: Luminiscent S. typhimurium TA1535/pTL210 inhibition 650% (n.f.i.)<br />
Positive<br />
Comet assay Chinese hamster V79 fibroblast cells,<br />
human lung carcinoma epithelial cell<br />
line A549, <strong>and</strong> human peripheral<br />
blood cells (pB)<br />
0, 45, 90 mM DNA damage at cytotoxic<br />
concentrations (45 mM in A549,<br />
90 mM in V79 cells), extremely<br />
cytotoxic in pB (analyses not<br />
possible)<br />
Kreja <strong>and</strong> Seidel (2001, 2002)<br />
(continued on next page)
S22<br />
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46<br />
Table 4-1 (continued)<br />
Material Test system Concentration Results References<br />
Micronucleus test with <strong>and</strong> without<br />
S9 activation<br />
HPRT test with <strong>and</strong> without S9<br />
activation<br />
3,5,5-Trimethyl-1-hexanol Ames assay (preincubation assay)<br />
with <strong>and</strong> without metabolic<br />
activation OECD TG 471, 472<br />
Chromosomal aberration <strong>and</strong><br />
polyploidy OECD TG 473<br />
Chinese hamster V79 fibroblast cells 0, 23, 45 mM Not genotoxic Kreja <strong>and</strong> Seidel (2002)<br />
Chinese hamster V79 fibroblast cells Up to 46 mM (highest non-toxic<br />
concentration)<br />
S. typhimurium TA98, TA100, TA1535,<br />
TA1537, E. coli WP2uvrA<br />
up to 500 lg/plate cytotoxicity:<br />
P150 lg/plate (±S9)<br />
Chinese hamster lung cells (CHL/IU) up to 100 lg/ml cytotoxicity:<br />
200 lg/ml<br />
Not mutagenic Kreja <strong>and</strong> Seidel (2002)<br />
Not mutagenic MHW, Japan (1997c) as cited<br />
in OECD/SIDS (2003)<br />
Not genotoxic MHW, Japan (1997d) as cited<br />
in OECD/SIDS (2003)<br />
Subgroup: secondary<br />
2,6-Dimethyl-4-heptanol Ames assay with <strong>and</strong> without S9<br />
activation (st<strong>and</strong>ard plate assay)<br />
2,6-Dimethylheptan-4-one Mitotic gene conversion assay with<br />
<strong>and</strong> without S9<br />
4-Hydroxy-4-methyl-2-<br />
pentanone<br />
Ames assay with <strong>and</strong> without S9<br />
activation (st<strong>and</strong>ard plate assay)<br />
Ames assay with <strong>and</strong> without S9<br />
activation (st<strong>and</strong>ard plate assay)<br />
S. typhimurium TA98, TA100, TA1537,<br />
TA1538, TA 1535, E.coli WP2uvrA<br />
3.33–1000 lg/plate with S9 mix in<br />
DMSO,<br />
1.00–500 lg/plate iwith S9 mix in<br />
DMSO, cytotoxic concentration:<br />
P333 lg/plate<br />
Saccharomyces cerevisiae 0.01–5.0 mg/ml, cytotoxicity at<br />
0.5 mg/ml with S9, at 5.0 without S9<br />
S. typhimurium TA98, TA100, TA1535,<br />
TA1537, TA 1538, E.coli WP2uvrA<br />
31.25-4000 lg/plate in DMSO,<br />
cytotoxic concentration: P500 lg/<br />
plate<br />
S. typhimurium n.f.i. 1–333 lg/plate, no cytotoxicity<br />
observed<br />
Cytogenetic assay Rat liver cell (RL4) 62.5–500 lg/ml, cytotoxicity at the<br />
highest dose level tested<br />
Ames assay with <strong>and</strong> without<br />
metabolic activation<br />
Chromosomal aberrations <strong>and</strong><br />
polyploidy OECD TG 473<br />
S. typhimurium TA98, TA100, TA1535,<br />
TA1537, E. coli WP2uvr A<br />
313–5000 lg/plate no cytotoxicity<br />
was observed<br />
Chinese hamster lung cells (CHL/IU) 300–1200 lg/ml no cytotoxicity<br />
observed at the highest concentration<br />
Not mutagenic Mecchi (2002) as cited in<br />
DOW (2003)<br />
Negative Mortelmans et al. (1986)<br />
Not mutagenic Brooks et al. (1985) as cited<br />
in OECD/SIDS (2004) Brooks<br />
et al. (1988)<br />
Not mutagenic Mortelmans et al. (1986)<br />
No increased incidence of<br />
chromosome aberrations<br />
Brooks et al. (1985) as cited<br />
in OECD/SIDS (2004) Brooks<br />
et al. (1988)<br />
Not mutagenic MHW, Japan (1997) as cited<br />
in OECD/SIDS (2007)<br />
polyploidy increase at 600 <strong>and</strong><br />
1200 lg/ml, without dosedependence<br />
not genotoxic<br />
MHW, Japan, 1997, as cited<br />
in OECD/SIDS (2007)<br />
4-Methyl-2-pentanone UDS n.f.i. n.f.i. Negative IPCS, 1990 as cited in<br />
OECD/SIDS (2004)<br />
Ames assay n.f.i. n.f.i. Negative IPCS (1990) as cited in<br />
OECD/SIDS (2004)<br />
Mouse lymphoma test n.f.i. n.f.i. Equivocal IPCS (1990) as cited in<br />
OECD/SIDS (2004)<br />
4-Methyl-2-pentanol Ames assay with <strong>and</strong> without S9<br />
activation<br />
3,4,5,6,6-<br />
Pentamethylheptan-2-ol<br />
(55–80%) <strong>and</strong> 3,4,5,6,6-<br />
pentamethylheptan-2-<br />
on (20–45%)<br />
Ames assay with <strong>and</strong> without<br />
metabolic activation<br />
Gene mutation with <strong>and</strong> without<br />
metabolic activation<br />
S. typhimurium TA98, TA100, TA1535,<br />
TA1537, TA1538, E. coli WP2uvr A<br />
S. typhimurium TA98, TA100, TA1535,<br />
TA1537, TA1538, E. coli WP2 uvr A<br />
pkm 101<br />
up to 5000 lg/plate cytotoxicity:<br />
5000 lg/plate (±S9)<br />
31.25–4000 lg/plate no cytotoxicity<br />
was observed<br />
Saccharomyces cerevisiae JD1 10–5000 lg/plate cytotoxicity:<br />
5000 lg/plate<br />
Cytogenetic assay Rat liver cell (RL4) 0, 0.5, 1, 2 mg/ml no cytotoxicity was<br />
observed<br />
Ames assay with <strong>and</strong> without<br />
metabolic activation (plate<br />
incorporation test)<br />
S. typhimurium TA98, TA100, TA1535,<br />
TA1537, TA1538, E. coli WP2 uvrA<br />
1. test: up to 1000 lg/plate<br />
2. test: up to 100 lg/plate<br />
cytotoxicity: P500 lg/plate<br />
Not mutagenic Shimizu et al. (1985)<br />
Not mutagenic Clare (1983) as cited in<br />
OECD/SIDS (2007)<br />
Not mutagenic Clare (1983) as cited in<br />
OECD/SIDS (2007)<br />
Negative Clare (1983) as cited in<br />
OECD/SIDS (2007)<br />
Not mutagenic RIFM (1985b)<br />
DMSO: dimethylsulfoxide, n.f.i.: no further in<strong>for</strong>mation, n.s.: not statistically significant.
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46 S23<br />
Table 4-2<br />
Mutagenicity <strong>and</strong> genotoxicity: in vivo studies.<br />
Material Test system Species (No./dose) Dose/Concentration Results References<br />
Subgroup: primary<br />
2-Ethyl-1-hexanol DNA binding in vivo by [ 14 C] labeled<br />
2-ethyl-1-hexanol; 16 h after the<br />
administration of the radiolabeled<br />
test substance: isolation of liver DNA<br />
<strong>and</strong> analyzing <strong>for</strong> radioactivity<br />
DNA binding in vivo by [ 14 C] labeled<br />
2-ethyl-1-hexanol, 24 h after the<br />
administration of the radiolabeled<br />
test substance: isolation of liver DNA<br />
<strong>and</strong> analyzing <strong>for</strong> radioactivity<br />
Bone marrow micronucleus assay,<br />
n.f.i.<br />
Cytogenetic assay with bone marrow<br />
cells<br />
2 Female Fischer 344 rats<br />
<strong>and</strong> 2 female NMRI mice<br />
Diet containing 1% di(2-ethylhexyl)<br />
phthalate (rat) or di(2-ethylhexyl) adipate<br />
(mouse) <strong>for</strong> 4 weeks; radiolabeled [ 14 C] 2-<br />
ethyl-1-hexanol was administered by<br />
gavage (rat: 51.1 or 53.4 mg/kg body<br />
weight; mouse: 120.2 or 109.5 mg/kg<br />
body weight)<br />
Male Fischer rat, n.f.i. Animals were fed a diet containing 1%<br />
di(2-ethylhexyl) phthalate <strong>for</strong> 11 days ad<br />
libitum. On day 10 they were given a<br />
single oral dose of 100 lCi [1- 14 C] 2-ethyl-<br />
1-hexanol <strong>and</strong> on day 11 they were<br />
sacrificed<br />
B6C3F1 mouse, n.f.i. Test protocol according to st<strong>and</strong>ard tests<br />
per<strong>for</strong>med by Litton Bionetics Inc., n.f.i.<br />
5 Fischer 344 rat/group Oral gavage <strong>for</strong> 5 consecutive days with<br />
0.02, 0.07, <strong>and</strong> 0.21 ml/kg body weight/<br />
day (17, 58, 174 mg/kg body weight/<br />
day) = up to 1/10 of the 5-day-LD50<br />
Dominant lethal test Male ICR/SIM mouse n.f.i. 250, 500, <strong>and</strong> 1000 mg/kg body weight/<br />
day (based on 5-day-LD50) <strong>for</strong> 5<br />
consecutive days, after treatment each<br />
male was housed with 2 virgin femals per<br />
week <strong>for</strong> 8 consecutive days, sacrifice of<br />
the females on days 14–17 of caging with<br />
the males; positive control:<br />
trimehtylenemelamine<br />
Isoamyl alcohol Micronucleus Test with bone marrow<br />
cells<br />
NMRI mice (5/sex/dose) 500, 1000, or 2000 mg/kg body weight/<br />
day<br />
No indication <strong>for</strong> a covalent binding<br />
of 2-ethyl-1-hexanol to liver DNA of<br />
rats or mice; most if not all<br />
radioactivity in liver DNA was due to<br />
biosynthetic incorporation<br />
No binding of the labeled test<br />
substance to liver DNA<br />
Däniken et al. (1984)<br />
Albro et al. (1982)<br />
Not genotoxic, n.f.i. Astill et al. (1986); Barber et al.<br />
(1985)<br />
No increase in chromatid <strong>and</strong><br />
chromosome breaks compared to the<br />
controls; mitotic index was not<br />
affected, no toxicity observed, no<br />
reliable negative result<br />
No dominant lethal mutations;<br />
fertility indices <strong>and</strong> average numbers<br />
of dead <strong>and</strong> total implants per<br />
pregnancy were within the normal<br />
range<br />
Putman et al. (1983)<br />
Rushbrook et al. (1982)<br />
Non-mutagenic RIFM (2008)<br />
Subgroup: secondary<br />
4-Methyl-2-pentanone Micronucleus test n.f.i. n.f.i. Negative IPCS (1990) as cited in OECD/<br />
SIDS (2004)<br />
3,4,5,6,6-<br />
Pentamethylheptan-2-ol<br />
Bone marrow micronucleus assay<br />
(i.p.), sacrified: 30, 48, 72 h after<br />
application<br />
Mouse (5/sex/dose) 0, 900 mg/kg body weight in corn oil Not genotoxic PCE/NCE reduced 48<br />
<strong>and</strong> 72 h after dosing<br />
RIFM (1985d)<br />
n.f.i.: no further in<strong>for</strong>mation, PCE: polychromatic erythrocytes, NCE: normochromatic erythrocytes.
S24<br />
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46<br />
5.5.2.2. Oral.<br />
5.5.2.2.1. Primary alcohols. Wistar rats were given a single dose<br />
of 6.25 or 12.5 mmol 2-ethyl-1-hexanol/kg body weight (833 or<br />
1666 mg/kg body weight) by gavage on day 12 of pregnancy, <strong>and</strong><br />
underwent caesarean section on day 20 of pregnancy. At the higher<br />
dose, 22.2% of the surviving fetuses had mal<strong>for</strong>mations (lower dose<br />
group 2% <strong>and</strong> controls 0%). These included hydronephrosis (7.8%),<br />
tail anomalies (4.9%), mal<strong>for</strong>med limbs (9.7%), <strong>and</strong> ‘‘others” (1%).<br />
In the higher dose group the average fetal weight was reduced.<br />
Implantation index, numbers of dead <strong>and</strong> resorbed fetuses were<br />
unaffected. Although the dose of 1666 mg/kg body weight is<br />
around half of the oral LD 50 , no maternal toxicity was reported<br />
(Ritter et al., 1987).<br />
Pregnant Sprague–Dawley rats (6/group) were gavaged with a<br />
single dose of 0, 6.25, 9.38, or 12.5 mmol 2-ethyl-1-hexanol/kg<br />
body weight (equivalent to 0, 813, 1219, <strong>and</strong> 1625 mg/kg body<br />
weight) in corn oil on gestation day 11.5, followed 8 h later by<br />
32 lCi 65 Zn <strong>and</strong> killed on gestation day 12.5. From 1219 mg/kg<br />
body weight the maternal food intake was reduced, maternal liver<br />
metallothionein <strong>and</strong> 65 Zn concentrations were higher, whereas in<br />
the embryos the 65 Zn content was lower than in animals which<br />
did not receive 2-ethyl-1-hexanol. The percentage of resorptions<br />
was not affected by the test substance (Bui et al., 1998).<br />
2-Ethyl-1-hexanol was administered daily by gavage to Wistar<br />
rats (10/group) from gestation days 6 to 19 at doses of 0, 1, 5, or<br />
10 mmol/kg body weight/day (equivalent to 0, 130, 650, <strong>and</strong><br />
1300 mg/kg body weight/day). At the lowest dose no maternal<br />
<strong>and</strong> fetal effects occurred. At 650 mg/kg body weight/day, fetus<br />
weights were significantly lower <strong>and</strong> the incidence of skeletal variations<br />
<strong>and</strong> retardations was increased. At 1300 mg/kg body<br />
weight/day maternal body weight measured on days 15 <strong>and</strong> 20<br />
was significantly reduced; clinical signs (salivation, CNS depression,<br />
nasal discharge) were observed, <strong>and</strong> 6 dams died. Postimplantation<br />
losses, resorptions, number, <strong>and</strong> percent of fetuses<br />
<strong>and</strong> litters with mal<strong>for</strong>mations <strong>and</strong> variations, <strong>and</strong> number <strong>and</strong><br />
percent of fetuses with retardations were increased. The fetal<br />
weight was decreased. The maternal <strong>and</strong> developmental NOAEL<br />
were 130 mg/kg body weight/day each (Hellwig <strong>and</strong> Jäckh, 1997).<br />
Groups of 28 CD-1 Swiss mice were given >99% pure 2-ethyl-1-<br />
hexanol microencapsulated in their diet at concentrations of 0%,<br />
0.009%, 0.03%, <strong>and</strong> 0.09% from days 0 to 17 of pregnancy. This corresponded<br />
to calculated doses of 0.13, 43, <strong>and</strong> 129 mg/kg body<br />
weight/day. No maternal toxicity was observed <strong>and</strong> the birth rate<br />
was 93–96% in all groups. All of the litters survived <strong>and</strong> all gestational<br />
parameters were normal. There were no external, visceral,<br />
or skeletal mal<strong>for</strong>mations <strong>and</strong> no increase in variations occurred.<br />
The authors concluded that 2-ethyl-1-hexanol plays essentially<br />
no role in the expression of DEHP-induced maternal <strong>and</strong> developmental<br />
toxicity (NTP, 1991; Price et al., 1991). As no toxic doses<br />
were reached, no conclusion on the potential of developmental<br />
toxicity of 2-ethyl-1-hexanol in mice can be drawn from this study.<br />
In a screening test, mice (Charles River CD-1) were given<br />
1525 mg 2-ethyl-1-hexanol/kg body weight/day by gavage from<br />
days 7 to 14 of pregnancy (50 animals treated <strong>and</strong> 50 controls).<br />
The dams <strong>and</strong> pups were observed until day 3 of lactation. Signs<br />
of toxicity in the dams included significantly reduced body weight<br />
<strong>and</strong> movement, ataxia, hypothermia, unkempt coats, <strong>and</strong> blood in<br />
the urine. Seventeen animals died of exposure-related causes. The<br />
number of live pups <strong>and</strong> their weight were significantly reduced<br />
(Hardin et al., 1987). A NOAEL cannot be deduced from this study.<br />
Twenty-five pregnant Wistar rats were gavaged with 0 (corn<br />
oil), 100, 500, or 1000 mg/kg body weight/day on gestation days<br />
6–15. The test material was a mixture of C7–9 branched alcohols,<br />
with isooctyl alcohol as the main component (CAS No. 68526-83-<br />
0). In the mid- <strong>and</strong> high-dose groups statistically significant increases<br />
in the number of lumbar ribs were observed. The authors<br />
state that, due to the lack of embryotoxicity these findings were<br />
attributed to maternal toxicity observed during treatment. However,<br />
in the 500 mg/kg body weight/day group no maternal toxicity<br />
was reported. In high-dosed dams emaciation, rales, hypoactivity,<br />
decreased food consumption, <strong>and</strong> body weight gain were observed.<br />
The total number of fetuses with skeletal variations <strong>and</strong> with hypoplastic<br />
skull bones was noted. These findings exceeded the historical<br />
control range of the laboratory but were not observed with<br />
litter-based analysis. The maternal NOAEL was set at 500 mg/kg<br />
body weight/day <strong>and</strong> the fetal NOAEL at 1000 mg/kg body<br />
weight/day (EBSI, 1994a, as cited in Nishimura et al., 1994). As increased<br />
incidences of lumbar ribs were seen from 500 mg/kg body<br />
weight/day at which dose no maternal toxicity was reported, the<br />
NOAEL <strong>for</strong> developmental toxicity should better be evaluated as<br />
100 mg/kg body weight/day.<br />
Two different isomeric mixes of isononyl alcohol (isononanol<br />
type 1 <strong>and</strong> isononanol type 2, CAS No. 68515-81-1 <strong>for</strong> both) <strong>and</strong><br />
isodecyl alcohol were administered by gavage to Wistar rats<br />
Table 5-1<br />
Carcinogenicity studies.<br />
Material Method Dose Species (No./dose) Results References<br />
Subgroup: primary<br />
2-Ethyl-1-hexanol<br />
Cell trans<strong>for</strong>mation<br />
assay with <strong>and</strong><br />
without metabolic<br />
activation<br />
Cell trans<strong>for</strong>mation,<br />
anchorage<br />
independence,<br />
without metabolic<br />
activation<br />
Oral (gavage),<br />
5 days/week,<br />
18 months<br />
Oral (gavage),<br />
5 days/w, 24 months<br />
96–180 nl/ml; survival:<br />
31.7–72% in the<br />
concomitant cytotoxicity<br />
test, positive control:<br />
cyclophosphamide<br />
4–77 10 7 mM, no<br />
in<strong>for</strong>mation on cytotoxicity<br />
0, 50, 200, 750 mg/kg body<br />
weight/day<br />
0, 50, 150, 500 mg/kg body<br />
weight/day<br />
BALB 3T3 cells Negative Barber et al. (1985) <strong>and</strong><br />
RIFM (1983b)<br />
JB6 cell line of<br />
mouse epidermis<br />
cells<br />
B6C3F1 mouse,<br />
50/sex/group<br />
F344 rat, 50/sex/<br />
group<br />
Negative Ward et al. (1986)<br />
750 mg/kg body weight/day:<br />
weak hepatocellular carcinoma<br />
increase (f), body weight gain<br />
decrease, mortality increase<br />
P150 mg/kg body weight/day:<br />
body weight gain decrease,<br />
lethargy, unkemptness 500 mg/<br />
kg body weight/day: mortality:<br />
52% f<br />
Astill et al. (1996b)<br />
Astill et al. (1996b)
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46 S25<br />
Table 6-1<br />
Reproductive <strong>and</strong> developmental toxicity studies - dermal.<br />
Material Method Concentration/dose Species (No./dose) Results References<br />
2-Ethyl-1-hexanol<br />
Occlusive, 6 h/day,<br />
on gestation days<br />
6–15, caesarean<br />
section at day 21<br />
Range-finding study: 0, 0.5, 1.0,<br />
2.0, <strong>and</strong> 3.0 ml/kg body weight/<br />
day (0, 420, 840, 1680, or<br />
2520 mg/kg body weight/day)<br />
Main study: 25/group 99.72%<br />
pure 0, 0.3, 1.0, <strong>and</strong> 3.0 ml/kg<br />
body weight/day (0, 252, 840, or<br />
2520 mg/kg body weight/day)<br />
F344 rats (range-finder:<br />
8 f/group; main study:<br />
25 f/group)<br />
NOAEL maternal toxicity: 252 mg/kg<br />
body weight/day based on skin<br />
irritation <strong>and</strong> 840 mg/kg body<br />
weight/day based on systemic<br />
toxicity NOAEL developmental<br />
toxicity: 2520 mg/kg body weight/<br />
day<br />
Maternal: P840 mg/kg body weight/<br />
day: Persistent exfoliation <strong>and</strong><br />
crusting <strong>and</strong> erythema at application<br />
site; maternal liver, kidney, thymus,<br />
spleen, adrenal, <strong>and</strong> uterine weights<br />
<strong>and</strong> gestational <strong>and</strong> fetal parameters<br />
were unaffected by treatment;<br />
P1680 mg/kg body weight/day:<br />
weight gain decrease<br />
Fetal: no treatment-related increases<br />
in incidence of individual or pooled<br />
external, visceral, or skeletal<br />
mal<strong>for</strong>mations or variations<br />
Deisinger et al. (1994);<br />
Tyl et al. (1992)<br />
(10/group) daily on gestation days 6–15. The doses <strong>for</strong> the isononyl<br />
alcohols were 0, 1, 5, 7.5, <strong>and</strong> 10 mmol/kg body weight/day (0, 144,<br />
720, 1080, <strong>and</strong> 1440 mg/kg body weight/day), <strong>for</strong> isodecyl alcohol<br />
0, 1, 5, <strong>and</strong> 10 mmol/kg body weight/day (0, 158, 790, <strong>and</strong><br />
1580 mg/kg body weight/day). Isononyl alcohol 1 mainly consists<br />
of dimethyl heptanols. Isononyl alcohol 2 mainly consists of dimethyl<br />
heptanols <strong>and</strong> methyl octanols. The test procedure was<br />
according to OECD TG 414 with the exception that 10 instead of<br />
20 animals per dose level were used. At the lowest dose of isononyl<br />
alcohol 1 there was an equivocal increase in the incidence of fetuses<br />
with hydroureter (11%, which was only slightly above the<br />
highest incidence of 4 control groups used in the study, 9.2%).<br />
The highest historical control incidence was reported to be 7.7%<br />
<strong>for</strong> studies conducted in the same time interval as the study under<br />
question. A clear dose–response was not seen. There<strong>for</strong>e, a substance-related<br />
effect is questionable. At the lowest dose of isononyl<br />
alcohol 2 no maternal <strong>and</strong> fetal toxicity was seen. At a dose of<br />
720 mg/kg body weight/day <strong>and</strong> more of isononyl alcohols 1 <strong>and</strong><br />
2, signs of maternal <strong>and</strong> developmental toxicity, including decreased<br />
body weight, increased resorption rates, <strong>and</strong> increased<br />
skeletal variations <strong>and</strong> retardations were observed. At doses of<br />
1080 mg/kg body weight/day <strong>and</strong> more the incidences of mal<strong>for</strong>mations<br />
were elevated. For isodecyl alcohol, maternal toxicity (reduced<br />
body weight gain <strong>and</strong> clinical signs) was evident at 790 mg/<br />
kg body weight/day <strong>and</strong> more. Developmental toxicity including<br />
reduced mean fetal body weight <strong>and</strong> skeletal retardations were observed<br />
only in the highest dose group. The maternal NOAEL <strong>for</strong><br />
isononyl alcohol 1 <strong>and</strong> isononyl alcohol 2 is 144 mg/kg body<br />
weight/day <strong>and</strong> <strong>for</strong> isodecyl alcohol 158 mg/kg body weight/day.<br />
The NOAEL <strong>for</strong> developmental toxicity <strong>for</strong> isononyl alcohol 1 <strong>and</strong><br />
2 is 144 mg/kg body weight/day <strong>and</strong> <strong>for</strong> isodecyl alcohol 790 mg/<br />
kg body weight/day. Isononyl <strong>and</strong> isodecyl alcohol are developmental<br />
toxins only at doses that produce maternal toxicity (Hellwig<br />
<strong>and</strong> Jäckh, 1997; RIFM, 1991a).<br />
In a combined repeated dose <strong>and</strong> reproductive/developmental<br />
toxicity screening test with gavage application of 3,5,5-trimethyl-<br />
1-hexanol (OECD TG 422) (see Section 5.2.1.1) the following results<br />
concerning developmental toxicity were observed: the number of<br />
pups born alive diminished in the 60 <strong>and</strong> 300 mg/kg body<br />
weight/day groups. In the high-dose group total litter loss was observed<br />
in two dams, the viability of neonates on day 4 of lactation<br />
was lower, <strong>and</strong> male <strong>and</strong> female pups showed lower body weights<br />
on day 0 of lactation (MHW, Japan, 1997b as cited in OECD/SIDS,<br />
2003). There<strong>for</strong>e, the NOAEL <strong>for</strong> systemic toxicity <strong>and</strong> developmental<br />
toxicity were considered 12 mg/kg body weight/day. Skeletal<br />
<strong>and</strong> visceral effects were not investigated in the pups.<br />
5.5.2.2.2. Secondary alcohols. In the combined repeated dose<br />
<strong>and</strong> reproductive/developmental toxicity screening test with gavage<br />
application of 4-hydroxy-4-methyl-2-pentanone [OECD TG<br />
422] (see Sections 5.2.1.1 <strong>and</strong> 5.5.2), a tendency <strong>for</strong> a decrease of<br />
developmental parameters was observed at the highest dose of<br />
1000 mg/kg body weight/day. These effects included the total<br />
number of pups born, delivery index, live birth index, number of<br />
pups alive <strong>and</strong> viability index on day 4 of lactation The NOAEL<br />
<strong>for</strong> developmental toxicity was 300 mg/kg body weight/day. The<br />
NOAEL <strong>for</strong> maternal toxicity was 100 mg/kg body weight/day<br />
(MHW, Japan 1997, as cited in OECD/SIDS, 2007). OECD TG 422<br />
does not provide <strong>for</strong> an evaluation of skeletal <strong>and</strong> visceral effects<br />
in pups.<br />
2,6-Dimethylheptan-4-one has been assessed in a reproduction/<br />
developmental toxicity screening test 20 rats (10/sex) were given<br />
0, 100, 300, or 1000 mg 2,6-dimethylheptan-4-one/kg body<br />
weight/day in corn oil by gavage from 2 weeks prior to mating<br />
throughout pregnancy until weaning day 5 post partum when<br />
the dams <strong>and</strong> offspring were sacrificed. Two dams at the top dose<br />
level died during lactation due to the test substance. There was no<br />
evidence of an effect on any of the reproductive parameters investigated<br />
or on any of the surviving litters. The NOAEL <strong>for</strong> developmental<br />
effects is the highest tested dose of 1000 mg 2,6-<br />
dimethylheptan-4-one/kg body weight/day, with a parental NOAEL<br />
of 300 mg/kg body weight/day (Shell HSE, 1996 as cited in OECD/<br />
SIDS, 2004). OECD TG 421 does not provide <strong>for</strong> an evaluation of<br />
skeletal <strong>and</strong> visceral effects in pups.<br />
5.5.2.2.3. Tertiary alcohols. No studies were available.<br />
5.5.2.3. Inhalation.<br />
5.5.2.3.1. Primary alcohols. Pregnant Wistar rats (20–25) were<br />
whole body exposed 6 h per day on gestation days 6–15 to 0,<br />
510, 2500, or 9800 mg isoamyl alcohol/m 3 (0, 138, 675, <strong>and</strong><br />
2646 ml/m 3 ). Body weight gain was decreased at the highest concentration<br />
between days 6 <strong>and</strong> 9 but there were no compound-related<br />
effects on conception rate, mean number of corpora lutea,<br />
implantation sites, pre- <strong>and</strong> post-implantation losses, <strong>and</strong> number<br />
of resorptions, viable fetuses, sex ratio, mean fetal, <strong>and</strong> placental<br />
weight. No external, visceral, or skeletal mal<strong>for</strong>mations were observed.<br />
The NOAEL <strong>for</strong> maternal toxicity was 2500 mg/m 3<br />
(675 ml/m 3 ) <strong>and</strong> the NOAEL <strong>for</strong> developmental toxicity 9800 mg/<br />
m 3 (2646 ml/m 3 ) (Klimisch <strong>and</strong> Hellwig, 1995).
S26<br />
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46<br />
Table 6-2<br />
Reproductive <strong>and</strong> developmental toxicity studies – oral.<br />
Material Method Concentration/dose Species (No./dose) Results References<br />
Subgroup: primary<br />
2-Ethyl-1-hexanol Gavage, 3 days/week, 3-day old males<br />
0, 167 mg/kg body<br />
weight/day<br />
Gavage, 5 days, 35-day 2.7 mmol/kg body<br />
old male rats<br />
weight/day (350 mg/kg<br />
body weight/day)<br />
Gavage on day 12 0 (untreated), 6.25 or<br />
Gavage, on gestation<br />
day 11.5; after 8 h<br />
intubated with 32 lCi<br />
65 Zn, killed on<br />
gestation day 12.5<br />
Gavage from days 6 to<br />
19 of pregnancy<br />
Days 0–17 of<br />
pregnancy<br />
12.5 mmol (833,<br />
1666 mg/kg body<br />
weight/day), undiluted<br />
0, 6.25, 9.38 or<br />
12.5 mmol 2-ethy-1-<br />
hexanol/kg body<br />
weight in corn oil<br />
(equivalent to 0, 813,<br />
1219, 1625 mg/kg body<br />
weight)<br />
0, 1, 5, <strong>and</strong> 10 mmol/kg<br />
body weight/day (0,<br />
130, 650, <strong>and</strong> 1300 mg/<br />
kg body weight/day)<br />
Diet: 0%, 0.009%, 0.03%,<br />
<strong>and</strong> 0.09%<br />
(microencapsulated)<br />
(0.13, 43 <strong>and</strong> 129 mg/<br />
kg body weight/day)<br />
>99% pure test<br />
substance<br />
CD Sprague–Dawley rats (4 m/group) No effect on Sertoli cells <strong>and</strong> gonocytes Li et al. (2000)<br />
Sprague–Dawley rats No testicular damage Sjoberg et al. (1986)<br />
Wistar rats (7 f/group) Maternal: no maternal toxicity was<br />
reported<br />
Fetal: 1666 mg/kg body weight/day: 22.2%<br />
of the surviving fetuses had<br />
mal<strong>for</strong>mations (lower dose group 2%,<br />
controls 0%). These included<br />
hydronephrosis (7.8%), tail anomalies<br />
(4.9%), mal<strong>for</strong>med limbs (9.7%) <strong>and</strong><br />
‘‘others” (1%); average fetal weight<br />
decreased<br />
Implantation index, average fetal weight,<br />
numbers of dead <strong>and</strong> resorbed fetuses<br />
were not affected<br />
Sprague–Dawley rats (6 f/group) Maternal: P1219 mg/kg body weight:<br />
maternal food intake decreased; 1625 mg/<br />
kg body weight: percentage of 65 Zn<br />
retained in maternal liver increase<br />
Fetal: the percentage of resorptions was<br />
not affected<br />
1625 mg/kg body weight: percentage of<br />
65 Zn retained in the embryos decreased<br />
Wistar rats (10 f/group) NOAEL maternal <strong>and</strong> developmental<br />
toxicity: 130 mg/kg body weight/day<br />
Maternal: P650 mg/kg body weight/day:<br />
1300 mg/kg body weight/day: body<br />
weight decreased; mortality increased<br />
Fetal: P650 mg/kg body weight/day:<br />
weight decreased, skeletal variations <strong>and</strong><br />
retardation increased<br />
1300 mg/kg body weight/day: postimplantation<br />
loss, resorptions, number<br />
<strong>and</strong> percent fetuses <strong>and</strong> litters with<br />
mal<strong>for</strong>mations <strong>and</strong> variations, <strong>and</strong><br />
number <strong>and</strong> percentage of fetuses with<br />
retardations increased; fetal weight<br />
decreased<br />
CD-1 Swiss mice (28 f/group) NOAEL maternal <strong>and</strong> developmental<br />
toxicity: 129 mg/kg body weight/day but<br />
no toxic dose tested<br />
No maternal toxicity; all of the litters<br />
survived <strong>and</strong> all gestational parameters<br />
were normal<br />
Ritter et al. (1987)<br />
Bui et al. (1998); Taubeneck et al.<br />
(1996)<br />
Hellwig <strong>and</strong> Jäckh (1997)<br />
NTP (1991) <strong>and</strong> Price et al. (1991)
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46 S27<br />
Isooctyl alcohol (C7–9<br />
alcohols, branched<br />
(CAS No. 68526-83-<br />
0))<br />
Isotridecan-1-ol<br />
(isomeric mixture)<br />
Isononyl alcohol<br />
(Isononanol type 1<br />
(CAS No. 68515-81-<br />
1))<br />
Gavage from days 7 to<br />
14 of pregnancy; the<br />
dams <strong>and</strong> pups were<br />
observed until day 3 of<br />
lactation<br />
0, 1525 mg/kg body<br />
weight/day in corn oil<br />
Gavage, days 6–15 p.c.,<br />
according to OECD TG<br />
414<br />
0, 100, 500, 1000 mg/<br />
kg body weight/day in<br />
corn oil<br />
Gavage, days 6–19 p.c. 0 (olive oil), 60, 250, or<br />
750<br />
Gavage, days 6–15 p.c.<br />
according to OECD TG<br />
414<br />
0 (control 1: water,<br />
control 2: water with<br />
0.005% Cremophor EL),<br />
1, 5, <strong>and</strong> 10 mmol/kg<br />
body weight/day (0,<br />
144, 720, <strong>and</strong> 1440 mg/<br />
kg body weight/day) in<br />
aqueous Cremophor EL<br />
Supplementary study:<br />
0 (control 1: water,<br />
control 2: water with<br />
0.005% Cremophor EL)<br />
<strong>and</strong> 7.5 mmol/kg body<br />
weight/day (0,<br />
1080 mg/kg body<br />
weight/day) because of<br />
mortality of all dams at<br />
10 mmol/kg (1440 mg/<br />
kg) body weight/day<br />
Charles River CD-1 mice (50 f/group) NOAEL <strong>for</strong> maternal/developmental<br />
toxicity cannot be derived<br />
Sprague–Dawley rat<br />
(25 f/group)<br />
Maternal: 1525 mg/kg/d: 17/49 died<br />
(controls 0), reduced movement, ataxia,<br />
hypothermia, unkempt coats <strong>and</strong> blood in<br />
the urine, body weight <strong>and</strong> fertility <strong>and</strong><br />
pregnancy index decrease<br />
Fetal: 1525 mg/kg/day: number of live<br />
pups <strong>and</strong> in their weight decrease. No<br />
further parameters were considered in<br />
this study<br />
NOAEL maternal toxicity: 500 mg/kg body<br />
weight/day<br />
NOAEL developmental toxicity: 100 mg/kg<br />
body weight/day<br />
Maternal: 1000 mg/kg: food consumption<br />
decreased, body weight gain from GD6–9<br />
<strong>and</strong> GD6–15 decreased, clinical signs<br />
(emaciation, rales, hypoactivity,<br />
abdominal/anogenital staining, little or no<br />
stool)<br />
Fetal: P500 mg/kg: number of lumbar ribs<br />
increased<br />
1000 mg/kg body weight/day: number of<br />
fetuses with skeletal variations increased,<br />
hypoplastic skull bones increased only on<br />
a per-fetus basis<br />
Hardin et al. (1987)<br />
Wistar rats (25/f/group) NOAEL <strong>for</strong> maternal toxicity: 250 mg/kg RIFM (2003b)<br />
NOAEL <strong>for</strong> developmental toxicity:<br />
750 mg/kg<br />
Maternal: 750 mg/kg: transient<br />
salivation;11% reduction of food<br />
consumption (6–10 p..c); increased<br />
alanine aminotransferase values;<br />
increased triglycerides (14%) <strong>and</strong> relative<br />
liver weights (18%); decreased total<br />
protein <strong>and</strong> globulin concentrations<br />
250 mg/kg: transient salivation<br />
Fetal: 750 mg/kg body weight/day: no<br />
effects<br />
Wistar rats (10 f/group) NOAEL <strong>for</strong> maternal toxicity: 144 mg/kg<br />
body weight/day NOAEL <strong>for</strong><br />
developmental toxicity: 144 mg/kg body<br />
weight/day<br />
EBSI (1994a) as cited in Exxon<br />
(2001a)<br />
Hellwig <strong>and</strong> Jäckh (1997) <strong>and</strong> EPA,<br />
1991<br />
Maternal: P720 mg/kg: food consumption<br />
(days 6–10 p.c.) decreased, clinical signs<br />
(apathy, nasal discharge)<br />
1080 mg/kg: severe maternal signs (n.f.i.),<br />
mortality (1/10)<br />
1440 mg/kg: mortality (10/10)<br />
Fetal: 144 mg/kg body weight/day: fetuses<br />
with hydroureter (8/73; 11.0%, control 1:<br />
0/68, control 2: 3/69, 4.3%), no further<br />
effects<br />
(continued on next page)
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D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46<br />
Table 6-2 (continued)<br />
Material Method Concentration/dose Species (No./dose) Results References<br />
Isodecyl alcohol Gavage, days 6–15 p.c.,<br />
according to OECD TG<br />
414 (10 instead of 20<br />
recommended<br />
animals/group)<br />
3,5,5-Trimethyl-1-<br />
hexanol<br />
Gavage, males:<br />
46 days, females: from<br />
14 days be<strong>for</strong>e mating<br />
to day 3 of lactation,<br />
OECD TG 422<br />
0, 1, 5, <strong>and</strong> 10 mmol/kg<br />
body weight/day (0,<br />
158, 790, <strong>and</strong> 1580 mg/<br />
kg body weight/day) in<br />
aqueous Cremophor EL<br />
0, 12, 60, 300 mg/kg<br />
body weight/day in<br />
olive oil<br />
720 mg/kg body weight/day: fetuses with<br />
hydroureter (8/67, 12.0%), fetal number<br />
decreased <strong>and</strong> % fetuses with skeletal<br />
variations <strong>and</strong> retardations increased<br />
1080 mg/kg: fetuses with hydroureter (3/<br />
37, 8.1%, control 1: 6/65, 9.2%, control 2: 2/<br />
58, 3.4%); mean uterine <strong>and</strong> fetal weights<br />
decreased, resorptions increased, postimplantation<br />
loss increased, number <strong>and</strong><br />
% fetuses <strong>and</strong> litters with mal<strong>for</strong>mations<br />
increased (mainly related to the heart),<br />
number <strong>and</strong> % fetuses with retardations<br />
increase, skeletal variation increase<br />
(rudimentary-cervical rib(s) increased<br />
(11/0 control 1, 11/1 control 2))<br />
1440 mg/kg body weight/day:<br />
examination of fetuses not possible<br />
because of maternal death<br />
Wistar rats (10 f/group) NOAEL maternal toxicity: 158 mg/kg body<br />
weight/day<br />
NOAEL developmental toxicity: 790 mg/<br />
kg body weight/day<br />
Maternal: P790 mg/kg: food consumption<br />
decreased, body weight on days 15 <strong>and</strong> 20<br />
decreased, clinical symptoms (nasal<br />
discharge, salivation, <strong>and</strong> CNS depression)<br />
1580 mg/kg: mortality increased<br />
Fetal: 1580 mg/kg: mean uterine <strong>and</strong> fetal<br />
weights decreased, resorptions increased,<br />
postimplantation loss increased, number<br />
<strong>and</strong> % fetuses with mal<strong>for</strong>mations <strong>and</strong><br />
retardations increased<br />
SD (Crj:CD) rat (12/sex/dose) NOAEL systemic toxicity males <strong>and</strong><br />
females: 12 mg/kg body weight/day<br />
NOAEL fertility: 12 mg/kg body weight/<br />
day (females)<br />
300 mg/kg body weight/day (males)<br />
NOAEL developmental toxicity: 12 mg/kg<br />
body weight<br />
Parental: P12 mg/kg body weight/day:<br />
renal hyaline droplets, eosinophilic bodies<br />
(m)<br />
P60 mg/kg body weight/day: rel. liver<br />
weight increase (m,f), abs. <strong>and</strong> rel. kidney<br />
weight increase (m), pale discoloration of<br />
kidneys (m), renal tubular epithelial<br />
regeneration (m), <strong>for</strong>mation of granular<br />
casts in kidney (m), renal epithelial fatty<br />
change (f); implantation index decrease (f)<br />
300 mg/kg body weight/day: 1 f died, 3 f<br />
killed (weakness); body weights increase<br />
(m), food consumption increase (m), body<br />
weights decrease (f), food consumption<br />
decrease (f); urine volume increase (m),<br />
water consumption increase (m); red<br />
blood cell counts decrease (m), hematocrit<br />
Hellwig <strong>and</strong> Jäckh (1997)<br />
MHW, Japan (1997b) as cited in<br />
OECD/SIDS (2003)
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46 S29<br />
decrease (m), hemoglobin decrease (m),<br />
BUN decrease (m), chloride decrease (m)<br />
abs. liver weight increase (m,f), rel. kidney<br />
weight increase (f), swelling of kidney (m),<br />
yellowish white discoloration of liver (f),<br />
irregularity in shape of follicles (m),<br />
columnar change of follicular epithelium<br />
(m), thyroid colloid decrease (m), thymus<br />
atrophy (f); total litter loss in 2 dams<br />
Fetal: P60 mg/kg body weight/day:<br />
decreased pups born alive<br />
300 mg/kg body weight/day: viability of<br />
neonates on day 4 of lactation decreased,<br />
body weights of male <strong>and</strong> female pups ?<br />
decreased<br />
Subgroup: secondary<br />
2,6-Dimethylheptan-4-<br />
one<br />
4-Hydroxy-4-methyl-2-<br />
pentanone<br />
Gavage, from 2 weeks<br />
prior to mating<br />
throughout pregnancy<br />
until weaning day 5<br />
post partum (OECD TG<br />
421)<br />
OECD TG 422<br />
(screening test): males:<br />
44 days, females: from<br />
14 days be<strong>for</strong>e mating<br />
to day 3 of lactation<br />
0 (vehicle), 100, 300,<br />
1000 mg/kg body<br />
weight/day in corn oil<br />
0, 30, 100, 300,<br />
1000 mg/kg body<br />
weight/day in water<br />
Alpk:ApfsSD rats (10/sex/group) NOAEL parental systemic toxicity:<br />
300 mg/kg body weight/day<br />
NOAEL developmental/reproductive<br />
effects: 1000 mg/kg body weight/day<br />
Maternal: 1000 mg/kg body weight/day:<br />
two dams died during lactation,<br />
attributable to the test substance. There<br />
was no effect on the number of<br />
pregnancies, positive smears, litters born,<br />
number of implantations or proportion of<br />
pups born live in any dose group<br />
Paternal: 1000 mg/kg body weight/day:<br />
male body weight gains decrease<br />
No changes in organ weight <strong>and</strong> no<br />
significant histopathological changes in<br />
the male or female reproductive organs;<br />
no evidence of an effect on any of the<br />
reproductive parameters investigated or<br />
on any of the surviving litters<br />
Crj:CD(SD) rat (10/sex/dose) NOAEL parental systemic toxicity:<br />
100 mg/kg body weight/day<br />
NOAEL <strong>for</strong> fertility <strong>and</strong> developmental<br />
toxicity: 300 mg/kg body weight/day<br />
Parental: tendency <strong>for</strong> lower reproductive<br />
indices (fertility <strong>and</strong> implants) (n.f.i.)<br />
Fetal:1000 mg/kg body weight/day:<br />
tendency <strong>for</strong> decrease of the following<br />
parameters: total number of pups born,<br />
delivery index, live birth index, number of<br />
pups alive, viability index on day 4 of<br />
lactation (n.f.i.)<br />
f: female, m: male, n.f.i.: no further in<strong>for</strong>mation, n.s.: not statistically significant, p.c.: post coitum<br />
Shell HSE (1996) as cited in OECD/<br />
SIDS (2003)<br />
MHW, Japan (1997) as cited in OECD/<br />
SIDS (2007)
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D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46<br />
Table 6-3<br />
Reproductive <strong>and</strong> developmental toxicity studies – inhalation.<br />
Material Method Concentration/dose Species (No./dose) Results References<br />
Subgroup: primary<br />
2-Ethyl-1-hexanol Whole body exposure from day 0<br />
to 19 of pregnancy<br />
Isoamyl alcohol Inhalation, days 6 through GD15,<br />
6 h/day, caesarean section on<br />
day 20 GD, OECD TG 414<br />
Inhalation, days 7 through 19 pi,<br />
6 h/day, caesarean section on<br />
day 29 pi OECD TG 414<br />
0, 850 mg/m 3 (160 ml/m 3 )<br />
the maximum vapor<br />
concentration that could<br />
be achieved without<br />
increasing exposure<br />
chamber temperature<br />
above 80°F<br />
0, 510, 2500, 9800 mg/m 3<br />
(0, 138, 675, 2646 ml/m 3 )<br />
0, 510, 2510, 9800 mg/m 3<br />
(0, 138, 678, 2646 ml/m 3 )<br />
Sprague–Dawley rats<br />
(15 f/group)<br />
Wistar female rat<br />
(20–25 f/group)<br />
Himalayan female<br />
rabbit (15 f/group)<br />
NOAEL 160 ml/m 3 Nelson et al. (1989)<br />
Maternal: 160 ml/m 3 : no maternal toxicity<br />
Fetal: 160 ml/m 3 : no significant differences in<br />
corpora lutea per litter, resorptions per litter,<br />
numbers of females or males per litter, or fetal<br />
weight of females or males, <strong>and</strong> no external,<br />
visceral, or skeletal mal<strong>for</strong>mations<br />
NOAEL maternal toxicity: 675 ml/m 3 Klimisch <strong>and</strong> Hellwig (1995)<br />
NOAEL developmental toxicity: 2646 ml/m 3 RIFM (1990a)<br />
Maternal: 2646 ml/m 3 : body weight gain (days 6–<br />
9)decreased; no test substance-related clinical signs<br />
Fetal: no litter parameters affected; no gross<br />
external, soft tissue, or skeletal fetal alterations<br />
NOAEL maternal toxicity: 678 ml/m 3 Klimisch <strong>and</strong> Hellwig (1995)<br />
NOAEL developmental toxicity: 2646 ml/m 3 RIFM (1990b)<br />
Maternal: 2646 ml/m 3 : body weight gain (days 7–<br />
10) decreased; eye irritation (redness, lid closure,<br />
slight discharge)<br />
Fetal: no litter parameters affected; no gross<br />
external, soft tissue, or skeletal fetal alterations<br />
Subgroup: secondary<br />
4-Methyl-2-pentanone Inhalation Two-generation study, exposure 0, 500, 1000, or<br />
2000 ml/m 3 (0, 2050,<br />
4090, or 8180 mg/m 3 )<br />
6 h/day, 7 days/w (30/sex/group)<br />
Sprague–Dawley rat NOAEL systemic toxicity: 1000 ml/m 3 (excluding<br />
male nephropathy)<br />
NOAEL reproductive toxicity: 2000 ml/m 3<br />
duration (F 0 ,F 1 ): F 0 adults: P500 ml/m 3 : centrilobular hepatocellular<br />
hypertrophy only in males, abs./rel. kidney weights<br />
Males: 70 d prior to end through<br />
increase (m)<br />
mating period<br />
Females: 70 d prior to mating to<br />
day 20 of gestation, resumed at<br />
5 days of lactation<br />
US EPA OPPTS Guideline 870-<br />
3800<br />
1000 ml/m 3 : nephropathy (basophilic tubules with<br />
inflammation <strong>and</strong> thickening of the tubular<br />
basement membrane) (m), sedative effect (absent<br />
or reduced reaction to auditory startle stimulus<br />
(normalized 1 h after end of exposure))<br />
2000 ml/m 3 : body weight gain decrease (f); abs.<br />
<strong>and</strong> rel. liver weights increase (m,f)<br />
Nemec et al. (2004)
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46 S31<br />
Inhalation, days 6–15 p.c.,<br />
6 h/day, duration of study:<br />
21 days, according to OECD TG<br />
414<br />
Inhalation, days 6–15 p.c.,<br />
6 h/day, duration of study:<br />
18 days, according to OECD TG<br />
414<br />
0 (air), 300, 1000,<br />
3000 ml/m 3 (0, 1230,<br />
4090, 123,000 mg/m 3 )<br />
0 (air), 300, 1000,<br />
3000 ml/m 3 (0, 1230,<br />
4090, 123,000 mg/m 3 )<br />
Fischer 344 rat<br />
(35 f/group)<br />
F 1 adults: P500 ml/m 3 : kidney changes (alpha-2uglobulin<br />
nephropathy) (m)<br />
P1000 ml/m 3 : sedative effect (s.a.) (m),<br />
centrilobular hepatocellular hypertrophy (m)<br />
2000 ml/m 3 : absent or reduced reaction to auditory<br />
startle stimulus (ameliorated 1 h after end of<br />
exposure) (f); 1 m died on PND 22, clinical signs of<br />
neurotoxicity (i.e., rocking, prostration, half-closed<br />
eyelids) approx. 1 h post-exposure (PND<br />
22) ) exposures <strong>for</strong> all groups of F1 weanlings<br />
suspended through PND 27; body weight gain<br />
(transient) decrease (m,f); abs. <strong>and</strong> rel. liver<br />
weights increase (m, f), centrilobular hepatocellular<br />
hypertrophy (m)<br />
F1/F2 Offspring: reproductive parameters unaffected<br />
NOAEL maternal toxicity: 1000 ml/m 3 Tyl et al. (1987)<br />
NOAEL developmental toxicity: 1000 ml/m 3<br />
Maternal: 3000 ml/m 3 : neuromuscular effects (e.g.<br />
loss of coordination, paresis); body weight <strong>and</strong> body<br />
weight gain decreased, food consumption<br />
decreased, rel. kidney weights increased<br />
Fetal: 3000 ml/m 3 : body weight per litter decreased,<br />
skeletal ossification retarded, unilateral<br />
rudimentary rib at the first lumbar arch increased<br />
CD-1 mice (30 f/group) NOAEL maternal toxicity: 1000 ml/m 3 Tyl et al., (1987)<br />
NOAEL developmental toxicity: 1000 ml/m 3<br />
Maternal: 3000 ml/m 3 : 3 dams died on GD 6;<br />
neuromuscular effects, abs. <strong>and</strong> rel. liver weights<br />
increased<br />
Fetal: 3000 ml/m 3 : body weight per litter decreased,<br />
number of dead fetuses increased, visceral<br />
variations (dilated lateral ventricles of the<br />
cerebrum <strong>and</strong> dilated renal blood vessels)<br />
increased, skeletal variations (vertebrae, sternbrae,<br />
<strong>and</strong> distal limbs) increased, skeletal ossification<br />
retarded<br />
DEHP: di(2-ethylhexyl) phthalate, f: female, GD: gestation day, m: male, s.a.: see above, n.f.i.: no further in<strong>for</strong>mation, MEHP: mono(2-ethylhexyl) phthalate, n.s.: not statistically significant, p.c.: post-coitum, pi: post-insemination.<br />
4-Methyl-2-pentanone is not a fragrance material, but is structurally related.
S32<br />
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46<br />
The same test procedure was per<strong>for</strong>med with 14–15 pregnant<br />
Himalayan rabbits. The animals were exposed to 0, 510, 2510, or<br />
9800 mg isoamyl alcohol/m 3 (0, 138, 678, <strong>and</strong> 2646 ml/m 3 ) from<br />
day 7 to day 19 post-insemination. In dams exposed to the highest<br />
concentration body weight gain was decreased between days 7 <strong>and</strong><br />
10 post insemination <strong>and</strong> irritant eye effects (reddish, lid closure,<br />
<strong>and</strong> slight discharge) were noted. Histopathological examination<br />
of the dams revealed no substance-related effects. The reproduction<br />
parameters (e.g. mean number of corpora lutea, implantation<br />
sites, values calculated <strong>for</strong> the pre- <strong>and</strong> post-implantation losses,<br />
<strong>and</strong> number of resorptions) <strong>and</strong> mal<strong>for</strong>mations (external, visceral,<br />
or skeletal) were within the levels of the concurrent control group<br />
or of historical control groups. The maternal NOAEL was 2500 mg/<br />
m 3 (678 ml/m 3 ) <strong>and</strong> the NOAEL <strong>for</strong> developmental toxicity was<br />
9800 mg/m 3 (2646 ml/m 3 ) (Klimisch <strong>and</strong> Hellwig, 1995).<br />
Fifteen pregnant Sprague–Dawley rats were exposed (whole<br />
body) 7 h per day on gestation days 0–19 to 850 mg 2-ethyl-1-hexanol/m<br />
3 (160 ml/m 3 ), the maximum vapor concentration that<br />
could be achieved without increasing exposure chamber temperature<br />
above 80 ° F. After caesarean section on day 20, one-half of the<br />
fetuses were examined <strong>for</strong> skeletal mal<strong>for</strong>mations, the other half<br />
<strong>for</strong> visceral mal<strong>for</strong>mations. Aside from a decrease in feed consumption<br />
in dams compared to control, there were no significant differences<br />
in maternal, reproductive, or developmental parameters<br />
(Nelson et al., 1989). The NOAEL <strong>for</strong> maternal <strong>and</strong> developmental<br />
toxicity was 850 mg/m 3 (160 ml/m 3 ).<br />
5.5.2.3.2. Secondary alcohols. Thirty-five pregnant Fischer 344<br />
rats or 30 pregnant CD-1 mice were exposed 6 h per day on gestation<br />
days 6–15 to 0, 300, 1000, <strong>and</strong> 3000 ml 4-methyl-2-pentanone/<br />
m 3 (0, 1230, 4090, <strong>and</strong> 12,300 mg/m 3 ). Maternal toxicity (neuromuscular<br />
effects, e.g. loss of coordination or paresis) was observed<br />
in both species after exposure to the highest concentration. Rat<br />
dams showed reductions in body weights, body weight gain, <strong>and</strong><br />
food consumption. The relative kidney weights were elevated. In<br />
mice, three dams died at the first exposure <strong>and</strong> the relative <strong>and</strong><br />
absolute liver weights were increased. Reduced fetal body weight<br />
per litter <strong>and</strong> delayed skeletal ossification was observed in both<br />
species at the highest concentration. Rat fetuses showed an increased<br />
incidence of unilateral rudimentary rib at the first lumbar<br />
arch. In mice, the number of dead fetuses as well as visceral <strong>and</strong><br />
skeletal variations was increased. The NOAELs <strong>for</strong> maternal <strong>and</strong> fetal<br />
toxicity were 1000 ml/m 3 <strong>for</strong> both species (Tyl et al., 1987 as cited<br />
in OECD/SIDS, 2007).<br />
5.5.2.3.3. Tertiary alcohols. No studies were available.<br />
5.6. Skin irritation<br />
5.6.1. Human studies<br />
Seven alcohols with saturated branched chain under review<br />
with a worldwide use of greater than 0.01 tons per year have been<br />
well studied <strong>for</strong> their potential to produce dermal irritation in humans<br />
(see Table 7-1).<br />
The following substances did not induce skin irritation in pretests<br />
<strong>for</strong> a maximization study with single occlusive application<br />
<strong>for</strong> 48 h with the highest concentrations tested, i.e., 20% 3,6-dimethyl-3-octanol<br />
(RIFM, 1972a, 1973c), 10% 3,7-dimethyl-7-methoxyoctan-2-ol<br />
(RIFM, 1982b), 10% 2,6-dimethyl-2-heptanol (RIFM,<br />
1976b, 1983a), 8% isoamyl alcohol (RIFM, 1976b), 8% 3,5,5-trimethyl-1-hexanol<br />
(RIFM, 1977b), <strong>and</strong> 4% 2-ethyl-1-hexanol (RIFM,<br />
1976c).<br />
No irritation was observed with 2% 2,6-dimethyl-2-heptanol<br />
during the induction phase of a human repeat insult patch test<br />
(HRIPT) in 10 healthy male <strong>and</strong> female volunteers (RIFM, 1969).<br />
The repeated application of 15% 3,4,5,6,6-pentamethylheptan-2-<br />
ol during the induction phase of a HRIPT led to erythema (6 grade<br />
1 of 4, 4 grade 2 of 4) in 5 of 51 volunteers (RIFM, 1983c).<br />
A patch test (5 min under occlusion) was conducted on 12<br />
healthy volunteers <strong>and</strong> with 3 or 12 subjects of oriental ancestry<br />
with a 75% aqueous solution of isoamyl alcohol. Irritation reactions<br />
were observed in all volunteers (Wilkin <strong>and</strong> Fortner, 1985a,b; Wilkin<br />
<strong>and</strong> Stewart, 1987).<br />
Further details on studies of dermal irritation in humans are<br />
provided in Table 7-1.<br />
5.6.2. Animal studies<br />
Twelve of the alcohols under review with a worldwide use of<br />
greater than 0.01 tons per year have been tested in animal models<br />
of skin irritation using rabbits, rats, or guinea pigs. Studies with<br />
single application are summarized in Table 7-2-1 <strong>and</strong> studies with<br />
repeated application are shown in Table 7-2-2.<br />
A single application of neat 3,4,5,6,6-pentamethylheptan-2-ol<br />
did not produce dermal irritation in rabbits (RIFM, 1984b) <strong>and</strong> rats<br />
(RIFM, 1985a). If applied undiluted as a single application, 2-ethyl-<br />
1-butanol, 2-ethyl-1-hexanol, isoamyl alcohol, 2-methylbutanol,<br />
3,5,5-trimethyl-1-hexanol, 2,6-dimethyl-4-heptanol, 4-methyl-2-<br />
pentanol, 2,6-dimethyl-2-heptanol, <strong>and</strong> 3,6-dimethyl-3-octanol<br />
(McOmie <strong>and</strong> Anderson, 1949; RIFM, 1973a, 1976a, 1977a; Scala<br />
<strong>and</strong> Burtis, 1973; Cornu et al., 1992, 1984, 1978) led to slight or<br />
moderate irritation in all studies with rabbits irrespectively of<br />
the method used. As an exception undiluted 2,6-dimethyl-2-heptanol<br />
was strongly irritating after 24 h occlusive application (RIFM,<br />
1979a). The diluted substances led to no or only slight effects in<br />
rabbits or guinea pigs: 3,6-dimethyl-3-octanol 15% no to slight<br />
reactions (RIFM, 1970), 2,6-dimethyl-2-heptanol 10% no reaction<br />
(RIFM, 1981a), 3,7-dimethyl-7-methoxyoctan-2-ol 1% slight reaction<br />
(RIFM, 1973e).<br />
Five percent 3,7-dimethyl-7-methoxyoctan-2-ol did not produce<br />
dermal irritation in guinea pigs after repeated application<br />
(RIFM, 1973d). Repeated application of neat 2-ethyl-1-hexanol<br />
led to slight dermal irritation in rats (Schmidt et al., 1973). Moderate<br />
or strong irritation was observed after repeated applications of<br />
undiluted 2,6-dimethyl-4-heptanol, 4-methyl-2-pentanol, <strong>and</strong><br />
3,4,5,6,6-pentamethylheptan-2-ol (also diluted) in rabbits (McOmie<br />
<strong>and</strong> Anderson, 1949; RIFM, 1985c, 1986a). Toxicity studies<br />
with repeated dermal application (see Section 5.2.1) also showed<br />
dermal irritation especially with 3,4,5,6,6-pentamethylheptan-2-<br />
ol. These studies were per<strong>for</strong>med with high doses under occlusion<br />
<strong>and</strong> are there<strong>for</strong>e not representative of human exposure.<br />
5.7. Mucous membrane irritation<br />
5.7.1. Sensory irritation<br />
5.7.1.1. Human data. The results of the human irritation studies are<br />
summarized in Table 8.<br />
Human male volunteers (with <strong>and</strong> without self-reported multiple<br />
chemical sensitivity) were exposed to 2-ethyl-1-hexanol by<br />
inhalation <strong>for</strong> 4 h (exposure chamber). Fluctuating concentrations<br />
(time weighted average concentrations: 1.5 (control), 10, <strong>and</strong><br />
20 ml/m 3 ) were used in the first experiment, <strong>and</strong> similar but constant<br />
vapor concentrations in a second experiment. Olfactory- <strong>and</strong><br />
trigeminal-mediated symptoms <strong>and</strong> intensities of odor, eye, <strong>and</strong><br />
nasal irritation were recorded. Self-reported nasal <strong>and</strong> eye irritation<br />
<strong>and</strong> perceived odor intensity were increased <strong>and</strong> concentration-related<br />
at concentrations of 10 ml/m 3 or more. Self-reported<br />
chemical sensitivity had only minor effects on chemosensory<br />
symptoms in the second experiment (constant concentrations)<br />
<strong>and</strong> no effect on intensity ratings in either experiment (van Thriel<br />
et al., 2005).<br />
An average of 12 subjects were exposed by inhalation to 2,6-dimethyl-4-heptanol<br />
<strong>for</strong> 15 min. At 5 ml/m 3 or more, eye irritation<br />
was observed, <strong>and</strong> at 10 ml/m 3 nose <strong>and</strong> throat irritation. The sensory<br />
response limit was reported to be less than 5 ml/m 3 (Silver-
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46 S33<br />
man et al., 1946). In the same study 4-methyl-2-pentanol led to<br />
eye irritation at 50 ml/m 3 <strong>and</strong> higher concentrations resulted in<br />
nose <strong>and</strong> throat irritation. The NOEL was 25 ml/m 3 (Silverman<br />
et al., 1946).<br />
5.7.1.2. Animal data. Sensory irritation was evaluated in 4 Swiss<br />
male mice via measurement of changes in respiratory rate during<br />
a 10-min exposure to isoamyl alcohol. The concentration of isoamyl<br />
alcohol that caused a 50% decrease in the respiratory rate<br />
(RD 50 ) of mice was 4452 ml/m 3 with 95% confidence limits of<br />
2885–12,459 ml/m 3 (Kane et al., 1980). Another study reported a<br />
RD 50 value of 2624 mg/m 3 (729 ml/m 3 ) (Korpi et al., 1999).<br />
After a 5-min exposure to 4-methyl-2-pentanol the RD 50 <strong>for</strong><br />
mice was 420 ml/m 3 (6 animals/group) (Muller <strong>and</strong> Greff, 1984<br />
as cited in Greim, 2002).<br />
5.7.2. Eye irritation<br />
No human studies on eye irritation are available. An overview of<br />
in vivo studies on eye irritation in rabbits can be found in Table 9.<br />
Several in vitro tests to investigate the eye irritation potential<br />
did show an irritating effect of 2-ethyl-1-hexanol (Adriaens <strong>and</strong><br />
Remon, 2002; Adriaens et al., 2005; Casterton et al., 1996; Gautheron<br />
et al., 1994; Gilleron et al., 1997; Goethem et al., 2006; Kennah<br />
et al., 1989a).<br />
For 3,7-dimethyl-7-methoxyoctan-2-ol only one study with a<br />
1% solution in propylene glycol was available, in which the substance<br />
did not cause irritating effects (RIFM, 1973e).<br />
In 4 of 5 studies, isotridecan-1-ol (isomeric mixture) elicited no<br />
eye irritation in rabbits (Greim, 2000). Further in<strong>for</strong>mation about<br />
the test method <strong>and</strong> the concentration were not given. The undiluted<br />
substance was moderately irritating to the rabbit eye in<br />
one study (Greim, 2000; Scala <strong>and</strong> Burtis, 1973).<br />
Undiluted 3,6-dimethyl-3-octanol was evaluated as an eye irritant.<br />
The substance led to redness <strong>and</strong> chemosis of the conjunctiva,<br />
slight corneal opacity, <strong>and</strong> swelling of the iris. The effects were not<br />
reversible within 3 days (RIFM, 1970).<br />
In three studies undiluted 2-ethyl-1-hexanol was moderately<br />
irritating to the rabbit eye (Carpenter <strong>and</strong> Smyth, 1946; Schmidt<br />
et al., 1973; Smyth et al., 1969). Observed effects were conjunctival<br />
redness <strong>and</strong> swelling, lacrimation, <strong>and</strong> discharge. The effects did<br />
not clear within 96 h. Corneal effects were not found (Schmidt<br />
et al., 1973). In three other studies, the undiluted substance was<br />
classified as a severe eye irritant (Kennah et al., 1989b; RIFM,<br />
1978b; Scala <strong>and</strong> Burtis, 1973). These studies resulted in dullness<br />
<strong>and</strong> vascularization of the cornea (Scala <strong>and</strong> Burtis, 1973). The corneal<br />
effects were persistent (RIFM, 1978b). In addition, iritis, conjunctival<br />
erythema, chemosis, <strong>and</strong> discharge appeared (Scala <strong>and</strong><br />
Burtis, 1973).<br />
Undiluted 2,6-dimethyl-2-heptanol, 2,6-dimethyl-4-heptanol,<br />
4-methyl-2-pentanol, <strong>and</strong> 3,4,5,6,6-pentamethylheptan-2-ol were<br />
moderate eye irritants (McOmie <strong>and</strong> Anderson, 1949; RIFM,<br />
1979a, 1984c; Smyth et al., 1951). The substances caused conjunctivitis<br />
with edema <strong>and</strong> corneal injury. The effects disappeared<br />
within 7 days (McOmie <strong>and</strong> Anderson, 1949; RIFM, 1984c) except<br />
<strong>for</strong> those caused by 2,6-dimethyl-2-heptanol (RIFM, 1979a).<br />
Undiluted 2-ethyl-1-butanol, isoamyl alcohol, <strong>and</strong> 2-methylbutanol<br />
were highly irritating to the rabbit eye (Smyth et al., 1954,<br />
1962, 1969).<br />
5.8. Skin sensitization<br />
5.8.1. Human studies<br />
Seven of the alcohols under review with a worldwide use of<br />
greater than 0.01 tons per year have been evaluated <strong>for</strong> their potential<br />
to induce sensitization in humans (see Tables 10-1 <strong>and</strong><br />
10-2).<br />
In both subgroups of primary <strong>and</strong> secondary alcohols no evidence<br />
of a sensitizing effect in a maximization test or in a human<br />
repeated insult patch test (HRIPT) with volunteers was observed<br />
with 4% 2-ethyl-1-hexanol (RIFM, 1976c), 8% isoamyl alcohol<br />
(RIFM, 1976b), 8% 3,5,5-trimethyl-1-hexanol (RIFM, 1977b), 10%<br />
3,7-dimethyl-7-methoxyoctan-2-ol (RIFM, 1982b), <strong>and</strong> 15%<br />
3,4,5,6,6-pentamethylheptan-2-ol (RIFM, 1983c). In the subgroup<br />
of tertiary alcohols 2,6-dimethyl-2-heptanol did not induce positive<br />
reactions in a maximization test (10%, RIFM, 1976b) or a HRIPT<br />
(2%, RIFM, 1969). In a maximization test with 20% 3,6-dimethyl-3-<br />
octanol in petrolatum (RIFM, 1972a), 4 of 25 volunteers exhibited<br />
positive reactions 24 <strong>and</strong> 48 h after challenge. However, since<br />
these four subjects also reacted strongly to a control material it<br />
was concluded that the reactions observed were due to a ‘‘spill<br />
over” effect from the other material. In a second test with 10% in<br />
petrolatum, the positive reactions could not be confirmed (RIFM,<br />
1973c).<br />
With a sub-irritating concentration (no further in<strong>for</strong>mation) of<br />
3,7-dimethyl-7-methoxyoctan-2-ol in petrolatum, 0.9% positive<br />
reactions (2 patients) were found in patch tests with 218 patients<br />
with proven sensitization to fragrance materials (Table 10-2; Larsen<br />
et al., 2002).<br />
5.8.2. Animal studies<br />
Results of available animal studies are shown in Table 10-3. In<br />
comparison to humans, limited data on sensitization in animals<br />
are available. Only one secondary <strong>and</strong> one tertiary alcohol were<br />
tested.<br />
2,6-Dimethyl-2-heptanol was negative in guinea pigs at a concentration<br />
of 10% (Watanabe et al., 1988). No delayed-type hypersensitivity<br />
was observed <strong>for</strong> 3,7-dimethyl-7-methoxyoctan-2-ol in<br />
the same species (RIFM, 1973d).<br />
5.9. Phototoxicity <strong>and</strong> photoallergenicity<br />
Limited data were available with regard to the phototoxicity<br />
<strong>and</strong> photoallergenicity of the alcohols with saturated branched<br />
chain (see Table 11). From human or animal studies reliable data<br />
were available only on the phototoxicity <strong>and</strong> photoallergenicity<br />
of the tertiary alcohol 2,6-dimethyl-2-heptanol.<br />
No phototoxic reactions were observed in 6 healthy female volunteers<br />
exposed to 10% 2,6-dimethyl-2-heptanol in 1:1 ethanol/<br />
acetone, followed by irradiation by UVA (RIFM, 1983a).<br />
In the only animal phototoxicity study, 10% 2,6-dimethyl-2-<br />
heptanol in ethanol produced no phototoxic reactions after UVA<br />
or UVB irradiation in guinea pigs (RIFM, 1981a).<br />
No studies have been per<strong>for</strong>med which investigate the photoallergic<br />
potential in humans.<br />
2,6-Dimethyl-2-heptanol was tested <strong>for</strong> its photoallergenicity<br />
in a reliable test with guinea pigs (RIFM, 1981b). No photoallergenicity<br />
was seen in the animals induced with 10% in rectified alcohol,<br />
followed by irradiation with UVB <strong>and</strong> UVA (9 times in 18 days),<br />
<strong>and</strong> challenged after a 10-day rest with 10% of the test substance in<br />
rectified alcohol <strong>and</strong> irradiation.<br />
As the alcohols under review do not contain double bonds, they<br />
cannot absorb UVA or UVB light. Indeed, UV spectra have been<br />
obtained <strong>for</strong> 12 materials (2-ethyl-1-hexanol, isoamyl alcohol,<br />
isotridecan-1-ol (isomeric mixture), 2-methylbutanol, 3-methyl-<br />
1-pentanol, 2-methylundecanol, 3,5,5-trimethyl-1-hexanol, 2,6-dimethyl-4-heptanol,<br />
3,7-dimethyl-7-methoxyoctan-2-ol, 6,8-dimethylnonan-2-ol,<br />
3,4,5,6,6-pentamethylheptan-2-ol, <strong>and</strong> 2,6-<br />
dimethyl-2-heptanol). Five materials did not absorb UV light, the<br />
remaining 5 peaked in the UVC range (
S34<br />
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46<br />
Table 7-1<br />
Skin irritation studies in humans.<br />
Material Method Concentration Subjects Results References<br />
Subgroup: primary<br />
2-Ethyl-1-hexanol 48 h, occlusive (pretest<br />
<strong>for</strong> a maximization<br />
study)<br />
Isoamyl alcohol 48 h, occlusive (pretest<br />
<strong>for</strong> a maximization<br />
study)<br />
3-Methyl-1-pentanol 24 h, occlusive (pretest<br />
<strong>for</strong> a HRIPT)<br />
4% in petrolatum 29 healthy male volunteers No irritation RIFM (1976c)<br />
8% in petrolatum 25 healthy volunteers No irritation RIFM (1976b)<br />
5 min, occlusive 75% in water 12 volunteers Irritation in all 12<br />
volunteers<br />
5 min, occlusive 75% in water 12 volunteers (oriental) Irritation in all 12<br />
volunteers<br />
5 min, occlusive 75% in water 3 volunteers (oriental) Irritation in all 3<br />
volunteers<br />
3,5,5-Trimethyl-1-hexanol 48 h, occlusive (pretest<br />
<strong>for</strong> a maximization<br />
study)<br />
0.5% in alcohol SDA 39 C 41 healthy volunteers Little or no irritation RIFM (1973f)<br />
Wilkin <strong>and</strong> Stewart (1987)<br />
8%, in petrolatum 25 healthy volunteers No irritation RIFM (1977b)<br />
Wilkin <strong>and</strong> Fortner (1985a)<br />
Wilkin <strong>and</strong> Fortner (1985b)<br />
Subgroup: secondary<br />
3,7-Dimethyl-7-methoxyoctan-2-ol 48 h, occlusive (pretest<br />
<strong>for</strong> a maximization<br />
study)<br />
3,4,5,6,6-Pentamethylheptan-2-ol During the induction<br />
phase of a repeated<br />
insult patch test<br />
(HRIPT): 9 applications<br />
with a duration of 24 h<br />
within a 3-week<br />
period, occlusive,<br />
0.2 ml, observations on<br />
the application days<br />
10%, petrolatum 27 healthy male <strong>and</strong> female volunteers No irritation RIFM (1982b)<br />
15% v/v solution in ethanol SDA 39C (99%) 51 healthy male <strong>and</strong> female volunteers 10/48 positive<br />
reactions: 5 grade 1<br />
reactions (erythema<br />
confined to the contact<br />
site <strong>and</strong> exceeding that<br />
of the untreated skin)<br />
<strong>and</strong> 5 grade 2 reactions<br />
(erythema confined to<br />
the contact site <strong>and</strong><br />
definitely exceeding<br />
that of the untreated<br />
skin; papules may or<br />
may not be present)<br />
RIFM (1983c)<br />
Subgroup: tertiary<br />
2,6-Dimethyl-2-heptanol 48 h, occlusive (pretest<br />
<strong>for</strong> a maximization<br />
study)<br />
0.025 ml/2 cm 2 ,<br />
occlusive, up to 72 h<br />
Induction phase of<br />
HRIPT<br />
3,6-Dimethyl-3-octanol a 48 h, occlusive (pretest<br />
<strong>for</strong> a maximization<br />
study)<br />
48 h, occlusive (pretest<br />
<strong>for</strong> a maximization<br />
study)<br />
3-Methyloctan-3-ol a 48 h, occlusive (pretest<br />
<strong>for</strong> a maximization<br />
study)<br />
10% in petrolatum 25 healthy volunteers No irritation RIFM (1976b)<br />
10% in 1:1 ethanol/acetone 6 healthy female volunteers No irritation RIFM (1983a)<br />
2% in dimethyl phthalate 10 healthy male <strong>and</strong> female volunteers No irritation RIFM (1969)<br />
10% in petrolatum 5 healthy male volunteers No irritation RIFM (1973c)<br />
20% in petrolatum 5 healthy male volunteers No irritation RIFM (1972a)<br />
10% in petrolatum 29 healthy volunteers No irritation RIFM (1978a)<br />
a<br />
No relevant use was reported.
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46 S35<br />
Table 7-2-1<br />
Skin irritation studies in animals, single application.<br />
Material Method Concentration Species Results References<br />
Subgroup: primary<br />
2-Ethyl-1-butanol 24 h, uncovered, 0.01 ml sample on<br />
the clipped skin<br />
Undiluted Rabbit (n = 5) An average reaction to a trace of capillary injection Smyth et al. (1954)<br />
2-Ethyl-1-hexanol 5000 mg/kg, n.f.i. Undiluted Rabbit (n = 10) Moderate redness <strong>and</strong> edema in 10/10 RIFM (1977a)<br />
Rabbit (n = 5) Moderate irritation observed Smyth et al. (1969)<br />
24 h, uncovered, 0.01 ml sample on<br />
the clipped skin<br />
24 h, occlusive, 0.1, 0.316, 1.0,<br />
3.16 mg/kg body weight, on the<br />
clipped intact skin, observations daily<br />
up to 7 days<br />
Undiluted or as a solution in water,<br />
propylene glycol or acetone<br />
Undiluted Rabbit (n = 4) Moderate irritation: moderate erythema, moderate<br />
edema, atonia, blanching, desquamation,<br />
coriaceousness, necrosis, <strong>and</strong> eschar<br />
Scala <strong>and</strong> Burtis (1973)<br />
Isoamyl alcohol Single application of 5.0 g/kg Undiluted Rabbit (n = 10) Marked erythema <strong>and</strong> moderate edema RIFM (1976a)<br />
Single application Undiluted Rabbit (n = 6) Very irritating RIFM (1979c)<br />
isotridecan-1-ol (mixed<br />
isomers)<br />
24 h, uncovered, 0.01 ml sample on<br />
the clipped skin<br />
Single occlusive patch <strong>for</strong> 24 h to<br />
intact skin of 4 rabbits<br />
Single uncovered application of<br />
0.01 ml <strong>for</strong> 24 h<br />
Percutaneously to the intact dorsal<br />
skin <strong>for</strong> 20 h<br />
Undiluted or as a solution in water,<br />
propylene glycol or acetone<br />
Rabbit (n = 5) Irritation was observed Smyth et al. (1969)<br />
Undiluted Rabbits Moderately irritating Scala <strong>and</strong> Burtis (1973)<br />
Undiluted Rabbits Moderately irritating Smyth et al. (1962)<br />
Undiluted Rabbits Severe erythema <strong>and</strong> distinct edema at 24 h distinct<br />
scarring <strong>and</strong> severe scaling at 8 days<br />
4-h semi-occlusive irritation Undiluted Rabbits Slight to marked erythema, slight or moderate<br />
edema <strong>and</strong> scaling<br />
2-Methylbutanol 24 h, uncovered, 0.01 ml sample on<br />
the clipped skin<br />
Undiluted Rabbit (n = 5) Irritation defined as the least visible capillary<br />
injection from the undiluted material<br />
RIFM (1963d,e)<br />
RIFM (2003a)<br />
Smyth et al. (1962)<br />
n.f.i. Undiluted Rabbit (n = 2) Moderately irritating RIFM (1979b)<br />
3-Methyl-1-pentanol 0.5 ml application, 24 h contact, 0.5% in alcohol SDA 39C Rabbit (n = 3) No erythema <strong>and</strong> edema observed RIFM (1972c)<br />
observed again at 48 h<br />
3,5,5-Trimethyl-1-hexanol 5000 mg/kg body weight, n.f.i. Undiluted Rabbit (n = 10) Redness: mild: 2/10, moderate: 4/10, severe: 4/10; edema: mild: 1/10, moderate: 9/10, severe: 0/10<br />
RIFM (1977a)<br />
Subgroup: secondary<br />
2,6-Dimethyl-4-heptanol Neat application as part ofl LD 50 Undiluted Rabbit (n = 5) No irritation Smyth et al. (1949)<br />
4 h, semi-occlusive, 3.9-9.4 ml/kg body weight on the shaved skin<br />
Undiluted Rabbit (n = 5) 2/5 some erythema <strong>and</strong> slight edema McOmie <strong>and</strong> Anderson<br />
(1949)<br />
3,7-Dimethyl-7-<br />
methoxyoctan-2-ol<br />
24 h, occlusive, 0.5 ml, abraded <strong>and</strong><br />
intact skin, observations after 24,<br />
72 h<br />
1% in propylene glycol Rabbit (n = 6) Mildly irritating, PII 0.5, 5/6 very slight erythema in<br />
the intact <strong>and</strong> abraded sites after 24 h, 1/6 very<br />
slight erythema in the intact <strong>and</strong> abraded sites after<br />
72 h<br />
4-Methyl-2-pentanol Details of the method not reported Concentration <strong>and</strong> vehicle not reported Rabbit, n.f.i. 2/10 defined as an average reaction equivalent to a<br />
trace of capillary injection<br />
3,4,5,6,6-<br />
Pentamethylheptan-2-ol<br />
0.25 h, observation period of 10 days,<br />
n.f.i.<br />
7 applications (5 h) to the intact skin<br />
<strong>for</strong> 21 days<br />
4 h, occlusive, 0.5 ml, clipped skin,<br />
observations at 24, 48, 72 h<br />
24 h, occlusive, 2000 mg/kg body<br />
weight, observations at 24 h, <strong>and</strong><br />
daily <strong>for</strong> 14 days<br />
Undiluted Rabbit (n = 3) Immediate slight erythema <strong>and</strong> delayed moderate<br />
erythema with drying of surface<br />
Undiluted Rabbits (n = 2) Erythema, flaking, <strong>and</strong> cracking of the skin with<br />
bleeding fissures by the 7th exposure<br />
RIFM (1973e)<br />
Smyth et al. (1951)<br />
McOmie <strong>and</strong> Anderson<br />
(1949)<br />
McOmie <strong>and</strong> Anderson<br />
(1949)<br />
Undiluted Rabbit (n = 6) No irritation RIFM (1984b)<br />
Undiluted Rats (n = 5/sex) No irritation RIFM (1985a)<br />
Subgroup: tertiary<br />
2,6-Dimethyl-2-heptanol 5000 mg/kg body weight, n.f.i. Undiluted Rabbit (n = 10) 2/10 slight redness, 8/10 moderate redness, 1/10<br />
slight edema, 9/10 moderate edema<br />
RIFM (1976a)<br />
(continued on next page)
S36<br />
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46<br />
the UV spectra <strong>and</strong> review of phototoxic/photoallergy data, the<br />
materials in this group would not be expected to elicit phototoxicity<br />
or photoallergy under the current conditions of use as a fragrance<br />
ingredient.<br />
Table 7-2-1 (continued)<br />
Material Method Concentration Species Results References<br />
RIFM (1979a)<br />
Undiluted Rabbit (n = 6) PII 5.1, strongly irritating, after 24 h on intact skin:<br />
6/6 strong redness, 5/6 slight edema, 1/6 strong<br />
edema, slight redness already after 5 min reversible<br />
within 8 days, redness after 24 h application not<br />
reversible within 8 days<br />
1, 5, 15 min, 2, 20 h, intact <strong>and</strong><br />
abraded skin, observations after 24 h,<br />
48 h, 8 days; (Federal Register 38, No.<br />
187, § 1500.41, S. 27019, 27. Sept.<br />
1973)<br />
No irritation RIFM (1981a)<br />
10% in ethanol Albino guinea-pig<br />
(n =8)<br />
4 h, patch test, observations after 4 h,<br />
24 h, 48 h (control of a phototoxicity<br />
study)<br />
RIFM (1973a)<br />
3,6-Dimethyl-3-octanol a 5000 mg/kg body weight, n.f.i. Undiluted Rabbit (n = 8) 8/8: slight redness, 3/8: slight edema, 4/8:<br />
moderate edema<br />
RIFM (1970)<br />
Undiluted, 15% in distilled water Rabbit (n = 6) Undiluted PII: 3.4, very slight to moderate/severe<br />
erythema, very slight to slight edema, no<br />
observations were made after 3 days; 15% PII: 2.0,<br />
very slight to well-defined erythema no edema to<br />
very slight edema, 3/6 animals were not entirely<br />
recovered within 7 days a score of 5 or more is<br />
regarded as signifying a primary skin irritant<br />
24 h, occlusive, 0.5 ml, intact <strong>and</strong><br />
abraded skin, observations at 24, 48,<br />
72 h<br />
RIFM (1978c)<br />
3-Methyloctan-3-ol a 5000 mg/kg body weight Undiluted Rabbit (n = 10) 4/10: slight redness, 4/10: moderate redness, 2/10:<br />
slight edema, 8/10: moderate edema<br />
n.f.i.: no further in<strong>for</strong>mation, PII: primary irritation index.<br />
a<br />
No relevant use was reported.<br />
5.10. Miscellaneous studies<br />
To address hepatotoxicity, several miscellaneous studies were<br />
conducted. Ex vivo studies on the mechanism of hepatotoxicity<br />
were conducted with 2-ethyl-1-hexanol, 2-methylbutanol, <strong>and</strong><br />
isoamyl alcohol, in vitro enzyme induction <strong>and</strong> peroxisome proliferation<br />
studies were conducted with 2-ethyl-1-hexanol <strong>and</strong> isoamyl<br />
alcohol <strong>and</strong> in vivo repeated dose toxicity studies with 2-<br />
ethyl-1-hexanol, isoamyl alcohol, isodecyl alcohol, isononyl alcohol,<br />
isooctane-1-ol (isomeric mixture) <strong>and</strong> 3,5,5-trimethyl-1-hexanol<br />
were per<strong>for</strong>med. These studies are not summarized here but<br />
may be found in detail in individual <strong>Fragrance</strong> Material Reviews<br />
(McGinty et al., 2010a,b,c,d,e,f,g,h,i,j,k,l,m,n,o,p,q). The data show<br />
that 2-ethyl-1-hexanol is a peroxisome proliferator <strong>and</strong> that 2-<br />
ethyl-1-hexanol, 2-methylbutanol, <strong>and</strong> isoamyl alcohol induce liver<br />
enzymes.<br />
6. Conclusion<br />
The compounds assessed in this group have a close structural<br />
relationship, similar metabolism, <strong>and</strong> toxicity profiles.<br />
Data on metabolism <strong>for</strong> the compounds under review are available<br />
only <strong>for</strong> the primary alcohols 2-ethyl-1-butanol, 2-ethyl-1-<br />
hexanol, isoamyl alcohol, 2-methylbutanol, <strong>and</strong> <strong>for</strong> the secondary<br />
alcohol 4-methyl-2-pentanol.<br />
The major pathways of metabolism <strong>and</strong> fate which are common<br />
to the primary, secondary <strong>and</strong> tertiary alcohols in this group are:<br />
– conjugation of the alcohol group with glucuronic acid;<br />
– oxidation of the alcohol group;<br />
– side-chain oxidation yielding polar metabolites, which may be<br />
conjugated <strong>and</strong> excreted – or further oxidation to an aldehyde,<br />
a carboxylic acid, <strong>and</strong> to CO 2 ;<br />
– excretion of the unchanged parent compound.<br />
In most cases metabolism yields innocuous substances, which<br />
are excreted in the urine <strong>and</strong> feces.<br />
Because there is insufficient in<strong>for</strong>mation <strong>for</strong> many of the 20<br />
alcohols with saturated branched chain under review, the database<br />
is supplemented with studies of 3 metabolites of these alcohols.<br />
The Panel is of the opinion that there are no safety concerns<br />
regarding alcohols branched chain saturated under the present declared<br />
levels of use <strong>and</strong> exposure. These materials have not been<br />
evaluated at levels other than reported in this group summary.<br />
Use of these materials at higher maximum dermal levels or higher<br />
systemic exposure levels requires re-evaluation by the Panel. This<br />
conclusion was based on the following reasons:<br />
No, or only minimal, evidence of skin irritation in humans was<br />
caused by 6 compounds tested at concentrations of 2–10%. Due<br />
to the structural similarities, compounds not tested <strong>for</strong> skin irritation<br />
in humans are expected to show similar properties with<br />
respect to this endpoint. There<strong>for</strong>e, the alcohols under review pose<br />
no concern provided concentrations in end products are in the<br />
range of 2–10%, which is above the current concentrations of use.<br />
The 11 materials evaluated <strong>for</strong> eye irritation showed that the<br />
undiluted materials cause moderate to severe eye irritation.<br />
However, since these materials are not used undiluted they<br />
pose no concern <strong>for</strong> eye irritation at the concentrations currently<br />
in use in end products (0.001–1.7%).
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46 S37<br />
Table 7-2-2<br />
Skin irritation studies in animals, repeated application.<br />
Material Method Concentration Species Results References<br />
Subgroup: primary<br />
2-Ethyl-1-hexanol 12 applications, over a period of 12 days, uncovered,<br />
2 ml/kg body weight/day on the shaved skin,<br />
observations daily<br />
Undiluted Rat (n = 10) After 10 days slight redness <strong>and</strong> scabbing Schmidt et al.<br />
(1973)<br />
Subgroup: secondary<br />
2,6-Dimethyl-4-heptanol 7 applications, 5–12 h duration over a period of 15–<br />
21 days, uncovered, 3.0 ml/kg on 100 cm 2 ,<br />
nonabraded skin, observations daily<br />
3,7-Dimethyl-7-methoxyoctan-2-ol 10 applications, 24 h duration on alternate days<br />
during a 3-week period, occlusive, 0.2 ml, shaved<br />
skin, observations<br />
4-Methyl-2-pentanol 5 applications, 5–12 h duration over a period of 15–<br />
21 days, uncovered, 3.0 ml/kg on 100 cm 2 ,<br />
nonabraded skin, observations daily<br />
3,4,5,6,6-Pentamethylheptan-2-ol 9–28 applications, 6 h duration over a period of<br />
28 days, occlusive, nonabraded <strong>and</strong> clipped skin,<br />
observations daily<br />
Daily applications <strong>for</strong> 6 h, duration over 28 days,<br />
occlusive, 1000 mg/kg body weight/dayay,<br />
nonabraded skin, observations daily<br />
Undiluted Rabbit (n = 2) definite erythema after 2nd exposure; areas of flaking<br />
after 4th exposure; cracking of skin, fissures with some<br />
bleeding after 7th exposure<br />
2.5, 5% in water,<br />
applications 1–7:<br />
5%, applications<br />
8–10: 2.5%<br />
Guinea pig (n = 10) No irritation, isolated occurences of slight erythema<br />
during the treatment period<br />
Undiluted Rabbit (n = 3) Severe drying of the skin with some sloughing <strong>and</strong><br />
cracking<br />
Undiluted, 1.5%,<br />
5%, 15%, 50%<br />
dissolved in 1%<br />
w/v aqueous<br />
methylcellulose<br />
(ca. 30, 100, 300,<br />
1000 mg/kg body<br />
weight/dayay)<br />
Rabbit (n = 10/sex) P30 mg/kg body weight/dayay: erythema <strong>and</strong> edema<br />
increased dose-dependently; P300 mg/kg body weight/<br />
dayay: after 9 treatments the treatment was terminated<br />
as a result of irritation<br />
Undiluted Rabbit (n = 13/sex) Severe <strong>and</strong> persistent irritation: dermal irritation<br />
progressed rapidly in all animals to well defined to<br />
moderate erythema <strong>and</strong> edema within one week;<br />
irritation progressed further in several rabbits becoming<br />
severe within 2 weeks of treatment, scab <strong>for</strong>mation<br />
McOmie <strong>and</strong><br />
Anderson (1949)<br />
RIFM (1973d)<br />
McOmie <strong>and</strong><br />
Anderson (1949)<br />
RIFM (1986a)<br />
RIFM (1985c)
S38<br />
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46<br />
Table 8<br />
Sensory irritation studies in humans<br />
Clinical signs References<br />
Material Dose route No. subjects/<br />
concentration<br />
group<br />
van Thriel et al. (2005)<br />
P10 ml/m 3 : self-reported nasal <strong>and</strong> eye irritation<br />
<strong>and</strong> perceived odor intensity increase; no difference<br />
between subjects with <strong>and</strong> without sMCS<br />
Constant concentrations:<br />
7 males without <strong>and</strong><br />
12 males with sMCS<br />
Subgroup: primary<br />
2-Ethyl-1-hexanol Inhalation, exposure, 4 h: constant concentrations:<br />
(1.5, 10, 20 ml/m 3 ) or fluctuating concentrations<br />
(time-weighted average 1.5, 10, 20 ml/m 3 )<br />
Subgroup: secondary<br />
2,6-Dimethyl-4-heptanol Inhalation, exposure <strong>for</strong> 15 min 12 Eye irritation at 5 <strong>and</strong> 10 ml/m 3 , nose <strong>and</strong> throat<br />
irritation at 10 ml/m 3<br />
4-Methyl-2-pentanol Inhalation exposure <strong>for</strong> 15 min 12 Eye irritation at 50 ml/m 3 , nose <strong>and</strong> throat<br />
irritation >50 ml/m 3<br />
sMCS: self-reported multiple chemical sensitivity.<br />
These materials have no or low sensitizing potential. Available<br />
data <strong>for</strong> five of the substances show that they do not possess a<br />
sensitization potential. However, <strong>for</strong> 3,6-dimethyl-3-octanol, a<br />
low sensitization potential in humans cannot be excluded. Saturated<br />
alcohols do not <strong>for</strong>m hydroperoxides. They oxidize <strong>and</strong><br />
become aldehydes or ketones. The use of these materials under<br />
the declared levels of use <strong>and</strong> exposure will not induce sensitization.<br />
For those individuals who are already sensitized, there is a<br />
possibility that an elicitation reaction may occur. The relationship<br />
between the no effect level <strong>for</strong> induction <strong>and</strong> the no effect<br />
level <strong>for</strong> elicitation is not known <strong>for</strong> this group of materials.<br />
Based on the lack of structures, which could absorb UVA or UVB<br />
light, <strong>and</strong> review of phototoxic/photoallergy data, the alcohols<br />
with saturated branch chains would not be expected to elicit<br />
phototoxicity or photoallergy under the current conditions of<br />
use as a fragrance ingredient.<br />
The 15 compounds tested have a low order of acute toxicity.<br />
The seven branched chain saturated alcohols <strong>and</strong> three of their<br />
metabolites (see Tables in Section 5.2) tested were of low systemic<br />
toxicity after repeated application. Changes indicative of<br />
enzyme induction in the liver (liver enlargement), peroxisome<br />
proliferation <strong>and</strong> alpha-2u-nephropathy in male rats have been<br />
observed at doses of 60 mg/kg body weight/day <strong>and</strong> more. The<br />
lowest NOAEL of all the subacute <strong>and</strong> sub-chronic oral studies<br />
available, which were per<strong>for</strong>med with five of the substances<br />
under review <strong>and</strong> the metabolite 4-hydroxy-4-methyl-2-pentanone,<br />
is 10 mg/kg body weight/day <strong>for</strong> 3,5,5-trimethyl-1-hexanol.<br />
This value is taken as representative <strong>for</strong> all members of<br />
the group as a worst-case. The database does not allow a definite<br />
conclusion that the toxicity after dermal application is<br />
lower than after oral application by gavage (oral bolus dose<br />
vs. slow uptake via the skin). However, at least 3,4,5,6,6-pentamethylheptan-2-ol<br />
had a much higher systemic NOAEL of<br />
1000 mg/kg body weight/day in a subacute dermal study compared<br />
to the lowest oral NOAEL of 10 mg/kg body weight/day<br />
mentioned above. Several subacute <strong>and</strong> subchronic inhalation<br />
studies showed a lowest NOAEL of 120 ml/m 3 <strong>for</strong> 2-ethyl-1-<br />
hexanol corresponding to a dose of 175 mg/kg body weight/<br />
day, assuming a body weight of 261 g, a minute volume of<br />
0.2 l <strong>for</strong> a rat (Bide et al., 2000) <strong>and</strong> 100% retention. Comparing<br />
the oral worst-case NOAEL of 10 mg/kg body weight/day to the<br />
worst-case daily uptake of 0.14 mg/kg body weight/day which<br />
was estimated <strong>for</strong> 3,4,5,6,6-pentamethylheptan-2-ol (100% dermal<br />
absorption assumed as worst-case) the margin of safety is<br />
70 (100% oral absorption is assumed as shown with 2-ethyl-1-<br />
hexanol). For the other compounds <strong>for</strong> which systemic uptake<br />
in consumers (Table 1) has been estimated by RIFM, the margin<br />
of safety is between 90 <strong>and</strong> 50,000. There is an adequate margin<br />
of safety <strong>for</strong> the alcohols under review when applied in consumer<br />
products at the current concentrations.<br />
With 3,5,5-trimethyl-1-hexanol adverse effects on reproduction<br />
were noted at a rather low oral dose (60 mg/kg body weight/<br />
day) with a NOAEL of about 10 mg/kg body weight/day. For this<br />
compound the estimated systemic dose is 0.0036 mg/kg body<br />
weight <strong>for</strong> consumers (Table 1), leading to a margin of safety<br />
of 2700. 2-Ethyl-1-hexanol induced fetotoxic <strong>and</strong> teratogenic<br />
effects at high doses of 1300 mg/kg body weight/day in rats,<br />
however, none of the group members tested induced adverse<br />
effects on fertility <strong>and</strong> development at doses or concentrations<br />
that were not toxic to the parental animals. It should be noted<br />
that in a dermal study with 2-ethyl-1-hexanol no adverse<br />
effects on development in rats were seen with the highest dose<br />
of 2520 mg/kg body weight indicating, that dermal exposure is<br />
less effective in producing adverse effects than oral exposure<br />
most probably due to the different pharmacokinetic behavior<br />
<strong>for</strong> both application routes.
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46 S39<br />
Table 9<br />
Eye irritation studies in rabbits.<br />
Material Method Results References<br />
Subgroup: primary<br />
2-Ethyl-1-butanol Single application, undiluted or diluted in water of<br />
propylene glycol, grading after 18–24 h, n.f.i.<br />
2-Ethyl-1-hexanol Single application of 0.005 ml, undiluted, grading after<br />
18–24 h, n.f.i.<br />
Single application, one drop, undiluted, 50%, 25%, 12.5%<br />
solutions in oil, observations up to 96 h, one rabbit per<br />
concentration<br />
Single application of 0.1 ml, undiluted, observations<br />
after 1, 4, <strong>and</strong> 24 h, 2, 3, 4, <strong>and</strong> 7 days, 6 rabbits<br />
Single application of 0.1 ml, undiluted, observations<br />
after 24, 48, <strong>and</strong> 72 h, 6 rabbits<br />
Single application of 0.1 ml, undiluted <strong>and</strong> solution in<br />
propylene glycol or water: 110, 14, <strong>and</strong> 21 days, 6<br />
rabbits<br />
Produced an injury of necrosis to 63–87% of the eye Smyth et al. (1954)<br />
Severe burn Carpenter <strong>and</strong> Smyth (1946)<br />
Conjunctival redness <strong>and</strong> swelling, lacrimation,<br />
discharge, no effects on the cornea<br />
Undiluted test substance: effects not reversible within<br />
96 h<br />
Smyth et al. (1969)<br />
Schmidt et al. (1973)<br />
12.5% no effect<br />
Severe eye irritant Scala <strong>and</strong> Burtis (1973)<br />
Median scores after 24, 72 h, <strong>and</strong> 7 days: 19, 20, 0<br />
(Draize scores)<br />
Corneal dullness, opacity (widespread corneal opacity),<br />
<strong>and</strong> vascularization, irititis, conjunctival erythema,<br />
chemosis, <strong>and</strong> discharge<br />
Persistent corneal effects RIFM (1978b)<br />
Draize scores<br />
24 h: cornea: 17.5, iris: 2.5, conjunctivae: 7.0<br />
48 h: cornea: 10.8, iris: 0.8, conjunctivae: 7.0<br />
72 h: cornea: 7.5, iris: 0.8, conjunctivae: 5.3<br />
Draize scores Kennah et al. (1989b)<br />
100% solution: 51 (severe), 30%: 35 (severe/moderate),<br />
10%: 39 (moderate), 3%: 30 (moderate), 1%: 9 (mild)<br />
Corneal swelling in % of control:<br />
100% solution: 192%; 30%: 190%; 10%: 162%; 3%: 151%;<br />
1%: 94%<br />
Isoamyl alcohol Single application, undiluted or solution in water or<br />
propylene glycol, n.f.i.<br />
Severe burn Smyth et al. (1969)<br />
RIFM (1979c)<br />
Isotridecan-1-ol (isomeric mixture) Single application, undiluted <strong>and</strong> observations 1, 24, 48,<br />
Irritation was observed. In one animal slight corneal<br />
RIFM (2002b)<br />
72 h <strong>and</strong> 7 days after application<br />
opacity <strong>and</strong> loss of corneal tissue<br />
Single application, undiluted, 0.5 ml Small area of necrosis on the eye Smyth et al. (1962)<br />
Single application, undiluted <strong>and</strong> observations 1 ant 24 h<br />
after application<br />
Slight irritation RIFM (1963d)<br />
RIFM (1963f)<br />
Single application of 0.1 ml, undiluted, observations<br />
Moderately irritating Scala <strong>and</strong> Burtis (1973)<br />
after 1, 4, <strong>and</strong> 24 h, 2, 3, 4, <strong>and</strong> 7 days, 6 rabbits<br />
2-Methylbutanol Single application, undiluted or solution in water or<br />
Resulted in injury where corneal necrosis was observed Smyth et al. (1962)<br />
propylene glycol, observations <strong>and</strong> grading after 24 h, 6<br />
animals<br />
Single application, undiluted <strong>and</strong> observations after 24,<br />
48, <strong>and</strong> 72 h, 6 animals<br />
Turbidity at the cornea, inflammation on the iris, <strong>and</strong><br />
redness, swelling, or secretion of the conjunctivae<br />
RIFM (1979b)<br />
Subgroup: secondary<br />
2,6-Dimethyl-4-heptanol Undiluted, 0.5 ml application, n.f.i. An average reaction, at most a very small area of<br />
necrosis resulting from 0.5 ml of undiluted chemical in<br />
the eye<br />
Single application, undiluted, observations after 24 h,<br />
<strong>and</strong> 72 h, 1 animal<br />
Moderate; some conjunctivitis with some edema <strong>and</strong><br />
corneal injury; score 10 after 24 h, returned to score 0<br />
Smyth et al. (1949)<br />
McOmie <strong>and</strong> Anderson (1949)<br />
(continued on next page)
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D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46<br />
Table 9 (continued)<br />
Material Method Results References<br />
3,7-Dimethyl-7-methoxyoctan-2-ol 0.1 ml of a solution of 1% in propylene glycol, single<br />
application, observations after 24, 48, <strong>and</strong> 72 h, 6<br />
animals<br />
4-Methyl-2-pentanol Single application, undiluted or diluted in water or<br />
propylene glycol, grading after 18–24 h, n.f.i.<br />
Single application, undiluted, observations after 1 h, 24,<br />
<strong>and</strong> 72 h, 3 animals<br />
3,4,5,6,6-Pentamethylheptan-2-ol Single application, undiluted, 0.1 ml, irrigation <strong>for</strong> 5 min<br />
after 4 s or 30 s, respectively, or without irrigation,<br />
observations after 1 h, 1, 2, 3, 7 days, 3 animals/group<br />
within 72 h<br />
No irritation RIFM (1973b)<br />
5/6 animals: erythema of the conjunctiva, 1/6 animals:<br />
chemosis of the conjunctiva<br />
No corneal or iris involvement<br />
Effects cleared within 3 days<br />
Severe burn from 0.005 ml Smyth et al. (1951)<br />
Moderate; some conjunctivitis with some edema <strong>and</strong><br />
corneal injury; score 11 after 1 h, 25 after 24 h, 17 after<br />
72 h<br />
Returned to normal within 7 days<br />
moderately irritating RIFM (1984c)<br />
Without irrigation<br />
3/3 animals: hyperaemia of the conjunctiva after 1 h<br />
1/3 animals: chemosis of the conjunctiva after 1 h<br />
2/3 animals: corneal opacity after 1 h<br />
Returned to normal after 7 days<br />
1/3 animals was sacrificed in a moribund state after<br />
2 days (bacterial infection)<br />
Irrigation after 30 s<br />
3/3 animals: hyperaemia <strong>and</strong> chemosis of the<br />
conjunctiva after 1 h<br />
Returned to normal within 2 days<br />
Irrigation after 4 s<br />
2/3 animals: hyperaemia of the conjunctiva after 1 h<br />
Returned to normal within 1 day<br />
McOmie <strong>and</strong> Anderson (1949)<br />
Subgroup: tertiary<br />
2,6-Dimethyl-2-heptanol Single application, undiluted, observations after 24, 48,<br />
72 h, 8 days, 6 animals<br />
3,6-Dimethyl-3-octanol a 10% (5 animals), 15% (6 animals), 50% (1 animal),<br />
undiluted (6 animals), solutions in 1.25% Tween 20,<br />
observations at 24, 48, 72 h<br />
Primary irritation index (PII): 29.8, moderate irritant RIFM (1979a)<br />
After 24 h: 6/6 slight corneal opacity, 2/6 slight iris<br />
effects, 5/6 moderate conjunctival redness, 6/6 moderate<br />
conjunctival swellings, 3/6 conjunctival scars, which<br />
were not reversible within 8 days<br />
primary irritation index (PII): irritant RIFM (1970)<br />
10%: 2.8<br />
15%: 3.6<br />
50%: 4.0<br />
Undiluted: 3.6, ranges of grading: corneal opacity 0–1,<br />
iris swelling 0–1, redness <strong>and</strong> chemosis of conjunctiva<br />
1–2, not reversible within 3 days<br />
n.f.i.: no further in<strong>for</strong>mation.<br />
a<br />
No relevant use was reported.
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46 S41<br />
Table 10-1<br />
Skin sensitization studies in humans.<br />
Material Method Concentration Subjects Results References<br />
Subgroup: primary<br />
2-Ethyl-1-hexanol Maximization test 4% in petrolatum 29 healthy volunteers No sensitization reactions RIFM (1976c)<br />
Isoamyl alcohol Maximization test 8% in petrolatum 25 healthy volunteers No sensitization reactions RIFM (1976b)<br />
3-Methyl-1-pentanol HRIPT 0.5% in alcohol SDA 39C 41 healthy volunteers No sensitization reactions RIFM (1973f)<br />
3,5,5-Trimethyl-1-hexanol Maximization test 8% in petrolatum 25 healthy volunteers No sensitization reactions RIFM (1977b)<br />
Subgroup: secondary<br />
3,7-Dimethyl-7-<br />
methoxyoctan-2-ol<br />
3,4,5,6,6-Pentamethylheptan-<br />
2-ol<br />
Maximization test 10% in petrolatum 27 healthy volunteers No sensitization reactions RIFM (1982b)<br />
HRIPT<br />
15% v/v solution in ethanol<br />
SDA 39C (99%)<br />
51 healthy male <strong>and</strong><br />
female volunteers<br />
No sensitization reactions<br />
RIFM (1983c)<br />
Subgroup: tertiary<br />
2,6-Dimethyl-2-heptanol Maximization test 10% in petrolatum 25 healthy volunteers No sensitization reactions RIFM (1976b)<br />
HRIPT 2% in dimethyl phthalate 53 healthy volunteers No sensitization reactions RIFM (1969)<br />
(18 males <strong>and</strong> 35 females)<br />
HRIPT 5% in alcohol SDA 39C 45 healthy volunteers No sensitization reactions RIFM (1971, 1972b)<br />
(33 females, <strong>and</strong> 12 males)<br />
3,6-Dimethyl-3-octanol a Maximization test 20% in petrolatum 25 healthy male volunteers Inconclusive because subjects RIFM (1972a)<br />
reacted to other test material<br />
on the same Panel<br />
Maximization test 10% in petrolatum 25 healthy male volunteers No sensitization reactions RIFM (1973c)<br />
(this was a retest)<br />
3-Methyloctan-3-ol a Maximization test 10% in petrolatum 29 healthy male volunteers No sensitization reactions RIFM (1978a)<br />
HRIPT: human repeated insult patch test.<br />
a No relevant use was reported.<br />
Table 10-2<br />
Diagnostic patch tests.<br />
Material Method Concentration Subjects Results Reference<br />
Subgroup: secondary<br />
3,7-Dimethyl-7-<br />
methoxyoctan-2-ol<br />
Patch<br />
test<br />
Concentration <strong>and</strong> vehicle not<br />
reported<br />
218 patients with proven contact dermatitis<br />
were tested with 3,7-dimethyl-7-<br />
methoxyoctan-2-ol<br />
2 positive<br />
reactions<br />
Larsen et al.<br />
(2002)<br />
Table 10-3<br />
Skin sensitization studies in animals.<br />
Material Method Concentration Species Results References<br />
Subgroup: secondary<br />
3,7-Dimethyl-7- According to <strong>Food</strong> <strong>and</strong> Drug Administration of the<br />
methoxyoctan- United States of America in ‘‘Appraisal of the Safety of<br />
2-ol<br />
<strong>Chemical</strong>s in <strong>Food</strong>, Drugs <strong>and</strong> Cosmetics” 1959, p. 51,<br />
except that the test material was applied topically <strong>and</strong><br />
not injected: induction: 10 applications with 2.5 or 5%<br />
topically, challenge: 2 weeks later with 2.5% in water<br />
Applications 1–7: 5%<br />
(irritating),<br />
applications 8–10: 2.5%<br />
Guinea pig (n = 10)<br />
No delayed-type<br />
hypersensitivity<br />
RIFM<br />
(1973d)<br />
Subgroup: tertiary<br />
2,6-Dimethyl-2-<br />
heptanol<br />
Maximization test<br />
Induction: 10% in FCA<br />
(intradermal),<br />
challenge: 20% in acetone<br />
Guinea pig (10 in test<br />
group, 10 in control<br />
group)<br />
No sensitization<br />
reactions<br />
Watanabe<br />
et al.<br />
(1988)<br />
FCA: Freund’s complete adjuvant.<br />
Available data on genotoxicity <strong>for</strong> eight alcohols <strong>and</strong> three<br />
metabolites do not show such a potential in vitro or in vivo.<br />
Due to the structural similarities of the members of this group<br />
of alcohols, <strong>and</strong> because both terpene alcohols (Belsito et al.,<br />
2008) <strong>and</strong> unsaturated branched chain alcohols (Belsito et al.,<br />
2008) did not show a genotoxic potential, no genotoxicity is<br />
expected <strong>for</strong> the other materials of the group.<br />
A valid carcinogenicity study showed that 2-ethyl-1-hexanol is<br />
a weak inducer of liver tumors in female mice. Mechanistic<br />
studies showed that 2-ethyl-1-hexanol is an activator of<br />
PPAR-alpha. These substances can contribute to liver carcinogenesis<br />
by increasing tumor promotion. The relevance of this<br />
mechanism <strong>for</strong> humans is still a matter of debate. While this<br />
mechanism cannot be completely discounted, it is reasonable<br />
to assume that humans are less sensitive than rodents. In view<br />
of the low use of 2-ethyl-1-hexanol in cosmetic products (0.1–<br />
1 tons/y) <strong>and</strong> the low systemic exposure estimated by RIFM<br />
(0.0005 mg/kg body weight/day), the margin of exposure is<br />
100,000 compared to the NOAEL <strong>for</strong> liver carcinomas in mice<br />
of 50 mg/kg body weight, which is considered to be sufficient<br />
<strong>for</strong> a non-genotoxic compound.<br />
Conflict of interest statement<br />
This research was supported by the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong><br />
Materials, an independent research institute that is funded
S42<br />
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46<br />
Table 11<br />
Phototoxicity <strong>and</strong> photoallergenicity.<br />
Material Method Concentration Species Results References<br />
Subgroup: tertiary<br />
2,6-Dimethyl-2-heptanol 0.025 ml/test site on the back (36 test sites, 2 cm 2 ),<br />
covered, 30 min later the test sites were exposed to<br />
UVA irradiation (320–400 nm, 1, 2.5, 5, 10, 20 J/cm 2 ),<br />
observations 4, 24, 48 <strong>and</strong> 72 h after irradiation<br />
Patch applied 48 h, 4 h after the removal of the<br />
patches the animals did receive:<br />
Group A: UVA (320–400 nm), 30 min<br />
Group B: UVB (280–370 nm), 15 min<br />
Group C: no irradiation, Group D: not pretreated <strong>and</strong><br />
Radiated from both light sources, observations 4, 24,<br />
48 h after the irradiation<br />
Photoallergy test: induction: 0.1 ml on 8 cm 2 of the<br />
test area, 15 min UVB, 4 h UVA (Westinghouse black<br />
light tubes, from a distance of 25 cm) every 2nd day,<br />
total nine times in 18 days, challenge: after resting<br />
time of 10 days 0.025 ml applied on both flanks, left<br />
flank irradiated as <strong>for</strong> induction, skin reading 24 <strong>and</strong><br />
48 h after challenge<br />
10% in 1:1<br />
ethanol/acetone<br />
6 healthy<br />
volunteers<br />
(females)<br />
10% in ethanol Albino guinea pig<br />
(n = 8/group)<br />
10% in rectified<br />
alcohol<br />
Guinea pig<br />
(n = 8/sex)<br />
Not phototoxic<br />
Not phototoxic, after<br />
4 h 1/8 slight reaction<br />
(in each group), which<br />
was cleared within<br />
24 h<br />
No photoallergenicity<br />
RIFM<br />
(1983a)<br />
RIFM<br />
(1981a)<br />
RIFM<br />
(1981b)<br />
Table 12<br />
Summary of UV spectra data.<br />
Material<br />
UV spectra range of absorption (nm)<br />
2-Ethyl-1-hexanol Peaked at 210–215<br />
Returned to baseline at 400 (with minor absorption 290–400)<br />
Isoamyl alcohol<br />
Does not absorb UV light<br />
Isotridecan-1-ol (isomeric mixture)<br />
Does not absorb UV light<br />
2-Methylbutanol Peaked at 200–215<br />
Returned to baseline at 220–225<br />
3-Methyl-1-pentanol Peaked at 200–210<br />
Returned to baseline at 280–290<br />
2-Methylundecanol Peaked at 200–205<br />
Returned to baseline at 270–280<br />
3,5,5-Trimethyl-1-hexanol<br />
Does not absorb UV light<br />
2,6-Dimethyl-4-heptanol<br />
Does not absorb UV light<br />
3,7-Dimethyl-7-methoxyoctan-2-ol Peaked at 200–210<br />
Returned to baseline at 400 (with minor absorption 290–400)<br />
6,8-Dimethylnonan-2-ol Peaked at 200–210<br />
Returned to baseline 230–240 (with minor absorption 260–320)<br />
3,4,5,6,6-Pentamethylheptan-2-ol Peaked at 200–205<br />
Returned to baseline 264–271<br />
2,6-Dimethyl-2-heptanol<br />
Does not absorb UV light<br />
by the manufacturers of fragrances <strong>and</strong> consumer products containing<br />
fragrances. The authors are all members of the Expert Panel<br />
of the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, an independent<br />
group of experts who evaluate the safety of fragrance materials.<br />
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RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1963a. Report on the Study<br />
of the Acute Oral Toxicity of Isotridecan-1-ol in Mice. Unpublished Report from<br />
BASF. Report Number 55417. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1963b. Report on the<br />
Study of the Acute Intraperitoneal Toxicity of Isotridecan-1-ol in Mice.<br />
Unpublished Report from BASF. Report Number 55414. RIFM, Woodcliff Lake,<br />
NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1963c. Report on the Study<br />
of the Acute Inhalation Hazard of Isotridecan-1-ol in Rats (inhalation Hazard
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Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1963d. Results of the<br />
Analytical <strong>Toxicology</strong> Tests with Isotridecan-1-ol. Unpublished Report from<br />
BASF. Report Number 55424. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1963e. Report on the Study<br />
of the Primary Irritation/corrosion of Isotridecan-1-ol to the Intact Skin of<br />
Rabbits. Unpublished Report from BASF. Report Number 55426. RIFM,<br />
Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1963f. Report on the Study of<br />
the Primary Irritation of Isotridecan-1-ol to the Eye of Rabbits. Unpublished<br />
Report from BASF. Report Number 55431. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1969. Sensitization <strong>and</strong><br />
Irritation Studies of 2,6-dimethyl-2-heptanol. Unpublished Report from<br />
Givaudan, 30 June. Report Number 41345. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1970. Studies on the Effects<br />
of Local Application of <strong>Fragrance</strong> Materials. Unpublished Report from Fritzsche<br />
Dodge & Olcott Inc., 24 November. Report Number 33617. RIFM, Woodcliff Lake,<br />
NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1971. Repeated Insult Patch<br />
Test with 2,6-Dimethyl-2-heptanol. Unpublished report from International<br />
Flavors <strong>and</strong> <strong>Fragrance</strong>s. Report Number 53498. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1972a. The Contactsensitization<br />
Potential of <strong>Fragrance</strong> Materials by Maximization Testing in<br />
Humans. RIFM Report Number 1804, February–December 1972. RIFM,<br />
Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1972b. Repeated Insult Patch<br />
Test with 2,6-Dimethyl-2-heptanol. Unpublished Report from International<br />
Flavors <strong>and</strong> <strong>Fragrance</strong>s. Report Number 53499. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1972c. Skin Irritation Study<br />
with 3-Methyl-1-pentanol in Rabbits. Unpublished Report from International<br />
Flavors <strong>and</strong> <strong>Fragrance</strong>s. Report Number 53594. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1973a. Acute Toxicity<br />
Studies on Rats <strong>and</strong> Rabbits. RIFM report number 2021, February–December<br />
1973. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1973b. Irritant Effects of 3,7-<br />
Dimethyl-7-methoxyoctan-2-ol on Rabbit Eye Mucosa. Unpublished Report<br />
from Bush Boake Allen Ltd., 07 June 1973. Report Number 1767. RIFM,<br />
Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1973c. Report on Human<br />
Maximization Studies. RIFM Report Number 1802, February–December 1973.<br />
RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1973d. Screening Test <strong>for</strong><br />
Delayed Dermal Sensitization with 3,7-Dimethyl-7-methoxyoctan-2-ol in the<br />
Albino Guinea Pig. Unpublished Report from Bush Boake Allen Ltd., 03 May.<br />
Report Number 1766. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1973e. Irritant Effects of<br />
3,7-Dimethyl-7-methoxyoctan-2-ol on Rabbit Skin. Unpublished Report from<br />
Bush Boake Allen Ltd., 07 June. Report Number 1765. RIFM, Woodcliff Lake,<br />
NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1973f. Repeated Insult Patch<br />
Test with 3-Methyl-1-pentanol. Unpublished Report from International Flavors<br />
<strong>and</strong> <strong>Fragrance</strong>s. Report Number 53593. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1976a. Acute Toxicity<br />
Studies in Rats, Mice, Rabbits <strong>and</strong> Guinea Pigs. RIFM Report Number 2019,<br />
October 08. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1976b. Report on Human<br />
Maximization Studies. RIFM Report Number 1797, November 04. RIFM,<br />
Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1976c. Report on Human<br />
Maximization Studies. RIFM Report Number 1796, December 20. RIFM,<br />
Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1977a. Acute Toxicity Study<br />
in Rats, Rabbits <strong>and</strong> Guinea Pigs. RIFM Report Number 1695, January 24. RIFM,<br />
Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1977b. Report on Human<br />
Maximization Studies. RIFM Report Number 1702, May 09. RIFM, Woodcliff<br />
Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1978a. Report on Human<br />
Maximization Results. RIFM Report Number 1698, March 23. RIFM, Woodcliff<br />
Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1978b. Rabbit Eye Irritation<br />
on AEROFROTH? 88 Frother. Report from American Cyanamid Company. Report<br />
Number 18672. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1978c. Report on Acute Oral<br />
Toxicity. RIFM Report Number 1699. February–October 1978. RIFM, Woodcliff<br />
Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1979a. Acute Toxicity<br />
Studies on 2,6-Dimethyl-2-heptanol. Unpublished Report from BASF, 08<br />
February. Report Number 4458. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1979b. Acute Toxicity<br />
Studies on 2-Methylbutanol. Unpublished Report from BASF, Report Number<br />
55366. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1979c. Acute Toxicity<br />
Studies on Isoamyl Alcohol. Unpublished Report from BASF. Report Number<br />
55359. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1981a. Determination of<br />
Phototoxicity of 2,6-Dimethyl-2-heptanol in Guinea Pigs. Unpublished Report<br />
from Givaudan, 07 April. Report Number 41346. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1981b. Guinea Pig Assay of<br />
Photosensitizing Potential of 2,6-Dimethyl-2-heptanol. Unpublished Report<br />
from Givaudan, 09 July. Report Number 41343. RIFM, Woodcliff Lake, NJ,<br />
USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1982a. 14-Day LD50 Study on 3-<br />
Methyl-1-pentanol in Mice. Private Communication to FEMA. Unpublished Report<br />
from H.W. Engler B. Bahler. Report Number 9019. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1982b. Report on Human<br />
Maximization Studies. RIFM Report Number 1643, January–November 1982.<br />
RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1983a. 2,6-Dimethyl-2-<br />
heptanol: Phototoxicity Test on a <strong>Fragrance</strong> Raw Material in Humans.<br />
Unpublished Report from Givaudan, 23 September. Report Number 41344.<br />
RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1983b. Evaluation of 2-<br />
Ethylhexanol in the In Vitro Trans<strong>for</strong>mation of BALB/3T3 Cells with Metabolic<br />
Activation by Primary Rat Hepatocytes. Addendum to the Final Report of July<br />
1983. Unpublished Report from Litton Bionetics, Inc. RIFM Report Number<br />
13570. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1983c. Evaluation of<br />
Potential Irritation <strong>and</strong> Sensitization Hazards by Dermal Contact: Repeated<br />
Insult Patch Test with 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished Report<br />
from International Flavors <strong>and</strong> <strong>Fragrance</strong>s, 27 October, 14 November 1983.<br />
Report Number 48462. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1984a. Acute Oral LD 50<br />
Determination in the Rat on 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished<br />
Report from International Flavors <strong>and</strong> <strong>Fragrance</strong>s. RIFM Report Number 47552,<br />
August. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1984b. Primary Dermal<br />
Irritation Test of 3,4,5,6,6-Pentamethylheptan-2-ol on the Rabbit. Unpublished<br />
Report from International Flavors <strong>and</strong> <strong>Fragrance</strong>s. Report Number 47792. RIFM,<br />
Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1984c. Acute Eye Irritation<br />
Corrosion Test to the Rabbit of 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished<br />
Report from International Flavors <strong>and</strong> <strong>Fragrance</strong>s. RIFM Report Number 47677.<br />
RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1985a. Acute Dermal<br />
Toxicity to the Rat of 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished Report<br />
from International Flavors <strong>and</strong> <strong>Fragrance</strong>s. Report Number 47587. RIFM,<br />
Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1985b. Microbial Metabolic<br />
Activation Test to Assess the Potential Mutagenic Effect of 3,4,5,6,6-<br />
Pentamethylheptan-2-ol. Unpublished Report from International Flavors <strong>and</strong><br />
<strong>Fragrance</strong>s. Report Number 48164, March 1985. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1985c. The Effects of<br />
Repeated Dermal Application of 3,4,5,6,6-Pentamethylheptan-2-ol to Rabbits<br />
<strong>for</strong> Twenty-eight Days. Unpublished Report from International Flavors <strong>and</strong><br />
<strong>Fragrance</strong>s. Report Number 47793, June 1985. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1985d. Micronucleus Test<br />
(MNT) OECD on 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished Report from<br />
International Flavors <strong>and</strong> <strong>Fragrance</strong>s. Report Number 48252, June 1985. RIFM,<br />
Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1985e. Report on the Acute<br />
Oral Toxicity of 2-Methylbutanol in Rats. Unpublished Report from BASF. Report<br />
Number 55365. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1986a. Twenty-eight Day<br />
Dermal Irritation Study in Rabbits with 3,4,5,6,6-Pentamethylheptan-2-ol.<br />
Unpublished Report from International Flavors <strong>and</strong> <strong>Fragrance</strong>s. Report<br />
Number 48027, June 1986. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1986b. Twenty-eight Day<br />
Dermal Irritation Study in Rabbits with 3,4,5,6,6-Pentamethylheptan-2-ol.<br />
Unpublished Report from International Flavors <strong>and</strong> <strong>Fragrance</strong>s, Report<br />
Number 48027. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1988. 2-Ethylhexanol (2EH):<br />
Nine-day Dermal, Nine-day Oral Gavage, <strong>and</strong> Nine-day Drinking Water Studies<br />
in Rats. Report from Bushy Run. RIFM Report Number 20510. RIFM, Woodcliff<br />
Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1989. Report on the Study of<br />
Isotridecan-1-ol in the AMES Test. Unpublished Report from BASF. Report<br />
Number 55420. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1990a. Prenatal Toxicity of<br />
Isoamyl Alcohol in Wistar Rats after Inhalation. Unpublished Report from BASF.<br />
Report Number 55360. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1990b. Prenatal Toxicity of<br />
Isoamyl Alcohol in Rabbits after Inhalation. Unpublished Report from BASF.<br />
Report Number 55361. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1991a. Study of the Prenatal<br />
Toxicity of Usononylalcohol 1 <strong>and</strong> Isononylalcohol 2 in Rats after Oral<br />
Administration (gavage). Submission to EPA. Unpublished Report from Report<br />
Number 34403. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1991b. Study on the Oral<br />
Toxicity of Isoamyl Alcohol in Rats. Unpublished Report from BASF. Report<br />
Number 55354. RIFM, Woodcliff Lake, NJ, USA.
S46<br />
D. Belsito et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S1–S46<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1992a. Oral Toxicity of 2-<br />
Ethylhexanol in Mice after Administration by Gavage <strong>for</strong> 11 days. Unpublished<br />
Report from BASF. RIFM Report Number 18665. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1992b, Report on the Study<br />
of the Oral Toxicity of 2-Ethylhexanol in Mice after Administration by Gavage<br />
(Aqueous Emulsion) <strong>for</strong> 11 days (9 applications). RIFM Report Number 18666.<br />
RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1992c. Oral Toxicity of 2-<br />
Ethylhexanol in Rats after Administration of Microencapsulated Material via the<br />
Diet <strong>for</strong> 11 days. Unpublished Report from BASF. RIFM Report Number 18660.<br />
RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 2002a. Isotridecan-1-ol:<br />
Acute Oral Toxicity Study in Wistar Rats. Unpublished Report from BASF. Report<br />
Number 55416. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 2002b. Isotridecan-1-ol:<br />
Acute Eye Irritation in Rabbits. Unpublished Report from BASF. Report Number<br />
55430. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 2003a. Isotridecan-1-ol:<br />
Acute Dermal Irritation/corrosion in Rabbits. Unpublished Report from BASF.<br />
Report Number 55427. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 2003b. Isotridecan-1-ol:<br />
Prenatal Developmental Toxicity study in Wistar Rats by Oral Administration<br />
(Gavage). Unpublished Report from BASF. Report Number 55432. RIFM,<br />
Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 2008. Micronucleus Assay in<br />
Bone Marrow Cells of the Mouse with Isoamyl Alcohol. RIFM in DRAFT. RIFM,<br />
Woodcliff Lake, NJ, USA.<br />
Ritter, E.J., Scott Jr., W.J., R<strong>and</strong>all, J.L., Ritter, J.M., 1987. Teratogenicity of di(2-<br />
ethylhexyl)phthalate, 2-ethylhexanol, 2-ethylhexanoic acid, & valproic acid, &<br />
potentiation by caffeine. Teratology 35, 41–46.<br />
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<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S47–S50<br />
Contents lists available at ScienceDirect<br />
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong><br />
journal homepage: www.elsevier.com/locate/foodchemtox<br />
Review<br />
<strong>Fragrance</strong> material review on 3,5,5-trimethyl-1-hexanol<br />
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api<br />
<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA<br />
article<br />
Keywords:<br />
Review<br />
<strong>Fragrance</strong><br />
info<br />
abstract<br />
A toxicologic <strong>and</strong> dermatologic review of 3,5,5-trimethyl-1-hexanol when used as a fragrance ingredient<br />
is presented. 3,5,5-Trimethyl-1-hexanol is a member of the fragrance structural group branched chain<br />
saturated alcohols. The common characteristic structural elements of the alcohols with saturated<br />
branched chain are one hydroxyl group per molecule, <strong>and</strong> a C 4 to C 12 carbon chain with one or several<br />
methyl side chains. This review contains a detailed summary of all available toxicology <strong>and</strong> dermatology<br />
papers that are related to this individual fragrance ingredient <strong>and</strong> is not intended as a st<strong>and</strong>-alone document.<br />
A safety assessment of the entire branched chain saturated alcohol group will be published simultaneously<br />
with this document; please refer to Belsito et al. (2010) <strong>for</strong> an overall assessment of the safe<br />
use of this material <strong>and</strong> all other branched chain saturated alcohols in fragrances.<br />
Ó 2010 Published by Elsevier Ltd.<br />
Contents<br />
Introduction . . . ..................................................................................................... S48<br />
1. Identification . . ..................................................................................................... S48<br />
2. Physical properties . . . . . . . . . . . . . . . . . .................................................................................. S48<br />
3. Usage. . . . . . . . . ..................................................................................................... S48<br />
4. <strong>Toxicology</strong> data ..................................................................................................... S49<br />
4.1. Acute toxicity (see Table 2). ..................................................................................... S49<br />
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49<br />
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49<br />
4.2. Skin irritation. ................................................................................................ S49<br />
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49<br />
4.2.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49<br />
4.3. Mucous membrane (eye) irritation. ............................................................................... S49<br />
4.4. Skin sensitization. ............................................................................................. S49<br />
4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49<br />
4.5. Phototoxicity <strong>and</strong> photoallergy. . ................................................................................. S49<br />
4.6. Absorption, distribution <strong>and</strong> metabolism .......................................................................... S49<br />
4.7. Repeated dose toxicity . . ....................................................................................... S49<br />
4.7.1. Two to fourteen days studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49<br />
4.7.2. Subchronic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49<br />
4.7.3. Chronic (90+ days) studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S50<br />
4.8. Reproductive <strong>and</strong> developmental toxicity .......................................................................... S50<br />
4.9. Genotoxicity. ................................................................................................. S50<br />
4.9.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S50<br />
4.10. Carcinogenicity . . ............................................................................................. S50<br />
Conflict of interest statement . . . . . . . . .................................................................................. S50<br />
References . . . . ..................................................................................................... S50<br />
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.<br />
E-mail address: dmcginty@RIFM.org (D. McGinty).<br />
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.<br />
doi:10.1016/j.fct.2010.05.026
S48<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S47–S50<br />
Introduction<br />
This document provides a summary of the toxicologic review of<br />
3,5,5-trimethyl-1-hexanol when used as a fragrance ingredient<br />
including all human health endpoints. 3,5,5-Trimethyl-1-hexanol<br />
(see Fig. 1; CAS Number 3452-97-9) is a fragrance ingredient used<br />
in cosmetics, fine fragrances, shampoos, toilet soaps <strong>and</strong> other<br />
toiletries as well as in non-cosmetic products such as household<br />
cleaners <strong>and</strong> detergents. It is a colorless oily liquid with an oilyherbaceous<br />
odor (Arct<strong>and</strong>er, 1969). This material has been reported<br />
to occur in nature, with quantities observed in black currants, crab,<br />
<strong>and</strong> strawberry guava (VCF, 2009).<br />
In 2006, a complete literature search was conducted on 3,5,5-<br />
trimethyl-1-hexanol. On-line toxicological databases were<br />
searched including those from the <strong>Chemical</strong> Abstract Services,<br />
[e.g. ToxCenter (which in itself contains 18 databases including<br />
chemical abstracts)], <strong>and</strong> the National Library of Medicine [e.g.<br />
Medline, Toxnet (which contains 14 databases)] as well as 26 additional<br />
sources (e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition,<br />
fragrance companies were asked to submit all test data.<br />
The safety data on this material was last reviewed by Letizia et<br />
al. (2000). All relevant references are included in this document.<br />
More details have been provided <strong>for</strong> unpublished data. The number<br />
of animals, sex <strong>and</strong> strain are always provided unless they are not<br />
given in the original report or paper. Any papers in which the vehicles<br />
<strong>and</strong>/or the doses are not given have not been included in this<br />
review. In addition, diagnostic patch test data with fewer than 100<br />
consecutive patients have been omitted.<br />
1. Identification<br />
1.1. Synonyms: 1-hexanol, 3,5,5-trimethyl-; i-nonyl alcohol;<br />
nonylol; trimethylhexanol; 3,5,5-trimethylhexanol; 3,5,5-<br />
trimethylhexan-1-ol; 3,5,5-trimethylhexyl alcohol.<br />
1.2. CAS Registry Number: 3452-97-9.<br />
1.3. EINECS Number: 222-376-7.<br />
1.4. Formula: C 9 H 20 O.<br />
1.5. Molecular weight: 144.26.<br />
1.6. Council of Europe (2000): 3,5,5-trimethyl-1-hexanol was<br />
included by the Council of Europe in the list of substances<br />
HO<br />
Fig. 1. 3,5,5-Trimethyl-1-hexanol.<br />
granted B – in<strong>for</strong>mation required – 28 days oral study<br />
(COE No. 702).<br />
1.7. JECFA (1998): The Joint FAO/WHP Expert Committee on<br />
<strong>Food</strong> Additives (JECFA No. 268) concluded that the substance<br />
does not present a safety concern at current levels of intake<br />
when used as a flavouring agent.<br />
1.8. FEMA (1970): Flavor <strong>and</strong> Extract Manufacturers’ Association<br />
states: generally Recognized as safe as a flavor ingredient –<br />
GRAS 5.<br />
2. Physical properties<br />
2.1. Physical <strong>for</strong>m: a colorless oily liquid.<br />
2.2. Boiling point (calculated; EPA, 2010): 188.53 °C.<br />
2.3. Flash point: 174 °F; CC.<br />
2.4. Henry’s law (calculated; EPA, 2010): 0.0000412 atm m 3 /mol<br />
25 °C.<br />
2.5. Log K ow (calculated; EPA, 2010): 3.11.<br />
2.6. Refractive index: 1.4318.<br />
2.7. Specific gravity: 0.832 (20 °C); 0.8252 (25 °C).<br />
2.8. Vapor pressure (calculated; EPA, 2010): 0.2 mm Hg (20 °C);<br />
0.106 mm Hg (25 °C); 14.1 Pa (25 °C)2.9 water solubility<br />
(calculated; EPA, 2010): 572 mg/l (25 °C).<br />
2.9. UV spectra available. Does not absorb UV light.<br />
3. Usage<br />
3,5,5-Trimethyl-1-hexanol is a fragrance ingredient used in<br />
many fragrance compounds. It may be found in fragrances used<br />
in decorative cosmetics, fine fragrances, shampoos, toilet soaps<br />
<strong>and</strong> other toiletries as well as in non-cosmetic products such as<br />
household cleaners <strong>and</strong> detergents. Its use worldwide is in the region<br />
of 1–10 metric tons per annum (IFRA, 2004). The reported volume<br />
of use is <strong>for</strong> 3,5,5-trimethyl-1-hexanol as used in fragrance<br />
compounds (mixtures) in all finished consumer product categories.<br />
The volume of use is surveyed by IFRA approximately every 4 years<br />
through a comprehensive survey of IFRA <strong>and</strong> RIFM member companies.<br />
As such the volume of use data from this survey provides<br />
volume of use of fragrance ingredients <strong>for</strong> the majority of the<br />
fragrance industry.<br />
The dermal systemic exposure in cosmetic products (see Table 1)<br />
is calculated based on the concentrations of the same fragrance<br />
ingredient in ten types of the most frequently used personal care<br />
<strong>and</strong> cosmetic products (anti-perspirant, bath products, body lotion,<br />
eau de toilette, face cream, fragrance cream, hair spray, shampoo,<br />
shower gel, <strong>and</strong> toilet soap). The concentration of the fragrance<br />
ingredient in fine fragrances is obtained from examination of several<br />
thous<strong>and</strong> commercial <strong>for</strong>mulations. The upper 97.5 percentile<br />
concentration is calculated from the data obtained. This upper 97.5<br />
Table 1<br />
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 3,5,5-trimethyl-1-hexanol.<br />
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient mg/kg/day b<br />
Anti-perspirant 0.5 1 1 0.01 0.14 0.000100<br />
Bath products 17 0.29 0.001 0.02 0.14 0.000001<br />
Body lotion 8 0.71 1 0.004 0.14 0.000500<br />
Eau de toilette 0.75 1 1 0.08 0.14 0.001400<br />
Face cream 0.8 2 1 0.003 0.14 0.000100<br />
<strong>Fragrance</strong> cream 5 0.29 1 0.04 0.14 0.001400<br />
Hair spray 5 2 0.01 0.005 0.14 0.000010<br />
Shampoo 8 1 0.01 0.005 0.14 0.000010<br />
Shower gel 5 1.07 0.01 0.012 0.14 0.000010<br />
Toilet soap 0.8 6 0.01 0.015 0.14 0.000020<br />
Total 0.0036<br />
a<br />
b<br />
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.<br />
Based on a 60-kg adult.
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S47–S50 S49<br />
percentile concentration is then used <strong>for</strong> all 10 consumer products.<br />
These concentrations are multiplied by the amount of product applied,<br />
the number of applications per day <strong>for</strong> each product type,<br />
<strong>and</strong> a ‘‘retention factor” (ranging from 0.001 to 1.0) to account<br />
<strong>for</strong> the length of time a product may remain on the skin <strong>and</strong>/or<br />
likelihood of the fragrance ingredient being removed by washing.<br />
The resultant calculation represents the total consumer exposure<br />
(mg/kg/day) (Cadby et al., 2002; Ford et al., 2000).<br />
This is a conservative calculation of dermal systemic exposure<br />
because it makes the unlikely assumption that a consumer will<br />
use these 10 products containing; which are all perfumed with<br />
the upper 97.5 percentile level of the fragrance ingredient from a<br />
fine fragrance type of product (Cadby et al., 2002; Ford et al.,<br />
2000). The 97.5% percentile use level in <strong>for</strong>mulae <strong>for</strong> use in cosmetics<br />
in general has been reported to be 0.14 (IFRA, 2007), which<br />
would result in a maximum daily exposure on the skin of<br />
0.0035 mg/kg <strong>for</strong> high end users.<br />
A maximum skin level is then determined <strong>for</strong> consideration of<br />
potential sensitization. The exposure is calculated as the percent<br />
concentration of the fragrance ingredient applied to the skin based<br />
on the use of 20% of the fragrance mixture in the fine fragrance<br />
consumer product (IFRA, 2007). The average maximum use level<br />
in <strong>for</strong>mulae that go into fine fragrances has been reported to be<br />
0.68% (IFRA, 2007), assuming use of the fragrance oil at levels up<br />
to 20% the final product.<br />
4. <strong>Toxicology</strong> data<br />
4.1. Acute toxicity (see Table 2)<br />
4.1.1. Oral studies<br />
The acute oral LD 50 of 3,5,5-trimethyl-1-hexanol in rats (10/<br />
dose) was reported to be 2.3 (95% C.I. 1.7–3.1) g/kg. Mortality was<br />
0, 0, 7, <strong>and</strong> 10 of 10 rats at 0.67, 1.31, 2.56, <strong>and</strong> 5.0 g/kg, respectively.<br />
Deaths occurred on days 1, 2, or 3. The observation period<br />
was 14 days. Clinical signs included lethargy, coma, ataxia, diarrhea,<br />
piloerection, ptosis, <strong>and</strong> chromorhinorrhea. Necropsy observations<br />
included red/yellow oral/nasal exudates, yellow/brown<br />
anogenital exudates, dark areas/orange lungs, dark/mottled liver,<br />
dark/mottled kidneys, red/yellow areas of intestines, stomach<br />
bloated/red–yellow areas/fluid filled, spleen mottled (RIFM, 1977a).<br />
4.1.2. Dermal studies<br />
The acute dermal LD 50 of 3,5,5-trimethyl-1-hexanol in rabbits<br />
(10/dose) was reported to be greater than 5.0 g/kg. Mortality was<br />
3 of 10 rabbits at 5.0 g/kg. Deaths occurred on days 9, 13, <strong>and</strong> 14.<br />
Observation period was 14 days. Clinical signs included lethargy,<br />
diarrhea, <strong>and</strong> anorexia. Necropsy observations included mild, moderate,<br />
or severe erythema <strong>and</strong> mild or moderate edema, yellow/<br />
brown anogenital exudates, dark/mottled liver, dark/mottled/mal<strong>for</strong>med<br />
kidneys, red/yellow areas of intestines, stomach bloated<br />
(RIFM, 1977a).<br />
4.2. Skin irritation<br />
4.2.1. Human studies<br />
In a human maximization test pre-screen, 8% 3,5,5-trimethyl-1-<br />
hexanol was applied to the volar <strong>for</strong>earms or backs of 25 healthy<br />
Table 2<br />
Summary of acute toxicity studies.<br />
Route Species No. animals/dose group LD 50 (g/kg) References<br />
Oral Rat 10 2.3 RIFM (1977a)<br />
Dermal Rabbit 10 >5.0 RIFM (1977a)<br />
subjects <strong>for</strong> 48 h under occlusion. No subject had any irritation<br />
(RIFM, 1977b).<br />
4.2.2. Animal studies<br />
Irritation was evaluated during the acute dermal study of 3,5,<br />
5-trimethyl-1-hexanol in 10 rabbits. A single dose of 5.0 g/kg<br />
resulted in mild, moderate, or severe erythema <strong>and</strong> mild or<br />
moderate edema (RIFM, 1977a).<br />
4.3. Mucous membrane (eye) irritation<br />
No in<strong>for</strong>mation available.<br />
4.4. Skin sensitization<br />
4.4.1. Human studies<br />
4.4.1.1. Induction studies. In a study involving 25 subjects, a maximization<br />
test (Kligman, 1966; Kligman <strong>and</strong> Epstein, 1975) was<br />
carried out with 3,5,5-trimethyl-1-hexanol in petrolatum on various<br />
panels of volunteers. Application was under occlusion to the<br />
same site on the <strong>for</strong>earms or backs of all subjects <strong>for</strong> five alternate-day<br />
48 h periods. Patch sites were pre-treated <strong>for</strong> 24 h with<br />
2.5% aqueous sodium lauryl sulfate (SLS) under occlusion. Following<br />
a 10–14 days rest period, challenge patches were applied under<br />
occlusion to fresh sites <strong>for</strong> 48 h. Challenge applications were preceded<br />
by 60 min SLS treatment. Reactions were read at patch<br />
removal <strong>and</strong> again at 24 h. There was no evidence of contact<br />
sensitization to 8% 3,5,5-trimethyl-1-hexanol (RIFM, 1977b).<br />
4.4.1.2. Animal studies. No in<strong>for</strong>mation available.<br />
4.5. Phototoxicity <strong>and</strong> photoallergy<br />
No in<strong>for</strong>mation available.<br />
4.6. Absorption, distribution <strong>and</strong> metabolism<br />
No in<strong>for</strong>mation available.<br />
4.7. Repeated dose toxicity<br />
4.7.1. Two to fourteen days studies<br />
3,5,5-Trimethyl-1-hexanol was included in a repeat dose oral<br />
gavage study of a series of compounds related to diethylhexl<br />
phthalate <strong>and</strong> diethylhexyl adipate in male Alderley Park Wistarderived<br />
rats. Animals were dosed <strong>for</strong> 14 days with 1 mM/kg/d<br />
(144 mg/kg/d) 3,5,5-trimethyl-1-hexanol dissolved in polyethylene<br />
glycol 300. At termination of the study, there was no difference<br />
from controls in body weight, or any clinical or histopathological<br />
signs of hepatotoxicity. At necropsy, relative liver weight was significantly<br />
greater than that of controls, but peroxisome proliferation<br />
<strong>and</strong> hypocholesterolemia <strong>and</strong> hypotriglyceridaemia were not<br />
evident (Rhodes et al., 1984).<br />
4.7.2. Subchronic studies<br />
Male SD (CRJ:CD) rats were given 3,5,5-trimethyl-1-hexanol by<br />
gavage <strong>for</strong> 46 days at doses of 0, 12, 60, or 300 mg/kg body weight/<br />
day in olive oil. Females were dosed 14 days be<strong>for</strong>e mating <strong>and</strong><br />
through to day 3 of lactation. Renal hyaline droplets <strong>and</strong> eosinophilic<br />
bodies were observed (slight to moderate) in all dosed male<br />
rats, but these findings were not observed in females. The 60 mg/<br />
kg body weight/day dose group experienced relative liver <strong>and</strong> kidney<br />
weight increases (males <strong>and</strong> females), renal epithelial fatty<br />
changes (females), <strong>and</strong> a decreased implantation index (females).<br />
At 300 mg/kg body weight/day one female died, <strong>and</strong> three were<br />
put down because of weakness. Body weights increased <strong>and</strong> food
S50<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S47–S50<br />
consumption increased in males, but decreased in females. Females<br />
showed a litter loss in two dams. On the basis of these findings<br />
the NOAEL was considered to be 12 mg/kg/day <strong>for</strong> male <strong>and</strong><br />
female rats (MHW, Japan, 1997b as cited in OECD/SIDS (2003)).<br />
4.7.3. Chronic (90+ days) studies<br />
No in<strong>for</strong>mation available.<br />
4.8. Reproductive <strong>and</strong> developmental toxicity<br />
No in<strong>for</strong>mation available.<br />
4.9. Genotoxicity<br />
4.9.1. In vitro studies<br />
4.9.1.1. Bacterial test systems. 3,5,5-Trimethyl-1-hexanol was not<br />
mutagenic in an Ames test (preincubation assay with <strong>and</strong> without<br />
metabolic activation) in Salmonella typhimurium TA98, TA100,<br />
TA1535, TA1537 <strong>and</strong> in E. coli WP2 uvrA assays (MHW, Japan<br />
1997c as cited in OECD/SIDS (2003) <strong>and</strong> Kusakabe et al. (2002)).<br />
4.9.1.2. Studies in mammalian cells. 3,5,5-Trimethyl-1-hexanol up to<br />
100 lg/plate (cytotoxicity occurred at 200 lg/plate) with or without<br />
metabolic activation, did not induce chromosomal aberrations<br />
or polyploidy in an in vitro Chinese hamster lung cell (OECD TG<br />
473) study (MHW, Japan 1997c as cited in OECD/SIDS (2003) <strong>and</strong><br />
Kusakabe et al. (2002).<br />
4.9.1.3. In vivo studies. No in<strong>for</strong>mation available.<br />
4.10. Carcinogenicity<br />
No in<strong>for</strong>mation available.<br />
This individual fragrance material review is not intended as a<br />
st<strong>and</strong>-alone document. Please refer to A Safety Assessment of<br />
Branched Chain Saturated Alcohols When Used as <strong>Fragrance</strong> Ingredients<br />
(Belsito et al., 2010) <strong>for</strong> an overall assessment of this<br />
material.<br />
Conflict of interest statement<br />
This research was supported by the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong><br />
Materials, an independent research institute that is funded<br />
by the manufacturers of fragrances <strong>and</strong> consumer products containing<br />
fragrances. The authors are all employees of the <strong>Research</strong><br />
<strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials.<br />
References<br />
Arct<strong>and</strong>er, S., 1969. Perfume <strong>and</strong> Flavor <strong>Chemical</strong>s (Aroma <strong>Chemical</strong>s), vol. II, No.<br />
3006. S. Arct<strong>and</strong>er, Montclair, New Jersey.<br />
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,<br />
Sipes, I.G., Smith, R.L., Tagami, H. 2010. A safety assessment of branched chain<br />
saturated alcohols when used as fragrance ingredients, <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong><br />
<strong>Toxicology</strong> 48 (S4), S1–S46.<br />
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:<br />
providing estimates <strong>for</strong> safety evaluation. Regulatory <strong>Toxicology</strong> <strong>and</strong><br />
Pharmacology 36, 246–252.<br />
Council of Europe, 2000. Partial Agreement in the Social <strong>and</strong> Public Health Field.<br />
<strong>Chemical</strong>ly-defined Flavouring Substances. Group 2.1.3 Aliphatic Alcohols,<br />
Branched Chain. Number 702. Council of Europe Publishing, Strasbourg. p. 59.<br />
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface<br />
Suite <strong>for</strong> Microsoft Ò Windows, v 4.00 or insert version used. United States<br />
Environmental Protection Agency, Washington, DC, USA.<br />
FEMA (Flavor, Extract Manufacturers Association), 1970. Recent progress in the<br />
consideration of flavoring ingredients under the food additives amendment 4.<br />
GRAS substances. <strong>Food</strong> Technology 24 (5), 25–34.<br />
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria <strong>for</strong><br />
development of a database <strong>for</strong> safety evaluation of fragrance ingredients.<br />
Regulatory <strong>Toxicology</strong> <strong>and</strong> Pharmacology 31, 166–181.<br />
IFRA (International <strong>Fragrance</strong> Association), 2004. Use Level Survey, August 2004.<br />
IFRA (International <strong>Fragrance</strong> Association), 2007. Volume of Use Survey, February<br />
2007.<br />
JECFA (Joint Expert Committee on <strong>Food</strong> Additives), 1998. Safety Evaluation of<br />
Certain <strong>Food</strong> Additives. WHO <strong>Food</strong> Additives Series: 40. Prepared by the Fortyninth<br />
Meeting of the Joint FAO/WHO Expert Committee on <strong>Food</strong> Additives<br />
(JECFA). World Health Organization, Geneva, 1998.<br />
Kligman, A.M., 1966. The identification of contact allergens by human assay. III. The<br />
maximization test. A procedure <strong>for</strong> screening <strong>and</strong> rating contact sensitizers.<br />
Journal of Investigative Dermatology 47, 393–409.<br />
Kligman, A.M., Epstein, W., 1975. Updating the maximization test <strong>for</strong> identifying<br />
contact allergens. Contact Dermatitis 1, 231–239.<br />
Kusakabe, H., Yamakage, K., Wakuri, S., Sasaki, K., Nakagawa, Y., Watanabe, M.,<br />
Hayashi, M., Sofuni, T., Ono, H., Tanaka, N., 2002. Relevance of chemical<br />
structure <strong>and</strong> cytotoxicity to the induction of chromosome aberrations based on<br />
the testing results of 98 high production volume industrial chemicals. Mutation<br />
<strong>Research</strong> 517 (1–2), 187–198.<br />
Letizia, C.S., Cocchiara, J., Wellington, G.A., Funk, C., Api, A.M., 2000. Monographs on<br />
fragrance raw materials, 3,5,5-trimethyl-1-hexanol. <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong><br />
<strong>Toxicology</strong> 38 (Suppl. 3), S223–S235.<br />
OECD <strong>and</strong> Screening In<strong>for</strong>mation Datasets (SIDS), (2003). High Production Volume<br />
<strong>Chemical</strong>s 3,5,5 0 -trimethyl-1-hexanol (CAS No.: 3452-97-9). Processed by<br />
United Nations Environmental Program, (UNEP). Available online: .<br />
Rhodes, C., Soames, T., Stonard, M.D., Simpson, M.G., Vernall, A.J., Elcombe, C.R.,<br />
1984. The absence of testicular atrophy <strong>and</strong> in vivo <strong>and</strong> in vitro effects on<br />
hepatocyte morphology <strong>and</strong> peroxisomal enzyme activities in male rats<br />
following the administration of several alkanols. <strong>Toxicology</strong> Letters 21, 103–<br />
109.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1977a. Acute Toxicity Study<br />
in Rats, Rabbits <strong>and</strong> Guinea Pigs. RIFM Report Number 1695, July 25 (RIFM,<br />
Woodcliff Lake, NJ, USA).<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1977b. Report on Human<br />
Maximization Studies. RIFM Report Number 1702, May 09 (RIFM, Woodcliff<br />
Lake, NJ, USA).<br />
VCF (Volatile Compounds in <strong>Food</strong>): database. In: Nijssen, L.M., Ingen-Visscher, C.A.<br />
van, Donders, J.J.H. (Eds.), Version 11.1.1 – Zeist (The Netherl<strong>and</strong>s): TNO Quality<br />
of Life, 1963–2009.
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S51–S54<br />
Contents lists available at ScienceDirect<br />
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong><br />
journal homepage: www.elsevier.com/locate/foodchemtox<br />
Review<br />
<strong>Fragrance</strong> material review on 3,7-dimethyl-7-methoxyoctan-2-ol<br />
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api<br />
<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA<br />
article<br />
Keywords:<br />
Review<br />
<strong>Fragrance</strong><br />
info<br />
abstract<br />
A toxicologic <strong>and</strong> dermatologic review of 3,7-dimethyl-7-methoxyoctan-2-ol when used as a fragrance<br />
ingredient is presented. 3,7-Dimethyl-7-methoxyoctan-2-ol is a member of the fragrance structural<br />
group branched chain saturated alcohols. The common characteristic structural elements of the alcohols<br />
with saturated branched chain are one hydroxyl group per molecule, <strong>and</strong> a C 4 –C 12 carbon chain with one<br />
or several methyl side chains. This review contains a detailed summary of all available toxicology <strong>and</strong><br />
dermatology papers that are related to this individual fragrance ingredient <strong>and</strong> is not intended as a<br />
st<strong>and</strong>-alone document. A safety assessment of the entire branched chain saturated alcohol group will<br />
be published simultaneously with this document; please refer to Belsito et al. (2010) <strong>for</strong> an overall assessment<br />
of the safe use of this material <strong>and</strong> all other branched chain saturated alcohols in fragrances.<br />
Ó 2010 Published by Elsevier Ltd.<br />
Contents<br />
Introduction . . . ..................................................................................................... S52<br />
1. Identification . . ..................................................................................................... S52<br />
2. Physical properties . . . . . . . . . . . . . . . . . .................................................................................. S52<br />
3. Usage. . . . . . . . . ..................................................................................................... S52<br />
4. <strong>Toxicology</strong> data ..................................................................................................... S53<br />
4.1. Acutetoxicity................................................................................................ S53<br />
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53<br />
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53<br />
4.2. Skinirritation................................................................................................ S53<br />
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53<br />
4.2.2. Animal studies (see Table 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53<br />
4.3. Mucous membrane (eye) irritation. .............................................................................. S53<br />
4.4. Skinsensitization............................................................................................. S53<br />
4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53<br />
4.4.2. Diagnostic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53<br />
4.4.3. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53<br />
4.5. Phototoxicity <strong>and</strong> photoallergy. . . ............................................................................... S54<br />
4.6. Absorption, distribution <strong>and</strong> metabolism . . ....................................................................... S54<br />
4.7. Repeated dose toxicity . ....................................................................................... S54<br />
4.8. Reproductive <strong>and</strong> developmental toxicity . . ....................................................................... S54<br />
4.9. Genotoxicity. . ............................................................................................... S54<br />
4.10. Carcinogenicity.............................................................................................. S54<br />
Conflict of interest statement . . . . . . . . .................................................................................. S54<br />
References . . . . ..................................................................................................... S54<br />
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.<br />
E-mail address: dmcginty@RIFM.org (D. McGinty).<br />
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.<br />
doi:10.1016/j.fct.2010.05.027
S52<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S51–S54<br />
Introduction<br />
This document provides a summary of the toxicologic review,<br />
including all human health endpoints, of 3,7-dimethyl-7-methoxyoctan-2-ol<br />
when used as a fragrance ingredient. 3,7-Dimethyl-<br />
7-methoxyoctan-2-ol (see Fig. 1; CAS Number 41890-92-0) is a<br />
fragrance ingredient used in cosmetics, fine fragrances, shampoos,<br />
toilet soaps <strong>and</strong> other toiletries as well as in non-cosmetic products<br />
such as household cleaners <strong>and</strong> detergents. It is an almost colorless<br />
liquid <strong>and</strong> has a s<strong>and</strong>alwood odor with a flowery, woodsy note.<br />
In 2006, a complete literature search was conducted on 3,7-Dimethyl-7-methoxyoctan-2-ol.<br />
On-line toxicological databases<br />
were searched including those from the <strong>Chemical</strong> Abstract Services,<br />
[e.g. ToxCenter (which in itself contains 18 databases including<br />
<strong>Chemical</strong> Abstracts)], <strong>and</strong> the National Library of Medicine [e.g.<br />
Medline, Toxnet (which contains 14 databases)] as well as 26 additional<br />
sources (e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition,<br />
fragrance companies were asked to submit all test data.<br />
The safety data on this material was last reviewed by Ford et al.,<br />
1992. All relevant references are included in this document. More<br />
details have been provided <strong>for</strong> unpublished data. The number of<br />
animals, sex <strong>and</strong> strain are always provided unless they are not given<br />
in the original report or paper. Any papers in which the vehicles<br />
<strong>and</strong>/or the doses are not given have not been included in this<br />
review. In addition, diagnostic patch test data with fewer than 100<br />
consecutive patients have been omitted.<br />
1. Identification<br />
1.1. Synonyms: 7-Methoxy-3,7-dimethyloctan-2-ol; 2-Octanol,<br />
7-methoxy-3,7-dimethyl; Osirol; Osyrol; 7-Methoxy-3,7-<br />
dimethyloctan-2-ol.<br />
1.2. CAS Registry number: 41890-92-0.<br />
O<br />
HO<br />
Fig. 1. 3,7-Dimethyl-7-methoxyoctan-2-ol.<br />
1.3. EINECS number: 255-574-7.<br />
1.4. Formula: C 11 H 24 O 2.<br />
1.5. Molecular weight: 188.31.<br />
2. Physical properties<br />
2.1. Physical <strong>for</strong>m: An almost colorless liquid.<br />
2.2. Boiling point (calculated; EPA, 2010): 229.67 °C.<br />
2.3. Flash point:>110 °C (230°F).<br />
2.4. Henry’s law (calculated; EPA, 2010): 0.000000404 atm m 3 /<br />
mol 25 °C.<br />
2.5. Log K ow (calculated; EPA, 2010): 2.76.<br />
2.6. Refractive index: 1.446.<br />
2.7. Specific gravity: 0.898.<br />
2.8. Vapor pressure (calculated; EPA, 2010): 0.0119 mm Hg;<br />
1.58 Pa (25 °C).<br />
2.9. Water solubility (calculated; EPA, 2010): 707.1 mg/l (25 °C).<br />
2.10. UV spectra available at RIFM, peaks at 200–210 nm <strong>and</strong><br />
returns to baseline at 400 nm. Minor absorption from 290–<br />
400 nm.<br />
3. Usage<br />
3,7-Dimethyl-7-methoxyoctan-2-ol is a fragrance ingredient<br />
used in many fragrance compounds. It may be found in fragrances<br />
used in decorative cosmetics, fine fragrances, shampoos, toilet<br />
soaps <strong>and</strong> other toiletries as well as in non-cosmetic products such<br />
as household cleaners <strong>and</strong> detergents. Its use worldwide is in the<br />
region of 1–10 metric tons per annum (IFRA, 2004). The reported<br />
volume of use is <strong>for</strong> 3,7-dimethyl-7-methoxyoctan-2-ol as used<br />
in fragrance compounds (mixtures) in all finished consumer product<br />
categories. The volume of use is surveyed by IFRA approximately<br />
every 4 years through a comprehensive survey of IFRA<br />
<strong>and</strong> RIFM member companies. As such the volume of use data from<br />
this survey provides volume of use of fragrance ingredients <strong>for</strong> the<br />
majority of the fragrance industry.<br />
The dermal systemic exposure in cosmetic products (see Table 1)<br />
is calculated based on the concentrations of the same fragrance<br />
ingredient in ten types of the most frequently used personal care<br />
<strong>and</strong> cosmetic products (anti-perspirant, bath products, body lotion,<br />
eau de toilette, face cream, fragrance cream, hair spray, shampoo,<br />
shower gel, <strong>and</strong> toilet soap). The concentration of the fragrance<br />
ingredient in fine fragrances is obtained from examination of several<br />
thous<strong>and</strong> commercial <strong>for</strong>mulations. The upper 97.5 percentile concentration<br />
is calculated from the data obtained. This upper 97.5 percentile<br />
concentration is then used <strong>for</strong> all 10 consumer products.<br />
These concentrations are multiplied by the amount of product applied,<br />
the number of applications per day <strong>for</strong> each product type,<br />
<strong>and</strong> a ‘‘retention factor” (ranging from 0.001 to 1.0) to account <strong>for</strong><br />
Table 1<br />
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 3,7-dimethyl-7-methoxyoctan-2-ol.<br />
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient mg/kg/day b<br />
Anti-perspirant 0.5 1 1 0.01 3.52 0.0029<br />
Bath products 17 0.29 0.001 0.02 3.52 0.0001<br />
Body lotion 8 0.71 1 0.004 3.52 0.0133<br />
Eau de toilette 0.75 1 1 0.08 3.52 0.0352<br />
Face cream 0.8 2 1 0.003 3.52 0.0028<br />
<strong>Fragrance</strong> cream 5 0.29 1 0.04 3.52 0.0340<br />
Hair spray 5 2 0.01 0.005 3.52 0.0003<br />
Shampoo 8 1 0.01 0.005 3.52 0.0002<br />
Shower gel 5 1.07 0.01 0.012 3.52 0.0004<br />
Toilet soap 0.8 6 0.01 0.015 3.52 0.0004<br />
Total 0.0897<br />
a<br />
b<br />
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.<br />
Based on a 60-kg adult.
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S51–S54 S53<br />
Table 2<br />
Summary of animal irritation studies.<br />
Method Dose Species Results References<br />
Dermal application 1% Rabbit Slight erythema RIFM (1973a)<br />
Occluded dermal application Induction Guinea pig During the induction, three animals exhibited slight<br />
RIFM (1973b)<br />
5%<br />
2.5%<br />
Challenge<br />
2.5%<br />
erythema <strong>and</strong> one was moderate<br />
No response to challenge<br />
the length of time a product may remain on the skin <strong>and</strong>/or likelihood<br />
of the fragrance ingredient being removed by washing. The<br />
resultant calculation represents the total consumer exposure (mg/<br />
kg/day) (Cadby et al., 2002; Ford et al., 2000).<br />
This is a conservative calculation of dermal systemic exposure<br />
because it makes the unlikely assumption that a consumer will<br />
use these 10 products containing; which are all perfumed with<br />
the upper 97.5 percentile level of the fragrance ingredient from a<br />
fine fragrance type of product (Cadby et al., 2002; Ford et al.,<br />
2000). The 97.5% percentile use level in <strong>for</strong>mulae <strong>for</strong> use in cosmetics<br />
in general has been reported to be 3.52 (IFRA, 2007), which<br />
would result in a maximum daily exposure on the skin of<br />
0.0896 mg/kg <strong>for</strong> high end users.<br />
A maximum skin level is then determined <strong>for</strong> consideration of<br />
potential sensitization. The exposure is calculated as the percent<br />
concentration of the fragrance ingredient applied to the skin based<br />
on the use of 20% of the fragrance mixture in the fine fragrance<br />
consumer product (IFRA, 2007). The average maximum use level<br />
in <strong>for</strong>mulae that go into fine fragrances has been reported to be<br />
1.27% (IFRA, 2007), assuming use of the fragrance oil at levels up<br />
to 20% the final product.<br />
4. <strong>Toxicology</strong> data<br />
4.1. Acute toxicity<br />
4.1.1. Oral studies<br />
The acute oral LD 50 of 3,7-dimethyl-7-methoxyoctan-2-ol in<br />
rats was reported to be approximately 5.0 g/kg. Mortality was 2/<br />
5 males at less than 4 h after dosing <strong>and</strong> 3/5 females at less than<br />
23 h after dosing. Symptoms included lethargy, piloerection, diuresis,<br />
salivation, <strong>and</strong> ataxia. Necropsy revealed darkening of the liver<br />
<strong>and</strong> injection of blood vessels of the abdominal viscera. Recovery of<br />
survivors was apparently complete within 8 days of dosing.<br />
Slightly depressed body weight gains were observed during the<br />
first week after dosing in male rats, but returned to normal during<br />
the second week of observation. Terminal necropsy findings of survivors<br />
were normal (RIFM, 1976).<br />
4.1.2. Dermal studies<br />
No available in<strong>for</strong>mation.<br />
4.2. Skin irritation<br />
4.2.1. Human studies<br />
In a human maximization test pre-screen, 10% 3,7-Dimethyl-7-<br />
methoxyoctan-2-ol (6900 lg/cm 2 ) was applied under occlusion to<br />
the backs of 27 healthy subjects <strong>for</strong> 48 h. No significant evidence of<br />
irritation was observed (RIFM, 1982).<br />
4.2.2. Animal studies (see Table 2)<br />
In a rabbit (n = 6) dermal irritation study conducted according<br />
to US FDA Guidelines, 0.5 ml of 1% 3,7-Dimethyl-7-methoxyoctan-2-ol<br />
in propylene glycol on an occlusive 24 h patch was considered<br />
mildly irritating. Very slight erythema was observed in the<br />
intact <strong>and</strong> abraded sites of 5 animals at 24 h. In one animal there<br />
was no observable response to treatment. At 72 h, the reactions<br />
had ameliorated. One animal showed very slight erythema at the<br />
intact <strong>and</strong> abraded sites. There was no observable response to<br />
treatment in the remaining 5 animals. The Primary Irritation Index<br />
was calculated to be 0.5 (RIFM, 1973a).<br />
In a guinea pig (n = 10) sensitization study conducted according<br />
to US FDA Guidelines, irritation was not induced by 0.2 ml of 2.5%<br />
or 5% 3,7-Dimethyl-7-methoxyoctan-2-ol in water applied under<br />
occlusion to a 0.5 inch square to the shaved area of the shoulder<br />
24 h per day on alternate days during a 3 week period <strong>for</strong> a total<br />
of 10 applications. Applications 1 – 7 were at 5% <strong>and</strong> applications<br />
8 – 10 were at 2.5%. Challenge dose was applied in the same manner<br />
using 2.5% 14 days after the last induction dose. Three animals<br />
exhibited 1 grade 1 response <strong>for</strong> erythema once each during the<br />
induction period <strong>and</strong> 1 animal exhibited 2 grade 1 erythema responses<br />
during induction. There were no positive responses following<br />
challenge (RIFM, 1973b).<br />
4.3. Mucous membrane (eye) irritation<br />
In a rabbit (n = 6) eye irritation study conducted according to US<br />
FDA Guidelines, 0.1 ml of 1% 3,7-Dimethyl-7-methoxyoctan-2-ol in<br />
propylene glycol produced only temporary mild conjuctival reactions<br />
in 5 animals. In one animal chemosis of the conjunctiva<br />
was observed. No corneal or iris involvement occurred <strong>and</strong> all effects<br />
cleared within 3 days (RIFM, 1973c).<br />
4.4. Skin sensitization<br />
4.4.1. Human studies<br />
4.4.1.1. Induction studies. In a human Maximization study involving<br />
27 subjects, there was no evidence of contact sensitization to 10%<br />
3,7-Dimethyl-7-methoxyoctan-2-ol (6900 lg/cm 2 ). Test material<br />
was applied in petrolatum under occlusion to the <strong>for</strong>earms <strong>for</strong> a total<br />
of five alternate day, 48 h periods. Each application was preceded<br />
by a 24 h occlusive treatment of the patch sites with 7.5%<br />
aqueous sodium lauryl sulfate. Following a 10–14 day rest period,<br />
challenge patches were applied under occlusion to fresh sites <strong>for</strong><br />
48 h. Challenge applications were preceded by 30 min applications<br />
of 7.5% sodium lauryl sulfate under occlusion on the left side <strong>and</strong><br />
no pretreatment on the right side. Challenge sites were evaluated<br />
at removal of the patches <strong>and</strong> 24 h later (RIFM, 1982).<br />
4.4.1.2. Cross-sensitization. No available in<strong>for</strong>mation.<br />
4.4.2. Diagnostic studies<br />
In a diagnostic patch test study, there were positive responses<br />
to 3,7-dimethyl-7-methoxyoctan-2-ol (concentration not specified)<br />
in 2 of 218 dermatology patients with previous positive reaction<br />
to at least one fragrance material (Larsen et al., 2002).<br />
4.4.3. Animal studies<br />
4.4.3.1. Maximization Test. No available in<strong>for</strong>mation.<br />
4.4.3.2. Other studies. In a guinea pig (n = 10) sensitization study<br />
conducted according to US FDA Guidelines, sensitization was not
S54<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S51–S54<br />
induced by 0.2 ml of 2.5% or 5% 3,7-dimethyl-7-methoxyoctan-2-ol<br />
in water applied under occlusion to a 0.5 inch square to the shaved<br />
area of the shoulder 24 h per day on alternate days during a 3 week<br />
period <strong>for</strong> a total of 10 applications. Applications 1–7 were at 5%<br />
<strong>and</strong> applications 8–10 were at 2.5%. Challenge dose was applied<br />
in the same manner using 2.5% 14 days after the last induction<br />
dose. Three animals exhibited 1 grade 1 response <strong>for</strong> erythema<br />
once each during the induction period <strong>and</strong> 1 animal exhibited<br />
grade 1 erythema responses twice during induction. There were<br />
no positive responses following challenge (RIFM, 1973b).<br />
4.4.3.3. Local Lymph Node Assay (LLNA). No available in<strong>for</strong>mation.<br />
4.5. Phototoxicity <strong>and</strong> photoallergy<br />
No available in<strong>for</strong>mation.<br />
4.6. Absorption, distribution <strong>and</strong> metabolism<br />
No available in<strong>for</strong>mation.<br />
4.7. Repeated dose toxicity<br />
No available in<strong>for</strong>mation.<br />
4.8. Reproductive <strong>and</strong> developmental toxicity<br />
No available in<strong>for</strong>mation.<br />
4.9. Genotoxicity<br />
No available in<strong>for</strong>mation.<br />
4.10. Carcinogenicity<br />
No available in<strong>for</strong>mation.<br />
This individual <strong>Fragrance</strong> Material Review is not intended as a<br />
st<strong>and</strong>-alone document. Please refer to A Safety Assessment of<br />
Branched Chain Saturated Alcohols When Used as <strong>Fragrance</strong> Ingredients<br />
(Belsito et al., 2010) <strong>for</strong> an overall assessment of this<br />
material.<br />
Conflict of interest statement<br />
This research was supported by the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong><br />
Materials, an independent research institute that is funded<br />
by the manufacturers of fragrances <strong>and</strong> consumer products containing<br />
fragrances. The authors are all employees of the <strong>Research</strong><br />
<strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials.<br />
References<br />
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,<br />
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chain<br />
saturated alcohols when used as fragrance ingredients. <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong><br />
<strong>Toxicology</strong> 48 (S4), S1–S46.<br />
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:<br />
providing estimates <strong>for</strong> safety evaluation. Regulatory <strong>Toxicology</strong> <strong>and</strong><br />
Pharmacology 36, 246–252.<br />
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface<br />
Suite <strong>for</strong> Microsoft Ò Windows, V 4.00 or Insert Version Used. United States<br />
Environmental Protection Agency, Washington, DC, USA.<br />
Ford, R.A., Api, A.M., Letizia, C.S., 1992. Monograph on 3,7-dimethyl-7-<br />
methoxyoctan-2-ol. <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 30 (Suppl.), 25S.<br />
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria <strong>for</strong><br />
development of a database <strong>for</strong> safety evaluation of fragrance ingredients.<br />
Regulatory <strong>Toxicology</strong> <strong>and</strong> Pharmacology 31, 166–181.<br />
IFRA (International <strong>Fragrance</strong> Association), 2004. Use Level Survey, August 2004.<br />
IFRA (International <strong>Fragrance</strong> Association), 2007. Volume of Use Survey, February<br />
2007.<br />
Larsen, W., Nakayama, H., Fischer, T., Elsner, P., Frosch, P., Burrows, D., Jordan, W.,<br />
Shaw, S., Wilkinson, J., Marks, J., Sugawara, M., Nethercott, M., Nethercott, J.,<br />
2002. <strong>Fragrance</strong> contact dermatitis – a worldwide multicenter investigation<br />
(Part III). Contact Dermatitis 46 (3), 141–144.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1973a. Irritant Effects of<br />
3,7-Dimethyl-7-methoxyoctan-2-ol on Rabbit Skin. Unpublished Report from<br />
Bush Boake Allen Ltd., 07 June. Report Number 1765. RIFM, Woodcliff Lake,<br />
NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1973b. Screening Test <strong>for</strong><br />
Delayed Dermal Sensitization with 3,7-Dimethyl-7-methoxyoctan-2-ol in the<br />
Albino Guinea Pig. Unpublished Report from Bush Boake Allen Ltd., 03 May.<br />
Report Number 1766. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1973c. Irritant effects of 3,7-<br />
Dimethyl-7-methoxyoctan-2-ol on Rabbit Eye Mucosa. Unpublished Report<br />
from Bush Boake Allen Ltd., 07 June. Report Number 1767. RIFM, Woodcliff<br />
Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1976. Acute Oral Toxicity of<br />
Valanone B, Cytenol, 3,7-Dimethyl-7-methoxyoctan-2-ol, 8-Methoxy-pmenthene<br />
<strong>and</strong> Pinocarvyl Acetate in Rats. Unpublished Report from Bush<br />
Boake Allen Ltd., 23 March. Report Number 1764. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1982. Report on Human<br />
Maximization Studies. RIFM Report Number 1643, October 05. RIFM, Woodcliff<br />
Lake, NJ, USA.
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S55–S59<br />
Contents lists available at ScienceDirect<br />
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong><br />
journal homepage: www.elsevier.com/locate/foodchemtox<br />
Review<br />
<strong>Fragrance</strong> material review on 4-methyl-2-pentanol<br />
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api<br />
<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA<br />
article<br />
Keywords:<br />
Review<br />
<strong>Fragrance</strong><br />
info<br />
abstract<br />
A toxicologic <strong>and</strong> dermatologic review of 4-methyl-2-pentanol when used as a fragrance ingredient is<br />
presented. 4-Methyl-2-pentanol is a member of the fragrance structural group branched chain saturated<br />
alcohols. The common characteristic structural elements of the alcohols with saturated branched chain<br />
are one hydroxyl group per molecule, <strong>and</strong> a C 4 –C 12 carbon chain with one or several methyl side chains.<br />
This review contains a detailed summary of all available toxicology <strong>and</strong> dermatology papers that are<br />
related to this individual fragrance ingredient <strong>and</strong> is not intended as a st<strong>and</strong>-alone document. A safety<br />
assessment of the entire branched chain saturated alcohol group will be published simultaneously with<br />
this document; please refer to Belsito et al. (2010) <strong>for</strong> an overall assessment of the safe use of this material<br />
<strong>and</strong> all other branched chain saturated alcohols in fragrances.<br />
Ó 2010 Published by Elsevier Ltd.<br />
Contents<br />
Introduction . . . ..................................................................................................... S56<br />
1. Identification . . ..................................................................................................... S56<br />
2. Physical properties . . . . . . . . . . . . . . . . . .................................................................................. S56<br />
3. Usage. . . . . . . . . ..................................................................................................... S56<br />
4. <strong>Toxicology</strong> data ..................................................................................................... S57<br />
4.1. Acute toxicity (see Table 2). ..................................................................................... S57<br />
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57<br />
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57<br />
4.1.3. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57<br />
4.1.4. Miscellaneous studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57<br />
4.2. Skin irritation. ................................................................................................ S57<br />
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57<br />
4.2.2. Animal studies (see Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57<br />
4.3. Mucous membrane (eye) irritation (see Table 4) .................................................................... S57<br />
4.4. Skin sensitization. ............................................................................................. S57<br />
4.5. Phototoxicity <strong>and</strong> photoallergy. . ................................................................................. S57<br />
4.6. Absorption, distribution <strong>and</strong> metabolism .......................................................................... S57<br />
4.6.1. Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57<br />
4.6.2. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57<br />
4.6.3. Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57<br />
4.7. Repeated dose toxicity . . ....................................................................................... S58<br />
4.8. Reproductive <strong>and</strong> developmental toxicity .......................................................................... S58<br />
4.9. Genotoxicity. ................................................................................................. S58<br />
4.9.1. In vitro studies........................................................................................ S58<br />
4.9.2. In vivo studies ........................................................................................ S58<br />
4.10. Carcinogenicity . . ............................................................................................. S58<br />
Conflict of interest statement . . . . . . . . .................................................................................. S58<br />
References . . . . ..................................................................................................... S58<br />
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.<br />
E-mail address: dmcginty@RIFM.org (D. McGinty).<br />
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.<br />
doi:10.1016/j.fct.2010.05.028
S56<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S55–S59<br />
Introduction<br />
2. Physical properties<br />
This document provides a comprehensive summary of the<br />
toxicologic review, including all human health endpoints, of<br />
4-Methyl-2-pentanol when used as a fragrance ingredient.<br />
4-Methyl-2-pentanol (see Fig. 1; CAS Number 108-11-2) is a fragrance<br />
ingredient used in cosmetics, fine fragrances, shampoos,<br />
toilet soaps <strong>and</strong> other toiletries as well as in non-cosmetic products<br />
such as household cleaners <strong>and</strong> detergents. This material<br />
has been reported to occur in nature, with highest quantities<br />
observed in annatto extract (VCF, 2009).<br />
In 2006, a complete literature search was conducted on 4-<br />
Methyl-2-pentanol. On-line toxicological databases were searched<br />
including those from the <strong>Chemical</strong> Abstract Services, [e.g., ToxCenter<br />
(which in itself contains 18 databases including <strong>Chemical</strong> Abstracts)],<br />
<strong>and</strong> the National Library of Medicine [e.g., Medline,<br />
Toxnet (which contains 14 databases)] as well as 26 additional<br />
sources (e.g., BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance<br />
companies were asked to submit all test data.<br />
The safety data on this material has never been reviewed be<strong>for</strong>e<br />
by RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.). All relevant<br />
references are included in this document. More details have<br />
been provided <strong>for</strong> unpublished data. The number of animals, sex<br />
<strong>and</strong> strain are always provided unless they are not given in the original<br />
report or paper. Any papers in which the vehicles <strong>and</strong>/or the<br />
doses are not given have not been included in this review. In addition,<br />
diagnostic patch test data with fewer than 100 consecutive<br />
patients have been omitted.<br />
1. Identification<br />
1.1. Synonyms: Isobutyl methyl carbinol; 4-methylpentan-2-ol;<br />
methyl isobutyl carbinol; MIC; 2-pentanol, 4-methyl-<br />
1.2. CAS registry number: 108-11-2.<br />
1.3. EINECS number: 203-551-7.<br />
1.4. Formula: C 6 H 14 O.<br />
1.5. Molecular weight: 102.18.<br />
HO<br />
Fig. 1. 4-Methyl-2-pentanol.<br />
2.1. Physical <strong>for</strong>m: no in<strong>for</strong>mation available.<br />
2.2. Boiling point (calculated; EPA, 2010): 124.88 °C.<br />
2.3. Flash point: no in<strong>for</strong>mation available.<br />
2.4. Henry’s law (calculated; EPA, 2010): 0.0000176 atm m 3 /mol<br />
25 °C.<br />
2.5. Log K ow (calculated; EPA, 2010): 1.68.<br />
2.6. Refractive index: no in<strong>for</strong>mation available.<br />
2.7. Specific gravity: no in<strong>for</strong>mation available.<br />
2.8. Vapor pressure (calculated; EPA, 2010): 3.7 mm Hg 20 °C;<br />
3.74 mm Hg (25 °C); 498 Pa (25 °C).<br />
2.9. Water solubility (calculated; EPA, 2010): 13,800 mg/l at<br />
25 °C.<br />
2.10. UV spectra not available at RIFM.<br />
3. Usage<br />
4-Methyl-2-pentanol is a fragrance ingredient used in many fragrance<br />
compounds. It may be found in fragrances used in decorative<br />
cosmetics, fine fragrances, shampoos, toilet soaps <strong>and</strong> other<br />
toiletries as well as in non-cosmetic products such as household<br />
cleaners <strong>and</strong> detergents. Its use worldwide is in the region of<br />
0.01–0.1 metric tons per annum (IFRA, 2004). The reported volume<br />
is <strong>for</strong> the use of 4-methyl-2-pentanol used in fragrance compounds<br />
(mixtures) used in all finished consumer product categories. The<br />
volume of use is surveyed by IFRA approximately every four years<br />
through a comprehensive survey of IFRA <strong>and</strong> RIFM member companies.<br />
As such the volume of use data from this survey provides<br />
volume of use of fragrance ingredients <strong>for</strong> the majority of the fragrance<br />
industry.<br />
The dermal systemic exposure in cosmetic products (see Table 1)<br />
is calculated based on the concentrations of the same fragrance<br />
ingredient in ten types of the most frequently used personal care<br />
<strong>and</strong> cosmetic products (anti-perspirant, bath products, body lotion,<br />
eau de toilette, face cream, fragrance cream, hair spray, shampoo,<br />
shower gel, <strong>and</strong> toilet soap). The concentration of the fragrance<br />
ingredient in fine fragrances is obtained from examination of several<br />
thous<strong>and</strong> commercial <strong>for</strong>mulations. The upper 97.5 percentile concentration<br />
is calculated from the data obtained. This upper 97.5 percentile<br />
concentration is then used <strong>for</strong> all 10 consumer products.<br />
These concentrations are multiplied by the amount of product applied,<br />
the number of applications per day <strong>for</strong> each product type,<br />
<strong>and</strong> a ‘‘retention factor” (ranging from 0.001 to 1.0) to account <strong>for</strong><br />
the length of time a product may remain on the skin <strong>and</strong>/or likelihood<br />
of the fragrance ingredient being removed by washing. The<br />
resultant calculation represents the total consumer exposure (mg/<br />
kg/day) (Cadby et al., 2002; Ford et al., 2000).<br />
Table 1<br />
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 4-methyl-2-pentanol.<br />
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient (mg/kg/day) b<br />
Anti-perspirant 0.5 1 1 0.01 .02 0.000001<br />
Bath products 17 0.29 0.001 0.02 .02 0.000001<br />
Body lotion 8 0.71 1 0.004 .02 0.000100<br />
Eau de toilette 0.75 1 1 0.08 .02 0.000200<br />
Face cream 0.8 2 1 0.003 .02 0.000001<br />
<strong>Fragrance</strong> cream 5 0.29 1 0.04 .02 0.000200<br />
Hair spray 5 2 0.01 0.005 .02 0.000001<br />
Shampoo 8 1 0.01 0.005 .02 0.000001<br />
Shower gel 5 1.07 0.01 0.012 .02 0.000001<br />
Toilet soap 0.8 6 0.01 0.015 .02 0.000001<br />
Total 0.0005<br />
a<br />
b<br />
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.<br />
Based on a 60-kg adult.
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S55–S59 S57<br />
Table 2<br />
Summary of acute toxicity studies.<br />
Route Species No. animals/<br />
dose group<br />
This is a conservative calculation of dermal systemic exposure<br />
because it makes the unlikely assumption that a consumer will<br />
use these 10 products containing; which are all perfumed with<br />
the upper 97.5 percentile level of the fragrance ingredient from a<br />
fine fragrance type of product (Cadby et al., 2002; Ford et al.,<br />
2000). The 97.5 percentile use level in <strong>for</strong>mulae <strong>for</strong> use in cosmetics<br />
<strong>for</strong> 2-ethyl-1-hexanol has been reported to be 0.02% (IFRA,<br />
2007), which would result in a maximum daily exposure on the<br />
skin of 0.0005 mg/kg <strong>for</strong> high end users (see Table 1).<br />
A maximum skin level is then determined <strong>for</strong> consideration of<br />
potential sensitization. The exposure is calculated as the percent<br />
concentration of the fragrance ingredient applied to the skin based<br />
on the use of 20% of the fragrance mixture in the fine fragrance<br />
consumer product (IFRA, 2007). The maximum skin level that results<br />
from the use of 4-Methyl-2-pentanol in <strong>for</strong>mulae that go into<br />
fine fragrances has not been reported. A default value of 0.02% is<br />
used assuming use of the fragrance oils at levels up to 20% in the<br />
final product.<br />
4. <strong>Toxicology</strong> data<br />
4.1. Acute toxicity (see Table 2)<br />
LD 50<br />
(g/kg)<br />
References<br />
Oral Rat 5 2.59 Smyth et al., 1951<br />
Oral Rat N/A 2.95 Bar <strong>and</strong> Griepentrog, 1967<br />
Oral Rat N/A 2.59 Nishimura et al., 1994<br />
Dermal Rabbit 5 3.56 Smyth et al., 1951<br />
Table 3<br />
Summary of animal irritation studies.<br />
Method<br />
Dose<br />
(%)<br />
Species Reactions References<br />
Dermal irritation 100 Rabbit Trace of capillary<br />
injection<br />
Dermal irritation 100 Rabbit Dry skin with some<br />
sloughing <strong>and</strong><br />
cracking<br />
4.1.1. Oral studies<br />
The acute oral LD 50 of 4-methyl-2-pentanol in five rats was reported<br />
to be 2.59 (2.26–2.97) g/kg. No additional details were reported<br />
(Smyth et al., 1951).<br />
The acute oral LD 50 of 4-methyl-2-pentanol in rats was reported<br />
to be 2.95 g/kg. No additional details were reported (Bar <strong>and</strong> Griepentrog,<br />
1967).<br />
The acute oral LD 50 of 4-methyl-2-pentanol in rats was reported<br />
to be 2.59 g/kg. No additional details were reported (Nishimura<br />
et al., 1994).<br />
4.1.2. Dermal studies<br />
The acute dermal LD 50 of 4-methyl-2-pentanol in rabbits was<br />
reported to be 3.56 (2.72–4.76) ml/kg (3.56 g/kg). No additional<br />
details were reported (Smyth et al., 1951).<br />
Table 4<br />
Summary of eye irritation studies.<br />
Smyth et al.,<br />
1951<br />
McOmie <strong>and</strong><br />
Anderson,<br />
1949<br />
Dose (%) Reactions References<br />
100 Irritation observed Smyth et al., 1951<br />
100 Irritation observed McOmie <strong>and</strong> Anderson, 1949<br />
4.1.3. Inhalation studies<br />
The acute inhalation exposure of six rats to 4-methyl-2-pentanol<br />
at 2000 ppm <strong>for</strong> 8 h was reported to result in mortality of<br />
5/6. The maximum time <strong>for</strong> no death was 2 h. No additional details<br />
were reported (Smyth et al., 1951; Carpenter et al., 1949).<br />
When mice were exposed to 4-methyl-2-pentanol vapor saturated<br />
air at 20 °C, mortality was 0, 0, 6, <strong>and</strong> 8 of 10 animals following<br />
4, 8.5, 10, <strong>and</strong> 15 h, respectively. The observation period was<br />
7 days. Somnolence was induced in 1 h, anesthesia in 4 h, <strong>and</strong><br />
death in 10 h. No additional details were reported (McOmie <strong>and</strong><br />
Anderson, 1949).<br />
4.1.4. Miscellaneous studies<br />
No available In<strong>for</strong>mation.<br />
4.2. Skin irritation<br />
4.2.1. Human studies<br />
No available in<strong>for</strong>mation.<br />
4.2.2. Animal studies (see Table 3)<br />
In a rabbit skin irritation study, 4-methyl-2-pentanol induced<br />
grade 2 irritation defined as an average reaction equivalent to a<br />
trace of capillary injection. No additional details were reported<br />
(Smyth et al., 1951, 1949).<br />
In a three rabbit skin irritation study, exposure of rabbits to vapors<br />
of 4-methyl-2-pentanol <strong>for</strong> 0.25 h resulted in immediate<br />
slight erythema <strong>and</strong> delayed moderate erythema with drying of<br />
surface. Five direct applications of the 3.0 ml/kg over a 100 cm 2<br />
area material to the skin of rabbits (n = 3) resulted in severe drying<br />
of skin with some sloughing <strong>and</strong> cracking (McOmie <strong>and</strong> Anderson,<br />
1949).<br />
4.3. Mucous membrane (eye) irritation (see Table 4)<br />
In a rabbit eye irritation study, 0.005 ml of undiluted 4-methyl-<br />
2-pentanol induced injury of up to 5.0 points. A score of five points<br />
is given <strong>for</strong> necrosis on 63–87% visible after fluorescein staining,<br />
without corneal opacity. No additional details were reported<br />
(Smyth et al., 1951, 1949).<br />
In a three rabbit eye irritation study conducted according to the<br />
method of Draize, 4-methyl-2-pentanol produced moderate irritation;<br />
some conjunctivitis with some edema <strong>and</strong> corneal injury but<br />
returned to normal after 7 days (McOmie <strong>and</strong> Anderson, 1949).<br />
4.4. Skin sensitization<br />
No available in<strong>for</strong>mation.<br />
4.5. Phototoxicity <strong>and</strong> photoallergy<br />
No available in<strong>for</strong>mation.<br />
4.6. Absorption, distribution <strong>and</strong> metabolism<br />
4.6.1. Absorption<br />
No available in<strong>for</strong>mation.<br />
4.6.2. Distribution<br />
No available in<strong>for</strong>mation.<br />
4.6.3. Metabolism<br />
4.6.3.1. In vivo studies in animals. 4-Methyl-2-pentanol (methyl isobutyl<br />
carbinol, MIBC) is an oxygenated solvent that is metabolized<br />
to methylisobutyl ketone (MIBK) <strong>and</strong> then to 4-hydroxymethyl-2-<br />
pentanone (HMP). Plasma levels of MIBC, MIBK, <strong>and</strong> HMP were
S58<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S55–S59<br />
Table 5<br />
Summary of bacterial studies.<br />
Test system Concentration Results References<br />
Ames assay with <strong>and</strong> without S9 activation Salmonella typhimurium<br />
Up to 5000 lg/plate Not mutagenic Shimizu et al., 1985<br />
TA98, TA100, TA 1535, TA1537 <strong>and</strong> TA 1538<br />
Escerichia coli WP 2 uvrA<br />
Ames assay with <strong>and</strong> without S9 activation Salmonella typhimurium<br />
31.25–4000 lg/plate Not mutagenic OECD/SIDS, 2007<br />
TA98, TA100, TA 1535, TA1537 <strong>and</strong> TA 1538<br />
Escerichia coli WP 2 uvrA pkm 101<br />
Mutation assay Saccharomyces cerevisiae JD1 10–5000 lg/plate Not mutagenic OECD/SIDS, 2007<br />
determined up to 12 h after oral gavage administration of 5 mmol/<br />
kg of MIBC or MIBK (510 <strong>and</strong> 500 mg/kg, respectively) in corn oil to<br />
male Sprague–Dawley rats (n = at least three blood samples per<br />
sampling time). The major material in the plasma <strong>for</strong> both test<br />
materials was HMP, with similar areas under the curve (AUCs)<br />
<strong>and</strong> C-max at 9 h after dosing <strong>for</strong> both MIBC <strong>and</strong> MIBK. MIBK plasma<br />
levels <strong>and</strong> AUC were also comparable after MIBK or MIBC<br />
administration. MIBC AUC was only about 6% of the total material<br />
in the blood following MIBC administration, <strong>and</strong> insignificant after<br />
MIBK administration. No other metabolites were detected in the<br />
plasma. The extent of metabolism of MIBC to MIBK was at least<br />
73% (Gingell et al., 2003; Granvil et al., 1994).<br />
In an occupational exposure study of workers exposed to mixed<br />
solvents including MIBK or MIBK alone, 4-methyl-2-pentanol was<br />
identified by GCMS in the urine (Hirota, 1991a).<br />
4-Methyl-2-pentanol was identified as a metabolite following<br />
intraperitoneal administration of MIBK to rats (Hirota, 1991b).<br />
Excessive urinary glucuronide excretion, compared to that of<br />
controls, by rabbits (n = 3) following oral gavage administration<br />
of 3 ml/rabbit of 4-methyl-2-pentanol, represented 33.7% of the<br />
administered dose (Kamil et al., 1953).<br />
4.6.3.2. In vitro studies in animals. No available in<strong>for</strong>mation.<br />
4.7. Repeated dose toxicity<br />
4-Methyl-2-pentanol was exposed to nine mice 12 times <strong>for</strong> 4 h<br />
at 20 mg/l. No deaths were observed (McOmie <strong>and</strong> Anderson,<br />
1949).<br />
4-Methyl-2-pentanol was given at doses of 0, 50.5, 198, or<br />
886 ml/m 3 to Wistar rats (12/sex) <strong>for</strong> 6 h per day, 5 days a week,<br />
over the course of 6 weeks according to OECD guideline TG 407.<br />
At the two lowest doses the concentration of ketone bodies in<br />
the urine increased <strong>for</strong> males <strong>and</strong> females. At 886 ml/m 3 the absolute<br />
kidney weight increased (males) <strong>and</strong> the serum alkaline phosphatase<br />
increased (females). The authors concluded a NOAEC at<br />
198 ml/m 3 (OECD/SIDS 2007).<br />
4.8. Reproductive <strong>and</strong> developmental toxicity<br />
No available in<strong>for</strong>mation.<br />
4.9. Genotoxicity<br />
4.9.1. In vitro studies<br />
4.9.1.1. Bacterial test systems (see Table 5). 4-Methyl-2-pentanol up<br />
to 5000 lg/plate was not mutagenic in Salmonella typhimurium<br />
strains TA 98, TA 100, TA1535, TA 1537, <strong>and</strong> TA 1538 <strong>and</strong> Escerichia<br />
coli strain WP 2 uvrA, Ames with <strong>and</strong> without addition of S9 liver<br />
fractions from KC500 induced rats (Shimizu et al., 1985).<br />
An Ames assay with <strong>and</strong> without metabolic activation found 4-<br />
methyl-2-pentanol as non-mutagenic using Salmonella typhimurium<br />
TA98, TA100, TA1535, TA1537, TA1538, E. coli WP2 uvr A<br />
pkm 101 at 31.25–4000 lg/plate (OECD/SIDS, 2007).<br />
4-Methyl-2-pentanol is not mutagenic according to a gene<br />
mutation study with <strong>and</strong> without metabolic activation in saccharomyces<br />
cerevisiae JD1 at 10–5000 lg/plate (OECD/SIDS, 2007).<br />
4.9.1.2. Studies in mammalian cells. Rat liver cells (RL4) were tested<br />
in a cytogenetic assay with 0, 0.5, 1, or 2 mg/ml of 4-methyl-2-<br />
pentanol. According to the conditions of this study the results were<br />
negative (OECD/SIDS, 2007).<br />
4.9.2. In vivo studies<br />
No available in<strong>for</strong>mation.<br />
4.10. Carcinogenicity<br />
No available in<strong>for</strong>mation.<br />
This individual <strong>Fragrance</strong> Material Review is not intended as a<br />
st<strong>and</strong>-alone document. Please refer to A Safety Assessment of<br />
Branched Chain Saturated Alcohols When Used as <strong>Fragrance</strong> Ingredients<br />
(Belsito et al., 2010) <strong>for</strong> an overall assessment of this<br />
material.<br />
Conflict of interest statement<br />
This research was supported by the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong><br />
<strong>Fragrance</strong> Materials, an independent research institute that is<br />
funded by the manufacturers of fragrances <strong>and</strong> consumer products<br />
containing fragrances. The authors are all employees of the<br />
<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials.<br />
References<br />
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,<br />
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chain<br />
saturated alcohols when used as fragrance ingredients. <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong><br />
<strong>Toxicology</strong> 48 (S4), S1–S46.<br />
Bar, V.F., Griepentrog, F., 1967. Die Situation in der gesundheitlichen Beurteilung<br />
der Aromatisierungsmittel fur Lebensmittel (where we st<strong>and</strong> concerning the<br />
evaluation of flavoring substances from the viewpoint of health). Medizin<br />
Ernahr. 8, 244–251.<br />
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:<br />
providing estimates <strong>for</strong> safety evaluation. Regulatory <strong>Toxicology</strong> <strong>and</strong><br />
Pharmacology 36, 246–252.<br />
Carpenter, C.P., Smyth, H.F., Pozzani, U.C., 1949. The assay of acute vapor toxicity,<br />
<strong>and</strong> the grading <strong>and</strong> interpretation of results on 96 chemical compounds. The<br />
Journal of Industrial Hygiene <strong>and</strong> Toxicolology 31 (6), 343–346.<br />
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface<br />
Suite <strong>for</strong> Microsoft Ò Windows, v 4.00 or insert version used. United States<br />
Environmental Protection Agency, Washington, DC, USA.<br />
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria <strong>for</strong><br />
development of a database <strong>for</strong> safety evaluation of fragrance ingredients.<br />
Regulatory <strong>Toxicology</strong> <strong>and</strong> Pharmacology 31, 166–181.<br />
Gingell, R., Regnier, J.F., Wilson, D.M., Guillaumat, P.O., Appelqvist, T., 2003.<br />
Comparative metabolism of methyl isobutyl carbinol <strong>and</strong> methyl isobutyl<br />
ketone in male rats. <strong>Toxicology</strong> Letters 136 (1–2), 199–204.<br />
Granvil, C.P., Sharkawi, M., Plaa, G.L., 1994. Metabolic fate of methyl n-butyl ketone,<br />
methyl isobutyl ketone <strong>and</strong> their metabolites in mice. <strong>Toxicology</strong> Letters 70 (3),<br />
263–267.<br />
Hirota, N., 1991a. The metabolism of methyl isobutyl ketone <strong>and</strong> biological<br />
monitoring: part 2. Qualitative <strong>and</strong> quantitative study of 4-methyl-2-pentanol<br />
excreted in the urine of workers exposed to methyl isobutyl ketone. Okayama<br />
Igakkai Zasshi 103 (4), 327–336.
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S55–S59 S59<br />
Hirota, N., 1991b. The metabolism of methyl isobutyl ketone <strong>and</strong> its biological<br />
monitoring: part 1. Qualitative <strong>and</strong> quantitative studies of methyl isobutyl<br />
ketone exhaled from the lungs <strong>and</strong> excreted in the urine, <strong>and</strong> the metabolites in<br />
the urine of rats inject. Okayama Igakkai Zasshi 103 (4), 315–326.<br />
IFRA (International <strong>Fragrance</strong> Association), 2004. Use level survey, August 2004.<br />
IFRA (International <strong>Fragrance</strong> Association), 2007. Volume of use survey, February<br />
2007.<br />
Kamil, I.A., Smith, J.N., Williams, R.T., 1953. Studies in detoxication. 46. The<br />
metabolism of aliphatic alcohols. The glucuronic acid conjugation of acyclic<br />
aliphatic alcohols. Biochemical Journal 53, 129–136.<br />
McOmie, W.A., Anderson, H.H., 1949. Comparative toxicologic effects of some<br />
isobutyl carbinols <strong>and</strong> ketones. University Cali<strong>for</strong>nia Publications Pharmacology<br />
2 (17), 217–230.<br />
Nishimura, H., Saito, S., Kishida, F., Matsuo, M., 1994. Analysis of acute toxicity<br />
(LD50-value) of organic chemicals to mammals by solubility parameter (delta).<br />
1. Acute oral toxicity to rats. Sangyo Igaku 36 (5), 314–323. Japanese Journal<br />
Industrial Health.<br />
OECD <strong>and</strong> Screening In<strong>for</strong>mation Datasets (SIDS), (2007). High production volume<br />
chemicals 4-methylpentan-2-ol (Cas no: 108-11-2). Processed by United<br />
Nations Environmental Program, (UNEP) available online: .<br />
Shimizu, H., Suzuki, Y., Takemura, N., Goto, S., Matsushita, H., 1985. The results of<br />
microbial mutation test <strong>for</strong> <strong>for</strong>ty-three industrial chemicals. Japanese Journal of<br />
Industrial Health 27 (6), 400–419.<br />
Smyth, H.F., Carpenter, C.P., Weil, C.S., 1949. Range-finding toxicity data, list III. The<br />
Journal of Industrial Hygiene <strong>and</strong> Toxicolology 31 (1), 60–62.<br />
Smyth, H.F., Carpenter, C.P., Weil, C.S., 1951. Range finding toxicity data: List IV.<br />
Archives of Industrial Hygiene <strong>and</strong> Occupational Medicine 4, 119–122.<br />
VCF, 2009. (Volatile Compounds in <strong>Food</strong>): database/Nijssen, L.M., Ingen-Visscher,<br />
C.A. van, Donders, J.J.H. (Eds.). – Version 11.1.1 – TNO Quality of Life, Zeist, The<br />
Netherl<strong>and</strong>s, 1963–2009.
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S60–S62<br />
Contents lists available at ScienceDirect<br />
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong><br />
journal homepage: www.elsevier.com/locate/foodchemtox<br />
Review<br />
<strong>Fragrance</strong> material review on 2-methylundecanol<br />
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api<br />
<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA<br />
article<br />
Keywords:<br />
Review<br />
<strong>Fragrance</strong><br />
info<br />
abstract<br />
A toxicologic <strong>and</strong> dermatologic review of 2-methylundecanol when used as a fragrance ingredient is presented.<br />
2-Methylundecanol is a member of the fragrance structural group branched chain saturated alcohols.<br />
The common characteristic structural elements of the alcohols with saturated branched chain are<br />
one hydroxyl group per molecule, <strong>and</strong> a C 4 –C 12 carbon chain with one or several methyl side chains. This<br />
review contains the in<strong>for</strong>mation available on this individual fragrance ingredient <strong>and</strong> is not intended as a<br />
st<strong>and</strong>-alone document. A safety assessment of the entire branched chain saturated alcohol group will be<br />
published simultaneously with this document; please refer to Belsito et al. (2010) <strong>for</strong> an overall assessment<br />
of the safe use of this material <strong>and</strong> all other branched chain saturated alcohols in fragrances.<br />
Ó 2010 Published by Elsevier Ltd.<br />
Contents<br />
Introduction ........................................................................................................ S60<br />
1. Identification . . . . . . . . . . . . . . . ........................................................................................ S60<br />
2. Physical properties . . . . . . . . . . . ........................................................................................ S60<br />
3. Usage. . . . . . ........................................................................................................ S61<br />
4. <strong>Toxicology</strong> data . . . . . . . . . . . . . ........................................................................................ S61<br />
Conflict of interest statement . . ........................................................................................ S62<br />
References . ........................................................................................................ S62<br />
Introduction<br />
This document provides a summary of the toxicologic review,<br />
including all human health endpoints, of 2-methylundecanol when<br />
used as a fragrance ingredient. 2-Methylundecanol (see Fig. 1; CAS<br />
Number 10522-26-6) is a fragrance ingredient used in cosmetics,<br />
fine fragrances, shampoos, toilet soaps <strong>and</strong> other toiletries as well<br />
as in non-cosmetic products such as household cleaners <strong>and</strong><br />
detergents.<br />
In 2006, a complete literature search was conducted on 2-Methylundecanol.<br />
On-line toxicological databases were searched<br />
including those from the <strong>Chemical</strong> Abstract services, [e.g., ToxCenter<br />
(which in itself contains 18 databases including <strong>Chemical</strong> Abstracts)],<br />
<strong>and</strong> the National Library of Medicine [e.g., Medline,<br />
Toxnet (which contains 14 databases)] as well as 26 additional<br />
sources (e.g., BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance<br />
companies were asked to submit all test data.<br />
The safety data on this material has never been reviewed be<strong>for</strong>e<br />
by RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.). All relevant<br />
references are included in this document. More details have<br />
been provided <strong>for</strong> unpublished data. The number of animals, sex<br />
<strong>and</strong> strain are always provided unless they are not given in the original<br />
report or paper. Any papers in which the vehicles <strong>and</strong>/or the<br />
doses are not given have not been included in this review. In addition,<br />
diagnostic patch test data with fewer than 100 consecutive<br />
patients have been omitted.<br />
1. Identification<br />
1.1 Synonyms: 1-undecanol, 2-methyl-; 2-methylundecan-1-ol<br />
1.2 CAS registry number: 10522-26-6<br />
1.3 EINECS number: 234-067-4<br />
1.4 Formula: C 12 H 26 O<br />
1.5 Molecular weight: 186.39<br />
2. Physical properties<br />
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.<br />
E-mail address: dmcginty@RIFM.org (D. McGinty).<br />
2.1 Physical <strong>for</strong>m: no in<strong>for</strong>mation available<br />
2.2 Boiling point (calculated; EPA, 2010): 262.99 °C<br />
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.<br />
doi:10.1016/j.fct.2010.05.029
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S60–S62 S61<br />
2.3 Flash point: no in<strong>for</strong>mation available<br />
2.4 Henry’s law (calculated; EPA, 2010): 0.0000963 atm m 3 /mol<br />
25 °C<br />
2.5 Log K ow (calculated; EPA, 2010): 4.7<br />
2.6 Refractive index: no in<strong>for</strong>mation available<br />
2.7 Specific gravity: no in<strong>for</strong>mation available<br />
2.8 Vapor pressure (calculated; EPA, 2010): 0.0014 mm Hg;<br />
0.186 Pa (25 °C)<br />
2.9 Water solubility (calculated; EPA, 2010): 16.18 mg/l (25 °C)<br />
2.10 UV spectra available at RIFM, peaks at 200–205 nm <strong>and</strong><br />
returns to baseline at 270–280 nm<br />
3. Usage<br />
Fig. 1. 2-Methylundecanol.<br />
2-Methylundecanol is a fragrance ingredient used in many fragrance<br />
compounds. It may be found in fragrances used in decorative<br />
cosmetics, fine fragrances, shampoos, toilet soaps <strong>and</strong> other<br />
toiletries as well as in non-cosmetic products such as household<br />
cleaners <strong>and</strong> detergents. Its use worldwide is in the region of<br />
S62<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S60–S62<br />
Conflict of interest statement<br />
This research was supported by the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong><br />
Materials, an independent research institute that is funded<br />
by the manufacturers of fragrances <strong>and</strong> consumer products containing<br />
fragrances. The authors are all employees of the <strong>Research</strong><br />
<strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials.<br />
References<br />
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,<br />
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A toxicologic <strong>and</strong> dermatologic<br />
assessment of alcohols branched chain saturated when used as fragrance<br />
ingredients. <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong>, this issue 48 (S4), S1–S46.<br />
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:<br />
providing estimates <strong>for</strong> safety evaluation. Regulatory <strong>Toxicology</strong> <strong>and</strong><br />
Pharmacology 36, 246–252.<br />
EPA (Environmental Protection Agency), 2010. Estimation programs interface<br />
suite <strong>for</strong> Microsoft Ò Windows, v 4.00 or insert version used]. United States<br />
Environmental Protection Agency, Washington, DC, USA.<br />
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria <strong>for</strong><br />
development of a database <strong>for</strong> safety evaluation of fragrance ingredients.<br />
Regulatory <strong>Toxicology</strong> <strong>and</strong> Pharmacology 31, 166–181.<br />
IFRA (International <strong>Fragrance</strong> Association), 2004. Use level survey, August 2004.<br />
IFRA (International <strong>Fragrance</strong> Association), 2007. Volume of use survey, February<br />
2007.
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S63–S66<br />
Contents lists available at ScienceDirect<br />
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong><br />
journal homepage: www.elsevier.com/locate/foodchemtox<br />
Review<br />
<strong>Fragrance</strong> material review on 3,4,5,6,6-pentamethylheptan-2-ol<br />
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api<br />
<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA<br />
article<br />
Keywords:<br />
Review<br />
<strong>Fragrance</strong><br />
info<br />
abstract<br />
A toxicologic <strong>and</strong> dermatologic review of 3,4,5,6,6-pentamethylheptan-2-ol when used as a fragrance<br />
ingredient is presented. 3,4,5,6,6-Pentamethylheptan-2-ol is a member of the fragrance structural group<br />
branched chain saturated alcohols. The common characteristic structural elements of the alcohols with<br />
saturated branched chain are one hydroxyl group per molecule, <strong>and</strong> a C 4 –C 12 carbon chain with one or<br />
several methyl side chains. This review contains a detailed summary of all available toxicology <strong>and</strong> dermatology<br />
papers that are related to this individual fragrance ingredient <strong>and</strong> is not intended as a st<strong>and</strong>alone<br />
document. A safety assessment of the entire branched chain saturated alcohol group will be published<br />
simultaneously with this document; please refer to Belsito et al. (2010) <strong>for</strong> an overall assessment<br />
of the safe use of this material <strong>and</strong> all other branched chain saturated alcohols in fragrances.<br />
Ó 2010 Published by Elsevier Ltd.<br />
Contents<br />
Introduction . . . ...................................................................................................... S64<br />
1. Identification . . ...................................................................................................... S64<br />
2. Physical properties . . . . . . . . . . . . . . . . . ................................................................................... S64<br />
3. Usage. . . . . . . . . ...................................................................................................... S64<br />
4. <strong>Toxicology</strong> data ...................................................................................................... S65<br />
4.1. Acute toxicity (see Table 2) . . . . . . . . . . . . . . ......................................................................... S65<br />
4.1.1. Oral studies. . . . . . . . . . . . . . . .............................................................................. S65<br />
4.1.2. Dermal studies . . . . . . . . . . . . .............................................................................. S65<br />
4.1.3. Intraperitoneal studies . . . . . . .............................................................................. S65<br />
4.2. Skin irritation . . . . . . . . . ......................................................................................... S65<br />
4.2.1. Human studies . . . . . . . . . . . . .............................................................................. S65<br />
4.2.2. Animal studies . . . . . . . . . . . . .............................................................................. S65<br />
4.3. Mucous membrane (eye) irritation . . . . . . . . ......................................................................... S65<br />
4.4. Skin sensitization . . . . . . ......................................................................................... S65<br />
4.4.1. Human studies . . . . . . . . . . . . .............................................................................. S65<br />
4.4.2. Animal studies . . . . . . . . . . . . .............................................................................. S65<br />
4.5. Phototoxicity <strong>and</strong> photoallergy . . . . . . . . . . . ......................................................................... S65<br />
4.6. Absorption, distribution <strong>and</strong> metabolism . . . ......................................................................... S66<br />
4.7. Repeated dose toxicity . . ......................................................................................... S66<br />
4.7.1. Two to fourteen day studies . .............................................................................. S66<br />
4.7.2. Subchronic studies (see Table 3) . . . . . . . . . . . . . . . . . ........................................................... S66<br />
4.7.3. Chronic studies . . . . . . . . . . . . .............................................................................. S66<br />
4.8. Reproductive <strong>and</strong> developmental toxicity . . . ......................................................................... S66<br />
4.9. Genotoxicity . . . . . . . . . . ......................................................................................... S66<br />
4.9.1. In vitro studies . . . . . . . . . . . . .............................................................................. S66<br />
4.9.2. In vivo studies. . . . . . . . . . . . . .............................................................................. S66<br />
4.10. Carcinogenicity . . . . . . . ......................................................................................... S66<br />
Conflict of interest statement . . . . . . . . ................................................................................... S66<br />
References . . . . ...................................................................................................... S66<br />
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.<br />
E-mail address: dmcginty@RIFM.org (D. McGinty).<br />
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.<br />
doi:10.1016/j.fct.2010.05.030
S64<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S63–S66<br />
Introduction<br />
This document provides a summary of the toxicologic review,<br />
including all human health endpoints, of 3,4,5,6,6-pentamethylheptan-2-ol<br />
when used as a fragrance ingredient. 3,4,5,6,6-Pentamethylheptan-2-ol<br />
(see Fig. 1; CAS Number 87118-95-4) is a<br />
fragrance ingredient used in cosmetics, fine fragrances, shampoos,<br />
toilet soaps <strong>and</strong> other toiletries as well as in non-cosmetic products<br />
such as household cleaners <strong>and</strong> detergents.<br />
In 2006, a complete literature search was conducted on<br />
3,4,5,6,6-pentamethylheptan-2-ol. On-line toxicological databases<br />
were searched including those from the <strong>Chemical</strong> Abstract Services<br />
[e.g. ToxCenter (which in itself contains 18 databases including<br />
<strong>Chemical</strong> Abstracts)], <strong>and</strong> the National Library of Medicine [e.g.<br />
Medline, Toxnet (which contains 14 databases)] as well as 26 additional<br />
sources (e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition,<br />
fragrance companies were asked to submit all test data.<br />
The safety data on this material has never been reviewed be<strong>for</strong>e<br />
by RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.). All relevant<br />
references are included in this document. More details have<br />
been provided <strong>for</strong> unpublished data. The number of animals, sex<br />
<strong>and</strong> strain are always provided unless they are not given in the original<br />
report or paper. Any papers in which the vehicles <strong>and</strong>/or the<br />
doses are not given have not been included in this review. In addition,<br />
diagnostic patch test data with fewer than 100 consecutive<br />
patients have been omitted.<br />
1. Identification<br />
1.1. Synonyms: 2-heptanol, 3,4,5,6,6-pentamethyl-; Koavol DH.<br />
1.2. CAS Registry Number: 87118-95-4.<br />
1.3. EINECS Number: 401-030-0.<br />
1.4. Formula: C 12 H 26 O.<br />
1.5. Molecular weight: 186.39.<br />
2. Physical properties<br />
2.1. Physical <strong>for</strong>m: no in<strong>for</strong>mation available.<br />
2.2. Boiling point: 220.2–231.7 °C.<br />
2.3. Flash point: 365.5 K (92.5 °C).<br />
Fig. 1. 3,4,5,6,6-Pentamethylheptan-2-ol.<br />
2.4. Henry’s law (calculated; EPA, 2010): 0.0000963 atm m 3 /mole.<br />
2.5. Log K ow : 4.0587 at 19 °C.<br />
2.6. Refractive index: no in<strong>for</strong>mation available.<br />
2.7. Specific gravity: no in<strong>for</strong>mation available.<br />
2.8. Vapor pressure: 2.088 Pa at 298 K.<br />
2.9. Water solubility: 0.066 g/l at 19 °C.<br />
2.10. UV spectra available at RIFM, peaks at 200–205 nm <strong>and</strong><br />
returns to baseline 264–271 nm.<br />
3. Usage<br />
3,4,5,6,6-Pentamethylheptan-2-ol is a fragrance ingredient used<br />
in many fragrance compounds. It may be found in fragrances used<br />
in decorative cosmetics, fine fragrances, shampoos, toilet soaps <strong>and</strong><br />
other toiletries as well as in non-cosmetic products such as household<br />
cleaners <strong>and</strong> detergents. Its use worldwide is in the range of<br />
10–100 metric tons per annum (IFRA, 2004). The reported volume<br />
of use is <strong>for</strong> 3,4,5,6,6-pentamethylheptan-2-ol as used in fragrance<br />
compounds (mixtures) in all finished consumer product categories.<br />
The volume of use is surveyed by IFRA approximately every four<br />
years through a comprehensive survey of IFRA <strong>and</strong> RIFM member<br />
companies. As such the volume of use data from this survey provides<br />
volume of use of fragrance ingredients <strong>for</strong> the majority of<br />
the fragrance industry.<br />
The dermal systemic exposure in cosmetic products (see Table 1)<br />
is calculated based on the concentrations of the same fragrance<br />
ingredient in 10 types of the most frequently used personal care<br />
<strong>and</strong> cosmetic products (anti-perspirant, bath products, body lotion,<br />
eau de toilette, face cream, fragrance cream, hair spray, shampoo,<br />
shower gel, <strong>and</strong> toilet soap). The concentration of the fragrance<br />
ingredient in fine fragrances is obtained from examination of several<br />
thous<strong>and</strong> commercial <strong>for</strong>mulations. The upper 97.5 percentile<br />
concentration is calculated from the data obtained. This upper<br />
97.5 percentile concentration is then used <strong>for</strong> all 10 consumer products.<br />
These concentrations are multiplied by the amount of product<br />
applied, the number of applications per day <strong>for</strong> each product type,<br />
<strong>and</strong> a ‘‘retention factor” (ranging from 0.001 to 1.0) to account <strong>for</strong><br />
the length of time a product may remain on the skin <strong>and</strong>/or likelihood<br />
of the fragrance ingredient being removed by washing. The<br />
resultant calculation represents the total consumer exposure (mg/<br />
kg/day) (Cadby et al., 2002; Ford et al., 2000).<br />
This is a conservative calculation of dermal systemic exposure<br />
because it makes the unlikely assumption that a consumer will<br />
use these 10 products containing; which are all perfumed with<br />
the upper 97.5 percentile level of the fragrance ingredient from a<br />
fine fragrance type of product (Cadby et al., 2002; Ford et al.,<br />
2000). The 97.5 percentile use level in <strong>for</strong>mulae <strong>for</strong> use in cosmetics<br />
in general has been reported to be 5.5% (IFRA, 2007), which<br />
would result in a maximum daily exposure on the skin of<br />
0.1403 mg/kg <strong>for</strong> high end users.<br />
Table 1<br />
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 3,4,5,6,6-pentamethylheptan-2-ol.<br />
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient (mg/kg/day) b<br />
Anti-perspirant 0.5 1 1 0.01 5.5 0.0046<br />
Bath products 17 0.29 0.001 0.02 5.5 0.0001<br />
Body lotion 8 0.71 1 0.004 5.5 0.0208<br />
Eau de toilette 0.75 1 1 0.08 5.5 0.0550<br />
Face cream 0.8 2 1 0.003 5.5 0.0044<br />
<strong>Fragrance</strong> cream 5 0.29 1 0.04 5.5 0.0532<br />
Hair spray 5 2 0.01 0.005 5.5 0.0005<br />
Shampoo 8 1 0.01 0.005 5.5 0.0004<br />
Shower gel 5 1.07 0.01 0.012 5.5 0.0006<br />
Toilet soap 0.8 6 0.01 0.015 5.5 0.0007<br />
Total 0.1401<br />
a<br />
b<br />
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.<br />
Based on a 60-kg adult.
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S63–S66 S65<br />
A maximum skin level is then determined <strong>for</strong> consideration of<br />
potential sensitization. The exposure is calculated as the percent<br />
concentration of the fragrance ingredient applied to the skin based<br />
on the use of 20% of the fragrance mixture in the fine fragrance<br />
consumer product (IFRA, 2007). The average maximum use level<br />
in <strong>for</strong>mulae that go into fine fragrances has been reported to be<br />
1.73% (IFRA, 2007), assuming use of the fragrance oil at levels up<br />
to 20% in the final product.<br />
4. <strong>Toxicology</strong> data<br />
4.1. Acute toxicity (see Table 2)<br />
4.1.1. Oral studies<br />
Sprague–Dawley albino rats were divided into three groups of<br />
10 animals, consisting of five males <strong>and</strong> five females per group.<br />
The three dose levels of undiluted 3,4,5,6,6-pentamethylheptan-<br />
2-ol was orally administered (via gavage) at 7.81, 6.25, or 5.0 g/<br />
kg bodyweight. Animals were observed immediately after dosing,<br />
at 1 <strong>and</strong> 4 h, <strong>and</strong> twice daily thereafter <strong>for</strong> 14 days. At 5.0 g/kg 1<br />
of 10 died, <strong>and</strong> clinical signs included moderate salivation, piloerection,<br />
lethargy, lacrimation, hunched posture, <strong>and</strong> epistaxis. At<br />
6.25 g/kg, 8 of 10 died with clinical signs including diarrhea,<br />
hunched posture, lethargy, piloerection, ataxia, moderate tremors,<br />
lacrimation, <strong>and</strong> epistaxis. In the highest dosage group (7.81 g/kg)<br />
9 of 10 died, <strong>and</strong> clinical signs were the same as above. No controls<br />
were used <strong>and</strong> the LD 50 was calculated to be 5.845 (5.36–6.375) g/<br />
kg bodyweight (RIFM, 1984a).<br />
4.1.2. Dermal studies<br />
A group of 10 (5/sex) HC/CFY (remote Sprague–Dawley) rats<br />
were treated with the 3,4,5,6,6-pentamethylheptan-2-ol at 2.0 g/<br />
kg bodyweight. A dermal application was made to the dorso-lumbar<br />
region (which had been previously clipped free of fur), covered<br />
with a gauze patch, <strong>and</strong> held in place with an impermeable dressing.<br />
All animals were observed soon after dosing, frequently on day<br />
1, <strong>and</strong> at least twice per day <strong>for</strong> 14 days after dosing. There were no<br />
mortalities, clinical signs of toxicity, or skin reactions at the site of<br />
application. The acute LD 50 was determined to be greater than<br />
2.0 g/kg bodyweight (RIFM, 1985c).<br />
4.1.3. Intraperitoneal studies<br />
In a preliminary dose range finding study, 3,4,5,6,6-pentamethylheptan-2-ol<br />
was administered intraperitoneally to eight groups<br />
(2/sex/group) of CD-1 mice at doses of 50, 166, 500, 750, 1000,<br />
1250, 1666 <strong>and</strong> 3000 mg/kg bodyweight. Signs were observed at<br />
all levels of 1000 mg/kg <strong>and</strong> higher. One animal died at 1250 mg/<br />
kg <strong>and</strong> all animals at the two highest dosage levels. Due to the<br />
severity of the signs <strong>and</strong> mortality, 900 mg/kg was selected as<br />
the maximum tolerated dose (RIFM, 1985a).<br />
4.2. Skin irritation<br />
4.2.1. Human studies<br />
Irritation was evaluated during the induction phase in a human<br />
repeated insult patch test (HRIPT). A 0.2 ml aliquot of a 15% solution<br />
in alcohol SDA-39C was applied to clear plastic patches,<br />
1.5 1.5 in. (Parke–Davis Readi–B<strong>and</strong>ages). The patches were<br />
Table 2<br />
Summary of acute toxicity studies.<br />
Route Species Number of<br />
animals/dose group<br />
LD 50 (g/kg)<br />
References<br />
Oral Rat 10 5.8 RIFM (1984a)<br />
Dermal Rat 10 >2.0 RIFM (1985a)<br />
placed on the subjects’ skin between the left scapula <strong>and</strong> spinal<br />
mid-line <strong>for</strong> 24 h under occlusion. After a 24–48 h rest period, subjects<br />
were again patched at the same site. Nine applications were<br />
made in a three week period. Slight irritation was observed in 5<br />
of the 51 male <strong>and</strong> female volunteers (RIFM, 1983).<br />
4.2.2. Animal studies<br />
A group of six male albino New Zeal<strong>and</strong> rabbits were given<br />
0.5 ml of the undiluted 3,4,5,6,6-pentamethylheptan-2-ol <strong>and</strong> observed<br />
<strong>for</strong> up to 72 h. Erythema <strong>and</strong> edema were not observed in<br />
any of the six rabbits tested (RIFM, 1984b).<br />
4.3. Mucous membrane (eye) irritation<br />
3,4,5,6,6-Pentamethylheptan-2-ol was evaluated <strong>for</strong> eye irritation<br />
in nine healthy albino rabbits. Undiluted aliquots of 0.1 ml<br />
were instilled into one eye. The untreated eye of each animal<br />
served as a control. Observations were made at 1 h, <strong>and</strong> daily<br />
thereafter <strong>for</strong> a week. Irritation was observed in the cornea <strong>and</strong><br />
conjunctiva, but cleared by the seventh day (RIFM, 1984c).<br />
4.4. Skin sensitization<br />
4.4.1. Human studies<br />
4.4.1.1. Induction studies. A repeated insult patch tests was conducted<br />
to determine if 15% 3,4,5,6,6-pentamethylheptan-2-ol in<br />
alcohol SDA-39C would induce dermal sensitization in 51 human<br />
volunteers. During the induction phase 0.2 ml was applied onto<br />
Parke–Davis Readi–B<strong>and</strong>ages <strong>and</strong> applied to the backs of each volunteer<br />
<strong>for</strong> 24 h. Induction applications were made <strong>for</strong> a total of<br />
nine applications during three week period. Following a one week<br />
rest period, a challenge patch was applied to a site previously unexposed<br />
on the upper back. Patches were applied as in the induction<br />
phase <strong>and</strong> kept in place <strong>for</strong> 24 h after which time they were<br />
removed. Reactions to the challenge were scored at 24, 48, <strong>and</strong><br />
72 h after application. There were no sensitization reactions during<br />
the challenge phase (RIFM, 1983).<br />
4.4.2. Animal studies<br />
No in<strong>for</strong>mation available.<br />
4.5. Phototoxicity <strong>and</strong> photoallergy<br />
No in<strong>for</strong>mation available.<br />
4.6. Absorption, distribution <strong>and</strong> metabolism<br />
No in<strong>for</strong>mation available.<br />
4.7. Repeated dose toxicity<br />
4.7.1. Two to fourteen day studies<br />
No in<strong>for</strong>mation available.<br />
4.7.2. Subchronic studies (see Table 3)<br />
3,4,5,6,6-Pentamethylheptan-2-ol was assessed <strong>for</strong> its toxicity<br />
to 10 New Zeal<strong>and</strong> white rabbits (5/sex) when administered to<br />
the occluded skin. Applications of 1000 mg/kg were made <strong>for</strong> 6 h<br />
each day <strong>for</strong> 28 consecutive days. Irritation progressed rapidly in<br />
all rabbits <strong>and</strong> within two weeks severe erythema <strong>and</strong> edema were<br />
observed. Histopathological examination revealed the treated skin<br />
to have acanthotic <strong>and</strong> focal ulcerative changes in the epidermis,<br />
along with associated inflammation, hyperkeratosis, <strong>and</strong> scab <strong>for</strong>mation.<br />
A systemic NOAEL of 1000 mg/kg bodyweight/day was<br />
decided <strong>for</strong> 3,4,5,6,6-pentamethylheptan-2-ol although severe irritation<br />
was observed (RIFM, 1985d).<br />
At concentrations of 1.5%, 5.0%, 15%, <strong>and</strong> 50% 3,4,5,6,6-pentamethylheptan-2-ol<br />
in 1% aqueous methylcellulose (equivalent to 30,<br />
100, 300, <strong>and</strong> 1000 mg/kg/day) was applied to the intact skin of
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D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S63–S66<br />
Table 3<br />
Summary of subchronic studies.<br />
Method<br />
Dose<br />
(mg/kg/day)<br />
Species Results References<br />
Dermal application under occlusion 1000 Rabbits NOAEL: 1000 mg/kg bodyweight/day RIFM (1985d)<br />
Severe irritation; associated inflammation,<br />
hyperkeratosis, <strong>and</strong> scabbing<br />
Dermal application under occlusion Up to 1000 Rabbits NOAEL: 1000 mg/kg bodyweight/day RIFM (1986)<br />
Slight to moderate dermal irritation; severe<br />
irritation at high doses; reversible after 8 days<br />
New Zeal<strong>and</strong> white rabbits (10/sex). The two lowest dosages (30<br />
<strong>and</strong> 100 mg/kg/day) were allowed to run <strong>for</strong> 6 h per day, <strong>and</strong> 28<br />
consecutive days under an occlusive patch. Slight to moderate dermal<br />
irritation developed <strong>for</strong> both dosages but ameliorated by day<br />
16 <strong>for</strong> 30 mg/kg/day, <strong>and</strong> persisted to termination <strong>for</strong> 100 mg/kg/<br />
day. Treatment of the two highest dosages (300 <strong>and</strong> 1000 mg/kg/<br />
day) was terminated after nine applications because of the severity<br />
of the dermal reactions. However, after 8 days irritation subsided<br />
<strong>and</strong> the data suggests the dermal reactions are reversible. A systemic<br />
NOAEL of 1000 mg/kg bodyweight/day was decided <strong>for</strong><br />
3,4,5,6,6-pentamethylheptan-2-ol although severe irritation was<br />
observed (RIFM, 1986).<br />
4.7.3. Chronic studies<br />
No in<strong>for</strong>mation available.<br />
4.8. Reproductive <strong>and</strong> developmental toxicity<br />
No in<strong>for</strong>mation available.<br />
4.9. Genotoxicity<br />
4.9.1. In vitro studies<br />
4.9.1.1. Bacterial test systems. An Ames test using 0.1 ml of<br />
3,4,5,6,6-pentamethylheptan-2-ol was added to Escherichia coli<br />
WP2 uvrA, Salmonella typhimurium TA 98, 100, 1535, 1537, <strong>and</strong><br />
1538 cultures at concentrations up to 1000 lg/plate with <strong>and</strong><br />
without S9 activation. Toxicity was observed with tester strains<br />
TA 98, 100, <strong>and</strong> 1535 at the higher dose levels. A second round<br />
of tests, up to 100 lg/plate, did not show any substantial increases<br />
in revertant colony numbers. It was concluded that the test material<br />
showed no evidence of mutagenic activity in these bacterial<br />
systems (RIFM, 1985b).<br />
4.9.1.2. Studies in mammalian cells. No in<strong>for</strong>mation available.<br />
4.9.2. In vivo studies<br />
In a CD-1 mouse micronucleus test, three groups of 10 animals<br />
(5 males <strong>and</strong> 5 females per group) were given single doses of<br />
3,4,5,6,6-pentamethylheptan-2-ol in corn oil by intraperitoneal<br />
injection at 900 mg/kg <strong>and</strong> sacrificed at 30, 48, <strong>and</strong> 72 h. All groups<br />
showed significantly lower ratios of polychromatic erythrocytes to<br />
normochromatic erythrocytes (PCE/NCE) suggesting the bioavailability<br />
of the test article. Statistically significant increases in the<br />
incidence of micronuclei of experimental animals were not observed.<br />
Based upon the inability of the test article to produce a significant<br />
increase in the incidence of micronuclei per 1000<br />
polychromatic erythrocytes in the treated versus the negative control<br />
groups, 3,4,5,6,6-pentamethylheptan-2-ol was determined to<br />
be negative in the micronucleus test (RIFM, 1985c).<br />
4.10. Carcinogenicity<br />
No available in<strong>for</strong>mation.<br />
This individual <strong>Fragrance</strong> Material Review is not intended as a<br />
st<strong>and</strong>-alone document. Please refer to A Safety Assessment of<br />
Branched Chain Saturated Alcohols When Used as <strong>Fragrance</strong> Ingredients<br />
(Belsito et al., 2010) <strong>for</strong> an overall assessment of this<br />
material.<br />
Conflict of interest statement<br />
This research was supported by the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong><br />
Materials, an independent research institute that is funded<br />
by the manufacturers of fragrances <strong>and</strong> consumer products containing<br />
fragrances. The authors are all employees of the <strong>Research</strong><br />
<strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials.<br />
References<br />
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,<br />
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chain<br />
saturated alcohols when used as fragrance ingredients. <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong><br />
<strong>Toxicology</strong> 48 (S4), S1–S46.<br />
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:<br />
providing estimates <strong>for</strong> safety evaluation. Regulatory <strong>Toxicology</strong> <strong>and</strong><br />
Pharmacology 36, 246–252.<br />
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface<br />
Suite <strong>for</strong> Microsoft Ò Windows, v 4.00 or Insert Version Used. United States<br />
Environmental Protection Agency, Washington, DC, USA.<br />
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria <strong>for</strong><br />
development of a database <strong>for</strong> safety evaluation of fragrance ingredients.<br />
Regulatory <strong>Toxicology</strong> <strong>and</strong> Pharmacology 31, 166–181.<br />
IFRA (International <strong>Fragrance</strong> Association), 2004. Use Level Survey, August 2004.<br />
IFRA (International <strong>Fragrance</strong> Association), 2007. Volume of Use Survey, February<br />
2007.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1983. Evaluation of Potential<br />
Irritation <strong>and</strong> Sensitization Hazards by Dermal Contact: Repeated Insult Patch<br />
Test with 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished Report from<br />
International Flavors <strong>and</strong> <strong>Fragrance</strong>s, 27 October. Report Number 48462,<br />
RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1984a. Acute Oral LD50<br />
Determination in the Rat on 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished<br />
Report from International Flavors <strong>and</strong> <strong>Fragrance</strong>s, Report Number 47552, RIFM,<br />
Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1984b. Primary Dermal<br />
Irritation Test of 3,4,5,6,6-Pentamethylheptan-2-ol on the Rabbit. Unpublished<br />
Report from International Flavors <strong>and</strong> <strong>Fragrance</strong>s, Report Number 47792, RIFM,<br />
Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1984c. Acute Eye Irritation/<br />
Corrosion Test to the Rabbit of 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished<br />
Report from International Flavors <strong>and</strong> <strong>Fragrance</strong>s, Report Number 47677, RIFM,<br />
Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1985a. Acute Dermal<br />
Toxicity to the Rat of 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished Report<br />
from International Flavors <strong>and</strong> <strong>Fragrance</strong>s, Report Number 47587, RIFM,<br />
Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1985b. Microbial Metabolic<br />
Activation Test to Assess the Potential Mutagenic Effect of 3,4,5,6,6-<br />
Pentamethylheptan-2-ol. Unpublished Report from International Flavors <strong>and</strong><br />
<strong>Fragrance</strong>s, Report Number 48164, RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1985c. Micronucleus Test<br />
(MNT) OECD on 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished Report from<br />
International Flavors <strong>and</strong> <strong>Fragrance</strong>s, Report Number 48252, RIFM, Woodcliff<br />
Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1985d. Twenty-eight Day<br />
Dermal Irritation Study in Rabbits with 3,4,5,6,6-Pentamethylheptan-2-ol.<br />
Unpublished Report from International Flavors <strong>and</strong> <strong>Fragrance</strong>s, Report<br />
Number 47793, RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1986. Twenty-eight Day<br />
Dermal Irritation Study in Rabbits with 3,4,5,6,6-Pentamethylheptan-2-ol.<br />
Unpublished Report from International Flavors <strong>and</strong> <strong>Fragrance</strong>s, Report<br />
Number 48027, RIFM, Woodcliff Lake, NJ, USA.
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S67–S69<br />
Contents lists available at ScienceDirect<br />
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong><br />
journal homepage: www.elsevier.com/locate/foodchemtox<br />
Review<br />
<strong>Fragrance</strong> material review on isodecyl alcohol<br />
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api<br />
<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA<br />
article<br />
Keywords:<br />
Review<br />
<strong>Fragrance</strong><br />
info<br />
abstract<br />
A toxicologic <strong>and</strong> dermatologic review of isodecyl alcohol when used as a fragrance ingredient is presented.<br />
Isodecyl alcohol is a member of the fragrance structural group branched chain saturated alcohols.<br />
The common characteristic structural elements of the alcohols with saturated branched chain are one<br />
hydroxyl group per molecule, <strong>and</strong> a C 4 –C 12 carbon chain with one or several methyl side chains. This<br />
review contains a detailed summary of all available toxicology <strong>and</strong> dermatology papers that are related<br />
to this individual fragrance ingredient <strong>and</strong> is not intended as a st<strong>and</strong>-alone document. A safety assessment<br />
of the entire branched chain saturated alcohol group will be published simultaneously with this<br />
document; please refer to Belsito et al. (2010) <strong>for</strong> an overall assessment of the safe use of this material<br />
<strong>and</strong> all other branched chain saturated alcohols in fragrances.<br />
Ó 2010 Published by Elsevier Ltd.<br />
Contents<br />
Introduction . . . ..................................................................................................... S67<br />
1. Identification . . ..................................................................................................... S68<br />
2. Physical properties . . . . . . . . . . . . . . . . . .................................................................................. S68<br />
3. Usage. . . . . . . . . ..................................................................................................... S68<br />
4. <strong>Toxicology</strong> data ..................................................................................................... S69<br />
4.1. Acute toxicity. ................................................................................................ S69<br />
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S69<br />
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S69<br />
4.2. Skin irritation. ................................................................................................ S69<br />
4.3. Mucous membrane (eye) irritation. ............................................................................... S69<br />
4.4. Skin sensitization. ............................................................................................. S69<br />
4.5. Phototoxicity <strong>and</strong> photoallergy. . ................................................................................. S69<br />
4.6. Absorption, distribution <strong>and</strong> metabolism .......................................................................... S69<br />
4.7. Repeated dose toxicity . . ....................................................................................... S69<br />
4.8. Reproductive <strong>and</strong> developmental toxicity .......................................................................... S69<br />
4.9. Genotoxicity. ................................................................................................. S69<br />
4.10. Carcinogenicity . . ............................................................................................. S69<br />
Conflict of interest statement . . . . . . . . .................................................................................. S69<br />
References . . . . ..................................................................................................... S69<br />
Introduction<br />
This document provides a summary of the toxicologic review,<br />
including all human health endpoints, of isodecyl alcohol when<br />
used as a fragrance ingredient. Isodecyl alcohol (see Fig. 1; CAS<br />
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.<br />
E-mail address: dmcginty@RIFM.org (D. McGinty).<br />
Number 25339-17-7) is a fragrance ingredient used in cosmetics,<br />
fine fragrances, shampoos, toilet soaps <strong>and</strong> other toiletries as well<br />
as in non-cosmetic products such as household cleaners <strong>and</strong><br />
detergents.<br />
In 2006, a complete literature search was conducted on isodecyl<br />
alcohol. On-line toxicological databases were searched including<br />
those from the <strong>Chemical</strong> Abstract Services [e.g. ToxCenter (which<br />
in itself contains 18 databases including <strong>Chemical</strong> Abstracts)],<br />
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.<br />
doi:10.1016/j.fct.2010.05.031
S68<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S67–S69<br />
2. Physical properties<br />
2.1. Physical <strong>for</strong>m: no in<strong>for</strong>mation available.<br />
2.2. Boiling point (calculated; EPA, 2010): 227.56 °C.<br />
2.3. Flash point: no in<strong>for</strong>mation available.<br />
2.4. Henry’s law (calculated; EPA, 2010): 0.0000547 atm m 3 /mol<br />
(25 °C).<br />
2.5. Log K ow (calculated; EPA, 2010): 3.71.<br />
2.6. Refractive index: no in<strong>for</strong>mation available.<br />
2.7. Specific gravity: no in<strong>for</strong>mation available.<br />
2.8. Vapor pressure (calculated; EPA, 2010): 0.0204 mm Hg;<br />
2.72 Pa (25 °C).<br />
2.9. Water solubility (calculated; EPA, 2010): 151.8 mg/l (25 °C).<br />
2.10. UV spectra not available at RIFM.<br />
3. Usage<br />
<strong>and</strong> the National Library of Medicine [e.g. Medline, Toxnet<br />
(which contains 14 databases)] as well as 26 additional sources<br />
(e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance<br />
companies were asked to submit all test data.<br />
The safety data on this material has never been reviewed be<strong>for</strong>e<br />
by RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.). All relevant<br />
references are included in this document. More details have<br />
been provided <strong>for</strong> unpublished data. The number of animals, sex<br />
<strong>and</strong> strain are always provided unless they are not given in the original<br />
report or paper. Any papers in which the vehicles <strong>and</strong>/or the<br />
doses are not given have not been included in this review. In addition,<br />
diagnostic patch test data with fewer than 100 consecutive<br />
patients have been omitted.<br />
1. Identification<br />
Fig. 1. Isodecyl alcohol.<br />
1.1. Synonyms: isodecanol; 8-methylnonan-1-ol.<br />
1.2. CAS Registry Number: 25339-17-7.<br />
1.3. EINECS Number: 246-869-1.<br />
1.4. Formula: C 10 H 22 O.<br />
1.5. Molecular weight: 158.85.<br />
Isodecyl alcohol is a fragrance ingredient used in many fragrance<br />
compounds. It may be found in fragrances used in decorative<br />
cosmetics, fine fragrances, shampoos, toilet soaps <strong>and</strong> other<br />
toiletries as well as in non-cosmetic products such as household<br />
cleaners <strong>and</strong> detergents. Its use worldwide is in the region of<br />
0.1–1.0 metric tons per annum (IFRA, 2004). The reported volume<br />
of use is <strong>for</strong> isodecyl alcohol as used in fragrance compounds (mixtures)<br />
in all finished consumer product categories. The volume of<br />
use is surveyed by IFRA approximately every four years through<br />
a comprehensive survey of IFRA <strong>and</strong> RIFM member companies.<br />
As such the volume of use data from this survey provides volume<br />
of use of fragrance ingredients <strong>for</strong> the majority of the fragrance<br />
industry.<br />
The dermal systemic exposure in cosmetic products (see<br />
Table 1) is calculated based on the concentrations of the same fragrance<br />
ingredient in 10 types of the most frequently used personal<br />
care <strong>and</strong> cosmetic products (anti-perspirant, bath products, body<br />
lotion, eau de toilette, face cream, fragrance cream, hair spray,<br />
shampoo, shower gel, <strong>and</strong> toilet soap). The concentration of the<br />
fragrance ingredient in fine fragrances is obtained from examination<br />
of several thous<strong>and</strong> commercial <strong>for</strong>mulations. The upper<br />
97.5 percentile concentration is calculated from the data obtained.<br />
This upper 97.5 percentile concentration is then used <strong>for</strong> all 10<br />
consumer products. These concentrations are multiplied by the<br />
amount of product applied, the number of applications per day<br />
<strong>for</strong> each product type, <strong>and</strong> a ‘‘retention factor” (ranging from<br />
0.001 to 1.0) to account <strong>for</strong> the length of time a product may remain<br />
on the skin <strong>and</strong>/or likelihood of the fragrance ingredient<br />
being removed by washing. The resultant calculation represents<br />
the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford<br />
et al., 2000).<br />
Table 1<br />
Calculation of the total human skin exposure from the use of multiple cosmetic products containing isodecyl alcohol.<br />
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient (mg/kg/day) b<br />
Anti-perspirant 0.5 1 1 0.01 0.0009 0.0000001<br />
Bath products 17 0.29 0.001 0.02 0.0009 0.0000001<br />
Body lotion 8 0.71 1 0.004 0.0009 0.0000001<br />
Eau de toilette 0.75 1 1 0.08 0.0009 0.0000100<br />
Face cream 0.8 2 1 0.003 0.0009 0.0000001<br />
<strong>Fragrance</strong> cream 5 0.29 1 0.04 0.0009 0.0000100<br />
Hair spray 5 2 0.01 0.005 0.0009 0.0000001<br />
Shampoo 8 1 0.01 0.005 0.0009 0.0000001<br />
Shower gel 5 1.07 0.01 0.012 0.0009 0.0000001<br />
Toilet soap 0.8 6 0.01 0.015 0.0009 0.0000001<br />
Total 0.00002<br />
a<br />
b<br />
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.<br />
Based on a 60-kg adult.
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S67–S69 S69<br />
This is a conservative calculation of dermal systemic exposure<br />
because it makes the unlikely assumption that a consumer will<br />
use these 10 products containing; which are all perfumed with<br />
the upper 97.5 percentile level of the fragrance ingredient from a<br />
fine fragrance type of product (Cadby et al., 2002; Ford et al.,<br />
2000). The 97.5 percentile use level in <strong>for</strong>mulae <strong>for</strong> use in cosmetics<br />
in general has been not been reported. As such the default value<br />
of 0.02% is used to calculate the maximum daily exposure on the<br />
skin of 0.00002 mg/kg <strong>for</strong> high end users.<br />
A maximum skin level is then determined <strong>for</strong> consideration of<br />
potential sensitization. The exposure is calculated as the percent<br />
concentration of the fragrance ingredient applied to the skin based<br />
on the use of 20% of the fragrance mixture in the fine fragrance<br />
consumer product (IFRA, 2007). The average maximum use level<br />
in <strong>for</strong>mulae that go into fine fragrances has not been reported. A<br />
default value of 0.02% is used, assuming use of the fragrance oil<br />
levels up to 20% in the final product.<br />
4. <strong>Toxicology</strong> data<br />
4.1. Acute toxicity<br />
4.1.1. Oral studies<br />
The acute oral LD 50 of isodecyl alcohol in rats was reported to be<br />
6.5 g/kg. No additional details available (Article in Japanese)<br />
(Nishimura et al., 1994).<br />
4.1.2. Dermal studies<br />
No in<strong>for</strong>mation available.<br />
4.2. Skin irritation<br />
No in<strong>for</strong>mation available.<br />
4.3. Mucous membrane (eye) irritation<br />
No in<strong>for</strong>mation available.<br />
4.4. Skin sensitization<br />
No in<strong>for</strong>mation available.<br />
4.5. Phototoxicity <strong>and</strong> photoallergy<br />
No in<strong>for</strong>mation available.<br />
4.6. Absorption, distribution <strong>and</strong> metabolism<br />
No in<strong>for</strong>mation available.<br />
4.7. Repeated dose toxicity<br />
No in<strong>for</strong>mation available.<br />
4.8. Reproductive <strong>and</strong> developmental toxicity<br />
In a comparative developmental toxicity study, isodecyl alcohol<br />
was administered by gavage to Wistar rats (10/group) at 0, 1, 5,<br />
<strong>and</strong> 10 mmol/kg (0, 158, 790, <strong>and</strong> 1580 mg/kg/day) on gestation<br />
days 6–15. Maternal toxicity <strong>and</strong> incidences of fetal retardations<br />
<strong>and</strong> rare mal<strong>for</strong>mations were observed at 10 mmol/kg. Maternal<br />
mortality was 4/10 in this dose group. Body weight on days 15<br />
<strong>and</strong> 20, uterus weight, <strong>and</strong> fetal weights were all significantly lower<br />
than controls in the 10 mmol/kg group. Post-implantation loss,<br />
resorptions, <strong>and</strong> number of fetuses with mal<strong>for</strong>mations were all<br />
higher than controls at 10 mmol/kg. There was no maternal mortality<br />
in any of the other groups. Some maternal signs, but no fetal<br />
signs were observed at 5 mmol/kg. The clinical signs included nasal<br />
discharge, salivation, <strong>and</strong> signs of CNS depression. None of the<br />
measured maternal or fetal parameters were significantly different<br />
than controls at this dose. The NOEL <strong>for</strong> maternal effects was<br />
1 mmol/kg <strong>and</strong> <strong>for</strong> fetal effects 5 mmol/kg (Hellwig <strong>and</strong> Jackh,<br />
1997).<br />
4.9. Genotoxicity<br />
No in<strong>for</strong>mation available.<br />
4.10. Carcinogenicity<br />
No in<strong>for</strong>mation available.<br />
This individual <strong>Fragrance</strong> Material Review is not intended as a<br />
st<strong>and</strong>-alone document. Please refer to A Safety Assessment of<br />
Branched Chain Saturated Alcohols When Used as <strong>Fragrance</strong> Ingredients<br />
(Belsito et al., 2010) <strong>for</strong> an overall assessment of this<br />
material.<br />
Conflict of interest statement<br />
This research was supported by the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong><br />
Materials, an independent research institute that is funded<br />
by the manufacturers of fragrances <strong>and</strong> consumer products containing<br />
fragrances. The authors are all employees of the <strong>Research</strong><br />
<strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials.<br />
References<br />
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,<br />
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chain<br />
saturated alcohols when used as fragrance ingredients. <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong><br />
<strong>Toxicology</strong> 48 (S4), S1–S46.<br />
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:<br />
providing estimates <strong>for</strong> safety evaluation. Regulatory <strong>Toxicology</strong> <strong>and</strong><br />
Pharmacology 36, 246–252.<br />
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface<br />
Suite <strong>for</strong> Microsoft Ò Windows v 4.00 or Insert Version Used. United States<br />
Environmental Protection Agency, Washington, DC, USA.<br />
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria <strong>for</strong><br />
development of a database <strong>for</strong> safety evaluation of fragrance ingredients.<br />
Regulatory <strong>Toxicology</strong> <strong>and</strong> Pharmacology 31, 166–181.<br />
Hellwig, J., Jackh, R., 1997. Differential prenatal toxicity of one straight-chain <strong>and</strong><br />
five branched-chain primary alcohols in rats. <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 35<br />
(5), 489–500.<br />
IFRA (International <strong>Fragrance</strong> Association), 2004. Use Level Survey, August 2004.<br />
IFRA (International <strong>Fragrance</strong> Association), 2007. Volume of Use Survey, February<br />
2007.<br />
Nishimura, H., Saito, S., Kishida, F., Matsuo, M., 1994. Analysis of acute toxicity<br />
(LD50-value) of organic chemicals to mammals by solubility parameter (delta).<br />
1. Acute oral toxicity to rats. Sangyo Igaku 36 (5), 314–323 (Japanese Journal<br />
Industrial Health).
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S70–S72<br />
Contents lists available at ScienceDirect<br />
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong><br />
journal homepage: www.elsevier.com/locate/foodchemtox<br />
Review<br />
<strong>Fragrance</strong> material review on isooctan-1-ol<br />
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api<br />
<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA<br />
article<br />
Keywords:<br />
Review<br />
<strong>Fragrance</strong><br />
info<br />
abstract<br />
A toxicologic <strong>and</strong> dermatologic review of isooctan-1-ol when used as a fragrance ingredient is presented.<br />
Isooctan-1-ol is a member of the fragrance structural group branched chain saturated alcohols. The common<br />
characteristic structural elements of the alcohols with saturated branched chain are one hydroxyl<br />
group per molecule, <strong>and</strong> a C 4 –C 12 carbon chain with one or several methyl side chains. This review contains<br />
a detailed summary of all available toxicology <strong>and</strong> dermatology papers that are related to this individual<br />
fragrance ingredient <strong>and</strong> is not intended as a st<strong>and</strong>-alone document. A safety assessment of the<br />
entire branched chain saturated alcohol group will be published simultaneously with this document;<br />
please refer to Belsito et al. (2010) <strong>for</strong> an overall assessment of the safe use of this material <strong>and</strong> all other<br />
branched chain saturated alcohols in fragrances.<br />
Ó 2010 Published by Elsevier Ltd.<br />
Contents<br />
Introduction ........................................................................................................ S70<br />
1. Identification . . . . . . . . . . . . . . . ........................................................................................ S71<br />
2. Physical properties . . . . . . . . . . . ........................................................................................ S71<br />
3. Usage. . . . . . ........................................................................................................ S71<br />
4. <strong>Toxicology</strong> data . . . . . . . . . . . . . ........................................................................................ S72<br />
4.1. Acute toxicity. ................................................................................................ S72<br />
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S72<br />
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S72<br />
4.1.3. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S72<br />
4.2. Skin irritation. ................................................................................................ S72<br />
4.3. Mucous membrane (eye) irritation. ............................................................................... S72<br />
4.4. Skin sensitization. ............................................................................................. S72<br />
4.5. Phototoxicity <strong>and</strong> photoallergy. . ................................................................................. S72<br />
4.6. Absorption, distribution <strong>and</strong> metabolism .......................................................................... S72<br />
4.7. Repeated dose toxicity . . ....................................................................................... S72<br />
4.8. Reproductive <strong>and</strong> developmental toxicity .......................................................................... S72<br />
4.9. Genotoxicity. ................................................................................................. S72<br />
4.10. Carcinogenicity . . ............................................................................................. S72<br />
Conflict of interest statement . . ........................................................................................ S72<br />
References . ........................................................................................................ S72<br />
Introduction<br />
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.<br />
E-mail address: dmcginty@RIFM.org (D. McGinty).<br />
This document provides a summary of the toxicologic review,<br />
including all human health endpoints, of isooctan-1-ol when used<br />
as a fragrance ingredient. Isooctan-1-ol (see Fig. 1; CAS Number<br />
26952-21-6) is a fragrance ingredient used in cosmetics, fine fragrances,<br />
shampoos, toilet soaps <strong>and</strong> other toiletries as well as in<br />
non-cosmetic products such as household cleaners <strong>and</strong> detergents.<br />
In 2006, a complete literature search was conducted on isooctan-1-ol.<br />
On-line toxicological databases were searched including<br />
those from the <strong>Chemical</strong> Abstract Services [e.g. ToxCenter (which<br />
in itself contains 18 databases including <strong>Chemical</strong> Abstracts)],<br />
<strong>and</strong> the National Library of Medicine [e.g. Medline, Toxnet (which<br />
contains 14 databases)] as well as 26 additional sources (e.g. BIO-<br />
SIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance companies<br />
were asked to submit all test data.<br />
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.<br />
doi:10.1016/j.fct.2010.05.032
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S70–S72 S71<br />
2.9. Water solubility (calculated; EPA, 2010): 1379 mg/l (25 °C).<br />
2.10. UV spectra are not available at RIFM.<br />
3. Usage<br />
The safety data on this material has never been reviewed be<strong>for</strong>e<br />
by RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.). All relevant<br />
references are included in this document. More details have<br />
been provided <strong>for</strong> unpublished data. The number of animals, sex<br />
<strong>and</strong> strain are always provided unless they are not given in the original<br />
report or paper. Any papers in which the vehicles <strong>and</strong>/or the<br />
doses are not given have not been included in this review. In addition,<br />
diagnostic patch test data with fewer than 100 consecutive<br />
patients have been omitted.<br />
1. Identification<br />
1.1. Synonyms: isooctanol; 6-methylheptan-1-ol.<br />
1.2. CAS Registry Number: 26952-21-6.<br />
1.3. EINECS Number: 248-133-5.<br />
1.4. Formula: C 8 H 18 O.<br />
1.5. Molecular weight: 130.31.<br />
2. Physical properties<br />
Fig. 1. Isooctan-1-ol.<br />
2.1. Physical <strong>for</strong>m: no in<strong>for</strong>mation available.<br />
2.2. Boiling point (calculated; EPA, 2010): 188.52 °C.<br />
2.3. Flash point: no in<strong>for</strong>mation available.<br />
2.4. Henry’s law (calculated; EPA, 2010): 0.000031 m 3 /mol<br />
(25 °C).<br />
2.5. Log K ow (calculated; EPA, 2010): 2.73.<br />
2.6. Refractive index: no in<strong>for</strong>mation available.<br />
2.7. Specific gravity: no in<strong>for</strong>mation available.<br />
2.8. Vapor pressure (calculated; EPA, 2010): 0.151 mm Hg;<br />
20.1 Pa (25 °C).<br />
Isooctan-1-ol is a fragrance ingredient used in many fragrance<br />
compounds. It may be found in fragrances used in decorative cosmetics,<br />
fine fragrances, shampoos, toilet soaps <strong>and</strong> other toiletries<br />
as well as in non-cosmetic products such as household cleaners<br />
<strong>and</strong> detergents. Its use worldwide is in the region of less than<br />
0.01 metric tons per annum (IFRA, 2004). The reported volume of<br />
use is <strong>for</strong> isooctan-1-ol as used in fragrance compounds (mixtures)<br />
in all finished consumer product categories. The volume of use is<br />
surveyed by IFRA approximately every four years through a comprehensive<br />
survey of IFRA <strong>and</strong> RIFM member companies. As such<br />
the volume of use data from this survey provides volume of use<br />
of fragrance ingredients <strong>for</strong> the majority of the fragrance industry.<br />
The dermal systemic exposure in cosmetic products (see Table<br />
1) is calculated based on the concentrations of the same fragrance<br />
ingredient in ten types of the most frequently used<br />
personal care <strong>and</strong> cosmetic products (anti-perspirant, bath products,<br />
body lotion, eau de toilette, face cream, fragrance cream, hair<br />
spray, shampoo, shower gel, <strong>and</strong> toilet soap). The concentration of<br />
the fragrance ingredient in fine fragrances is obtained from examination<br />
of several thous<strong>and</strong> commercial <strong>for</strong>mulations. The upper<br />
97.5 percentile concentration is calculated from the data obtained.<br />
This upper 97.5 percentile concentration is then used <strong>for</strong> all 10<br />
consumer products. These concentrations are multiplied by the<br />
amount of product applied, the number of applications per day<br />
<strong>for</strong> each product type, <strong>and</strong> a ‘‘retention factor” (ranging from<br />
0.001 to 1.0) to account <strong>for</strong> the length of time a product may remain<br />
on the skin <strong>and</strong>/or likelihood of the fragrance ingredient<br />
being removed by washing. The resultant calculation represents<br />
the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford<br />
et al., 2000).<br />
This is a conservative calculation of dermal systemic exposure<br />
because it makes the unlikely assumption that a consumer will<br />
use these 10 products containing; which are all perfumed with<br />
the upper 97.5 percentile level of the fragrance ingredient from a<br />
fine fragrance type of product (Cadby et al., 2002; Ford et al.,<br />
2000). The 97.5 percentile use level in <strong>for</strong>mulae <strong>for</strong> use in cosmetics<br />
in general has not been reported. As such the default value of<br />
0.02% is used to calculate the maximum daily exposure on the skin<br />
of 0.0005 mg/kg <strong>for</strong> high end users of these products (see Table 1).<br />
A maximum skin level is then determined <strong>for</strong> consideration of<br />
potential sensitization. The exposure is calculated as the percent<br />
concentration of the fragrance ingredient applied to the skin based<br />
on the use of 20% of the fragrance mixture in the fine fragrance<br />
consumer product (IFRA, 2007). The maximum skin level that<br />
Table 1<br />
Calculation of the total human skin exposure from the use of multiple cosmetic products containing isooctan-1-ol.<br />
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient (mg/kg/day) b<br />
Anti-perspirant 0.5 1 1 0.01 .02 0.000001<br />
Bath products 17 0.29 0.001 0.02 .02 0.000001<br />
Body lotion 8 0.71 1 0.004 .02 0.000100<br />
Eau de toilette 0.75 1 1 0.08 .02 0.000200<br />
Face cream 0.8 2 1 0.003 .02 0.000001<br />
<strong>Fragrance</strong> cream 5 0.29 1 0.04 .02 0.000200<br />
Hair spray 5 2 0.01 0.005 .02 0.000001<br />
Shampoo 8 1 0.01 0.005 .02 0.000001<br />
Shower gel 5 1.07 0.01 0.012 .02 0.000001<br />
Toilet soap 0.8 6 0.01 0.015 .02 0.000001<br />
Total 0.0005<br />
a<br />
b<br />
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.<br />
Based on a 60-kg adult.
S72<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S70–S72<br />
results from the use of isooctan-1-ol in <strong>for</strong>mulae that go into fine<br />
fragrances has been not been reported. A default value of 0.02%<br />
is used assuming use of the fragrance oils at levels up to 20% in<br />
the final product.<br />
4. <strong>Toxicology</strong> data<br />
4.1. Acute toxicity<br />
4.1.1. Oral studies<br />
No in<strong>for</strong>mation available.<br />
4.1.2. Dermal studies<br />
No in<strong>for</strong>mation available.<br />
4.1.3. Inhalation studies<br />
There was no mortality, clinical signs, or autopsy findings when<br />
three female Alderly-Park rats were exposed in whole body exposure<br />
chambers. Animals were exposed <strong>for</strong> up to 6 h a day, 5 days a<br />
weeks (a total of 13 over 4 weeks) to saturated vapor of a mixture<br />
of branched chain alcohols designated isooctan-1-ol, with a boiling<br />
point of 185–189 °C. Concentration was 1 mg/l or 188 ppm (Gage,<br />
1970).<br />
4.2. Skin irritation<br />
No in<strong>for</strong>mation available.<br />
4.3. Mucous membrane (eye) irritation<br />
No in<strong>for</strong>mation available.<br />
4.4. Skin sensitization<br />
No in<strong>for</strong>mation available.<br />
4.5. Phototoxicity <strong>and</strong> photoallergy<br />
No in<strong>for</strong>mation available.<br />
4.6. Absorption, distribution <strong>and</strong> metabolism<br />
No in<strong>for</strong>mation available.<br />
4.7. Repeated dose toxicity<br />
No in<strong>for</strong>mation available.<br />
4.8. Reproductive <strong>and</strong> developmental toxicity<br />
No in<strong>for</strong>mation available.<br />
4.9. Genotoxicity<br />
No in<strong>for</strong>mation available.<br />
4.10. Carcinogenicity<br />
No in<strong>for</strong>mation available.<br />
This individual <strong>Fragrance</strong> Material Review is not intended as a<br />
st<strong>and</strong>-alone document. Please refer to A Safety Assessment of<br />
Branched Chain Saturated Alcohols When Used as <strong>Fragrance</strong> Ingredients<br />
(Belsito et al., 2010) <strong>for</strong> an overall assessment of this<br />
material.<br />
Conflict of interest statement<br />
This research was supported by the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong><br />
Materials, an independent research institute that is funded<br />
by the manufacturers of fragrances <strong>and</strong> consumer products containing<br />
fragrances. The authors are all employees of the <strong>Research</strong><br />
<strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials.<br />
References<br />
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,<br />
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chain<br />
saturated alcohols when used as fragrance ingredients. <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong><br />
<strong>Toxicology</strong> 48 (S4), S1–S46.<br />
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:<br />
providing estimates <strong>for</strong> safety evaluation. Regulatory <strong>Toxicology</strong> <strong>and</strong><br />
Pharmacology 36, 246–252.<br />
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface<br />
Suite <strong>for</strong> Microsoft Ò Windows, v 4.00 or Insert Version Used. United States<br />
Environmental Protection Agency, Washington, DC, USA.<br />
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria <strong>for</strong><br />
development of a database <strong>for</strong> safety evaluation of fragrance ingredients.<br />
Regulatory <strong>Toxicology</strong> <strong>and</strong> Pharmacology 31, 166–181.<br />
Gage, J.C., 1970. The subacute inhalation toxicity of 109 industrial chemicals. British<br />
Journal of Industrial Medicine 27, 1–18.<br />
IFRA (International <strong>Fragrance</strong> Association), 2004. Use Level Survey, August 2004.<br />
IFRA (International <strong>Fragrance</strong> Association), 2007. Volume of Use Survey, February<br />
2007.
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S73–S78<br />
Contents lists available at ScienceDirect<br />
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong><br />
journal homepage: www.elsevier.com/locate/foodchemtox<br />
Review<br />
<strong>Fragrance</strong> material review on isotridecan-1-ol (isomeric mixture)<br />
D. McGinty * , S.P. Bhatia, J. Scognamiglio, C.S. Letizia, A.M. Api<br />
<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA<br />
article<br />
Keywords:<br />
Review<br />
<strong>Fragrance</strong><br />
info<br />
abstract<br />
A toxicologic <strong>and</strong> dermatologic review of isotridecan-1-ol (isomeric mixture) when used as a fragrance<br />
ingredient is presented. Isotridecan-1-ol (isomeric mixture) is a member of the fragrance structural group<br />
branched chain saturated alcohols. The common characteristic structural elements of the alcohols with<br />
saturated branched chain are one hydroxyl group per molecule, <strong>and</strong> a C 4 –C 12 carbon chain with one or<br />
several methyl side chains. This review contains a detailed summary of all available toxicology <strong>and</strong> dermatology<br />
papers that are related to this individual fragrance ingredient <strong>and</strong> is not intended as a st<strong>and</strong>alone<br />
document. A safety assessment of the entire branched chain saturated alcohol group will be published<br />
simultaneously with this document; please refer to Belsito et al. (2010) <strong>for</strong> an overall assessment<br />
of the safe use of this material <strong>and</strong> all other branched chain saturated alcohols in fragrances.<br />
Ó 2010 Published by Elsevier Ltd.<br />
Contents<br />
Introduction . . . ..................................................................................................... S73<br />
1. Identification . . ..................................................................................................... S74<br />
2. Physical properties . . . . . . . . . . . . . . . . . .................................................................................. S74<br />
3. Usage. . . . . . . . . ..................................................................................................... S74<br />
4. <strong>Toxicology</strong> data ..................................................................................................... S75<br />
4.1. Acute toxicity (see Table 2). ..................................................................................... S75<br />
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S75<br />
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S75<br />
4.1.3. Intraperitoneal studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S75<br />
4.1.4. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S75<br />
4.2. Skin irritation. ................................................................................................ S76<br />
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S76<br />
4.2.2. Animal studies (see Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S76<br />
4.3. Mucous membrane (eye) irritation (see Table 4) .................................................................... S76<br />
4.4. Skin sensitization. ............................................................................................. S76<br />
4.5. Phototoxicity <strong>and</strong> photoallergy. . ................................................................................. S76<br />
4.6. Absorption, distribution <strong>and</strong> metabolism .......................................................................... S76<br />
4.7. Repeated dose toxicity . . ....................................................................................... S76<br />
4.8. Reproductive <strong>and</strong> developmental toxicity .......................................................................... S77<br />
4.9. Genotoxicity. ................................................................................................. S77<br />
4.9.1. In vitro studies........................................................................................ S77<br />
4.9.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S77<br />
4.10. Carcinogenicity . . ............................................................................................. S77<br />
Conflict of interest statement . . . . . . . . .................................................................................. S77<br />
References . . . . ..................................................................................................... S77<br />
Introduction<br />
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.<br />
E-mail address: dmcginty@RIFM.org (D. McGinty).<br />
This document provides a summary of the toxicologic review,<br />
including all human health endpoints, of isotridecan-1-ol (isomeric<br />
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.<br />
doi:10.1016/j.fct.2010.05.033
S74<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S73–S78<br />
mixture) when used as a fragrance ingredient. Isotridecan-1-ol (see<br />
Fig. 1; CAS Number 27458-92-0) is a fragrance ingredient used in<br />
cosmetics, fine fragrances, shampoos, toilet soaps <strong>and</strong> other toiletries<br />
as well as in non-cosmetic products such as household cleaners<br />
<strong>and</strong> detergents. This material has been reported to occur in<br />
nature within beef (VCF, 2009).<br />
In 2006, a complete literature search was conducted on Isotridecan-1-ol.<br />
On-line toxicological databases were searched including<br />
those from the <strong>Chemical</strong> Abstract Services, [e.g., ToxCenter (which<br />
in itself contains 18 databases including <strong>Chemical</strong> Abstracts)], <strong>and</strong><br />
the National Library of Medicine [e.g., Medline, Toxnet (which contains<br />
14 databases)] as well as 26 additional sources (e.g., BIOSIS,<br />
Embase, RTECS, OSHA, ESIS). In addition, fragrance companies were<br />
asked to submit all test data.<br />
The safety data on this material has never been reviewed be<strong>for</strong>e<br />
by RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.). All relevant<br />
references are included in this document. More details have<br />
been provided <strong>for</strong> unpublished data. The number of animals, sex<br />
<strong>and</strong> strain are always provided unless they are not given in the original<br />
report or paper. Any papers in which the vehicles <strong>and</strong>/or the<br />
doses are not given have not been included in this review. In addition,<br />
diagnostic patch test data with fewer than 100 consecutive<br />
patients have been omitted.<br />
1. Identification<br />
1.1 Synonyms: Isotridecanol; 11-methyldodecan-1-ol<br />
1.2 CAS registry number: 27458-92-0<br />
1.3 EINECS number: 248-469-2<br />
1.4 Formula: C 13 H 28 O<br />
1.5 Molecular weight: 200.66<br />
2. Physical properties<br />
2.1 Physical <strong>for</strong>m: no in<strong>for</strong>mation available<br />
2.2 Boiling point (calculated; EPA, 2010): 279.35 °C<br />
2.3 Flash point: no in<strong>for</strong>mation available<br />
2.4 Henry’s law (calculated; EPA, 2010): 0.000128 atm m 3 /mol<br />
25 °C<br />
2.5 Log K ow (calculated; EPA, 2010): 5.19<br />
2.6 Refractive index: no in<strong>for</strong>mation available<br />
2.7 Specific gravity: no in<strong>for</strong>mation available<br />
2.8 Vapor pressure (calculated; EPA, 2010): 0.000462 mm Hg;<br />
0.0615 Pa (25 °C)<br />
2.9 Water solubility (calculated; EPA, 2010): 5.237 mg/l at 25°<br />
2.10 UV spectra available at RIFM. Does not absorb UV light.<br />
3. Usage<br />
Fig. 1. Isotridecan-1-ol (isomeric mixture).<br />
Isotridecan-1-ol (isomeric mixture) is a fragrance ingredient<br />
used in many fragrance compounds. It may be found in fragrances<br />
used in decorative cosmetics, fine fragrances, shampoos, toilet<br />
soaps <strong>and</strong> other toiletries as well as in non-cosmetic products such<br />
as household cleaners <strong>and</strong> detergents. Its use worldwide is in the<br />
region of 10–100 metric tons per annum (IFRA, 2004). The reported<br />
volume of use is <strong>for</strong> isotridecan-1-ol as used in fragrance compounds<br />
(mixtures) in all finished consumer product categories.<br />
The volume of use is surveyed by IFRA approximately every four<br />
years through a comprehensive survey of IFRA <strong>and</strong> RIFM member<br />
companies. As such the volume of use data from this survey provides<br />
volume of use of fragrance ingredients <strong>for</strong> the majority of<br />
the fragrance industry.<br />
The dermal systemic exposure in cosmetic products (see<br />
Table 1) is calculated based on the concentrations of the same fragrance<br />
ingredient in ten types of the most frequently used personal<br />
care <strong>and</strong> cosmetic products (anti-perspirant, bath products, body<br />
lotion, eau de toilette, face cream, fragrance cream, hair spray,<br />
shampoo, shower gel, <strong>and</strong> toilet soap). The concentration of the<br />
fragrance ingredient in fine fragrances is obtained from examination<br />
of several thous<strong>and</strong> commercial <strong>for</strong>mulations. The upper<br />
97.5 percentile concentration is calculated from the data obtained.<br />
This upper 97.5 percentile concentration is then used <strong>for</strong> all 10<br />
Table 1<br />
Calculation of the total human skin exposure from the use of multiple cosmetic products containing isotridecan-1-ol (isomeric mixture).<br />
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient (mg/kg/day) b<br />
Anti-perspirant 0.5 1 1 0.01 1.4 0.0012<br />
Bath products 17 0.29 0.001 0.02 1.4 0.00002<br />
Body lotion 8 0.71 1 0.004 1.4 0.0053<br />
Eau de toilette 0.75 1 1 0.08 1.4 0.0140<br />
Face cream 0.8 2 1 0.003 1.4 0.0011<br />
<strong>Fragrance</strong> cream 5 0.29 1 0.04 1.4 0.0135<br />
Hair spray 5 2 0.01 0.005 1.4 0.0001<br />
Shampoo 8 1 0.01 0.005 1.4 0.0001<br />
Shower gel 5 1.07 0.01 0.012 1.4 0.0001<br />
Toilet soap 0.8 6 0.01 0.015 1.4 0.0002<br />
Total 0.0357<br />
a<br />
b<br />
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.<br />
Based on a 60-kg adult.
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S73–S78 S75<br />
consumer products. These concentrations are multiplied by the<br />
amount of product applied, the number of applications per day<br />
<strong>for</strong> each product type, <strong>and</strong> a ‘‘retention factor” (ranging from<br />
0.001 to 1.0) to account <strong>for</strong> the length of time a product may remain<br />
on the skin <strong>and</strong>/or likelihood of the fragrance ingredient<br />
being removed by washing. The resultant calculation represents<br />
the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford<br />
et al., 2000).<br />
This is a conservative calculation of dermal systemic exposure<br />
because it makes the unlikely assumption that a consumer will<br />
use these 10 products containing; which are all perfumed with<br />
the upper 97.5 percentile level of the fragrance ingredient from a<br />
fine fragrance type of product (Cadby et al., 2002; Ford et al.,<br />
2000). The 97.5% percentile use level in <strong>for</strong>mulae <strong>for</strong> use in cosmetics<br />
in general has been reported to be 1.4 (IFRA, 2007), which<br />
would result in a maximum daily exposure on the skin of<br />
0.0356 mg/kg <strong>for</strong> high end users.<br />
A maximum skin level is then determined <strong>for</strong> consideration of<br />
potential sensitization. The exposure is calculated as the percent<br />
concentration of the fragrance ingredient applied to the skin based<br />
on the use of 20% of the fragrance mixture in the fine fragrance<br />
consumer product (IFRA, 2007). The average maximum use level<br />
in <strong>for</strong>mulae that go into fine fragrances has been reported to be<br />
0.69% (IFRA, 2007), assuming use of the fragrance oil at levels up<br />
to 20% the final product.<br />
4. <strong>Toxicology</strong> data<br />
4.1. Acute toxicity (see Table 2)<br />
4.1.1. Oral studies<br />
The acute oral LD 50 of isotridecan-1-ol (1-tridecanol: mixed primary<br />
isomers) in male rats (n = 5) was reported to be 17.2 (12.3–<br />
23.9) ml/kg (17.2; 12.3–23.6 g/kg). No additional details were reported<br />
(Smyth et al., 1962; Nishimura et al., 1994).<br />
Scala <strong>and</strong> Burtis (1973) reported an LD 50 <strong>for</strong> isotridecan-1-ol (1-<br />
tridecanol: mixed primary isomers) of 4.75 g/kg in Sprague–Dawley<br />
rats (five/dose). The principal clinical signs were central nervous<br />
system depression <strong>and</strong> labored respiration. The depression<br />
included inactivity, ataxia, limb sprawling, depressed righting<br />
<strong>and</strong> placement reflexes, prostration, <strong>and</strong> coma. The intensity of<br />
the signs was related to dose. The signs of effect had an early onset,<br />
<strong>and</strong> recovery was complete by the second or third day. Where<br />
deaths occurred, they were seen as late as 4 days.<br />
The LD 50 of isotridecan-1-ol in Wistar rats was found to be<br />
greater than 2 g/kg body weight <strong>for</strong> male <strong>and</strong> female rats. Single<br />
gavage doses of 2.0 g/kg body weight of isotridecan-1-ol in olive<br />
oil were given to six (three/sex/group) fasted animals. No mortality<br />
occurred in the 2 g/kg groups. Piloerection was the only clinical<br />
sign observed, in males, 5 h after administration. No clinical signs<br />
<strong>and</strong> findings were observed in the females of the 2 g/kg administration<br />
group. The mean body weights of the administration groups<br />
increased throughout the study period. No macroscopic pathologic<br />
abnormalities were observed. This study was based on the OECD,<br />
EU <strong>and</strong> US EPA OPPTS guidelines (RIFM, 2002a).<br />
Greim (2000) reported acute oral an LD 50 value of isotridecan-1-<br />
ol (isomeric mixture: 50% branched, 50% linear <strong>for</strong>m) as greater<br />
than 2.0 g/kg in rats (further in<strong>for</strong>mation not obtained, ECB, 1995).<br />
The acute oral LD 50 in mice with 30% isotridecan-1-ol (isomeric<br />
mixture) as an aqueous emulsion with tragacanth gum was reported<br />
to be >6.5 ml (6.5 g/kg) body weight. Observations were<br />
made <strong>for</strong> 7 days. The clinical signs noted were staggering, accelerated<br />
respiration, tremors, <strong>and</strong> slow recovery. The mortalities were<br />
sporadic <strong>and</strong> late (RIFM, 1963a).<br />
Greim (2000) reported acute oral an LD 50 value of isotridecan-1-<br />
ol (isomeric mixture) as 7.257 g/kg in mice (further in<strong>for</strong>mation<br />
not obtained, ECB, 1995; Hoechst, 1961a).<br />
4.1.2. Dermal studies<br />
The acute dermal LD 50 of isotridecan-1-ol (Tridecanol: mixed<br />
primary isomers) in male rabbits (n = 4) was reported to be 7.07<br />
(2.33–21.4) ml/kg (7.07; 2.33–24.4 g/kg). Contact time was 24 h<br />
<strong>and</strong> observation time was 14 days. No additional details were reported<br />
(Smyth et al., 1962).<br />
The dermal LD 50 <strong>for</strong> isotridecan-1-ol (Tridecanol: mixed primary<br />
isomers) applied occlusively <strong>for</strong> 24 h to rabbits (four/dose)<br />
was reported to be >2.6 g/kg. There were no clinical signs indicative<br />
of systemic effects at the highest level tested. Dermal irritation<br />
was dose dependent (Scala <strong>and</strong> Burtis, 1973).<br />
4.1.3. Intraperitoneal studies<br />
The intraperitoneal LD 50 of mice with 8% isotridecan-1-ol<br />
(mixed isomers) as an aqueous emulsion with tragacanth gum<br />
was reported to be about 0.6 ml/kg body weight (0.6 g/kg).<br />
Observations included staggering, accelerated respiration, tremors,<br />
<strong>and</strong> slow recovery. Mortalities were sporadic <strong>and</strong> late. Necropsy<br />
findings included adhesions in the abdominal cavity (RIFM, 1963b).<br />
4.1.4. Inhalation studies<br />
The study of the acute inhalation hazard of isotridecan-1-ol<br />
(isomeric mixture) in rats resulted in no deaths (0/12) <strong>and</strong> no<br />
abnormalities. Animals were exposed <strong>for</strong> 8 h to atmosphere saturated<br />
with vapor at 20 °C (room temperature). For saturation, air<br />
was conducted through a layer of about 5 cm of the product (RIFM,<br />
1963c; Smyth et al., 1962).<br />
No deaths were reported when 10 rats, mice, <strong>and</strong> guinea pigs<br />
were exposed by whole body inhalation <strong>for</strong> 6 h to air bubbled<br />
through isotridecan-1-ol (mixed isomers) to yield a nominal chamber<br />
concentration of 12 ppm (12 ml/m 3 ) at 30°C. Clinical signs<br />
indicated moderate local irritation <strong>and</strong> slight to moderate systemic<br />
effects. Local irritation involved the mucous membranes of the<br />
eyes, nose, throat, <strong>and</strong> respiratory passages <strong>and</strong> was manifest as<br />
blinking, lacrimation, preening, nasal discharge, salivation, gasping,<br />
<strong>and</strong> chewing movements. Responses were temporary <strong>and</strong> all<br />
animals had recovered within 1 h after termination of exposure.<br />
Table 2<br />
Summary of acute toxicity studies.<br />
Route Species No. animals/dose group LD 50 (g/kg) References<br />
Oral Rat 5 17.2 Smyth et al., 1962; Nishimura, 1994<br />
Oral Rat 5 4.75 Scala <strong>and</strong> Burtis, 1973<br />
Oral Rat 3 >2.0 RIFM, 2002a<br />
Oral Rat N/A >2.0 ECB, 1995 as cited in Greim, 2000<br />
Oral Mouse N/A 6.5 RIFM, 1963a<br />
Oral Mouse N/A 7.257 ECB, 1995; Hoechst, 1961a; as cited in Greim, 2000<br />
Dermal Rabbit 4 7.07 Smyth et al., 1962<br />
Dermal Rabbit 4 >2.6 Scala <strong>and</strong> Burtis, 1973<br />
Intraperitoneal Mouse N/A 0.6 RIFM, 1963b
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D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S73–S78<br />
Gross necropsy findings were normal in appearance (Scala <strong>and</strong><br />
Burtis, 1973).<br />
4.2. Skin irritation<br />
4.2.1. Human studies<br />
In an in vitro human study it was concluded that isotridecan-1-<br />
ol (mixed isomers) does not show a corrosive potential in the Epi-<br />
Derm skin corrosivity test (RIFM, 2003a).<br />
Table 4<br />
Summary of eye irritation studies.<br />
Dose<br />
(%)<br />
Reactions<br />
References<br />
100 Irritation was observed. In one animal slight RIFM, 2002b<br />
corneal opacity <strong>and</strong> loss of corneal tissue<br />
100 Slight irritation RIFM, 1963f<br />
100 Small area of necrosis on the eye Smyth et al., 1962<br />
100 Moderately irritating Scala <strong>and</strong><br />
Burtis, 1973<br />
4.2.2. Animal studies (see Table 3)<br />
Isotridecan-1-ol (mixed isomers) was applied ‘‘at full-strength”<br />
to the closely clipped, intact abdominal skin of albino rabbits (four/<br />
group). The exposed area was then covered with an occlusive patch<br />
<strong>for</strong> 24 h. Doses of 0.10, 0.316, 1.0, or 3.16 ml/kg were administered<br />
volumetrically <strong>and</strong> observations <strong>for</strong> signs of toxicity were made<br />
once daily <strong>for</strong> 7 days. Moderate irritation was observed (Scala<br />
<strong>and</strong> Burtis, 1973).<br />
A primary skin irritation evaluation was done on the clipped<br />
skin (uncovered) of five albino rabbits with undiluted isotridecan-1-ol<br />
(mixed isomers) <strong>and</strong> resulted in grade 4 (moderate) irritation<br />
(Smyth et al., 1962).<br />
Undiluted isotridecan-1-ol (mixed isomers) produced irritation<br />
when administered percutaneously to the intact dorsal <strong>and</strong> ear<br />
skin of rabbits. The time of exposure on the dorsal skin was 1, 5,<br />
15, <strong>and</strong> 20 h, <strong>and</strong> 20 h <strong>for</strong> the ears. The skin was checked after<br />
24 h <strong>and</strong> after 8 days. After 20 h of exposure, the dorsal skin resulted<br />
in severe erythema <strong>and</strong> distinct edema when observed at<br />
24 h, then distinct scarring <strong>and</strong> severe scaling at 8 days. When<br />
the dorsal skin was exposed <strong>for</strong> 1, 5, or 15 h severe erythema<br />
was observed at 24 h, then scaling at 8 days. Exposure of 20 h to<br />
the ear resulted in severe erythema at 24 h <strong>and</strong> severe erythema<br />
<strong>and</strong> scaring at 8 days (RIFM, 1963d,e).<br />
In order to assess the acute skin irritation potential of isotridecanol-1-ol<br />
in White New Zeal<strong>and</strong> rabbits a dermal irritation/corrosion<br />
test was per<strong>for</strong>med according to the method described in<br />
OECD guideline 404. A 0.5 ml sample of the isotridecanol-1-ol<br />
was applied <strong>for</strong> 4 h to the intact skin of three rabbits, using a patch<br />
of 2.5 cm 2.5 cm, covered with semi-occlusive dressing. After removal<br />
of the patch the application area was washed off. The skin<br />
reactions were assessed immediately after removal of the patch,<br />
approximately 1, 24, 48 <strong>and</strong> 72 h after removal <strong>and</strong> then win<br />
weekly intervals until day 14. Slight to marked erythema, slight<br />
or moderate edema <strong>and</strong> scaling were observed in almost all animals<br />
during the course of the study. Additionally the described<br />
findings above were partly extended beyond the area of exposure.<br />
Moreover severe scaling <strong>and</strong> petechiae, both extending beyond the<br />
area of exposure <strong>and</strong> thickening of the skin in the regions of the<br />
application area were noted in a single animal. The cutaneous reactions<br />
(such as slight erythema) were not reversible in all animals<br />
within study termination of day 14. The average score (24 to<br />
72 h) <strong>for</strong> irritation was calculated to be 3.0 <strong>for</strong> erythema <strong>and</strong> 0.3<br />
<strong>for</strong> edema (RIFM, 2003b).<br />
4.3. Mucous membrane (eye) irritation (see Table 4)<br />
An eye irritation test was conducted in three White New Zeal<strong>and</strong><br />
rabbits subjected to a single dose ocular application of<br />
0.1 ml of undiluted isotridecan-1-ol (mixed isomers). The ocular<br />
reactions were assessed approximately 1, 24, 48, 72 h <strong>and</strong> 7 days<br />
after application. Slight to moderate conjunctival redness, slight<br />
conjunctival chemosis <strong>and</strong> moderate to severe discharge were observed<br />
during the course of the study. In addition in one animal<br />
slight corneal opacity <strong>and</strong> loss of corneal tissue was noted during<br />
the observation period (RIFM, 2002b).<br />
An eye irritation test was conducted in rabbits. Undiluted isotridecan-1-ol<br />
(mixed isomers) was applied (1 50 mm 3 or<br />
50 mg) to the conjunctival sac of the eyelid. The findings after<br />
1 h included slight redness. The findings after 24 h <strong>and</strong> 8 days were<br />
nonirritating. No further in<strong>for</strong>mation (RIFM, 1963d; RIFM, 1963f).<br />
Application of to the eyes isotridecan-1-ol (mixed isomers) of<br />
rabbits produced irritation grade 2 on a ten-grade scale with Grade<br />
1 a very small area of necrosis from 0.5 ml of an undiluted chemical<br />
in the eye <strong>and</strong> Grade 5 representing a severe burn from<br />
0.005 ml (Smyth et al., 1962).<br />
Six rabbits were given single 0.1 ml application of isotridecan-<br />
1-ol (mixed isomers) undiluted. Observations were made after 1,<br />
4, <strong>and</strong> 24 h, 2, 3, 4, <strong>and</strong> 7 days. Moderate irritation was observed<br />
(Scala <strong>and</strong> Burtis, 1973).<br />
4.4. Skin sensitization<br />
No data available.<br />
4.5. Phototoxicity <strong>and</strong> photoallergy<br />
No data available.<br />
4.6. Absorption, distribution <strong>and</strong> metabolism<br />
No data available.<br />
4.7. Repeated dose toxicity<br />
Isotridecan-1-ol (isomeric mixture) in polyethylene glycol was<br />
given to Alderley Park Wistar-derived rats, five rats treated <strong>and</strong><br />
10 controls, by gavage <strong>for</strong> 14 days. At 1 mmol/kg body weight/<br />
Table 3<br />
Summary of animal irritation studies.<br />
Method<br />
Dose<br />
(%)<br />
Species Reactions References<br />
Single occlusive patch <strong>for</strong> 24 h to intact skin of<br />
four rabbits<br />
100 Rabbits Moderately irritating Scala <strong>and</strong> Burtis,<br />
1973<br />
Single uncovered application of 0.01 ml <strong>for</strong> 24 h 100 Rabbits Moderately irritating Smyth et al., 1962<br />
Percutaneously to the intact dorsal skin <strong>for</strong> 20 h 100 Rabbits Severe erythema <strong>and</strong> distinct edema at 24 h. Distinct scarring <strong>and</strong> severe RIFM, 1963e<br />
scaling at 8 days<br />
4-h semi-occlusive irritation 100 Rabbits Slight to marked erythema, slight or moderate edema <strong>and</strong> scaling RIFM, 2003b
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S73–S78 S77<br />
day (200 mg/kg body weight/day) the liver weight was unaffected,<br />
no hepatomegaly, peroxisome proliferation, hypolipidemia, or testicular<br />
atrophy was observed (Rhodes et al., 1984).<br />
4.8. Reproductive <strong>and</strong> developmental toxicity<br />
Isotridecan-1-ol (isomeric mixture) was tested <strong>for</strong> its prenatal<br />
developmental toxicity in 25 mated female Wistar rats as a solution<br />
in olive oil. Gavage administration of 0, 60, 250, or 750 mg/<br />
kg body weight were given on days 6 through day 19 post coitum<br />
(p.c.). A st<strong>and</strong>ard dose volume of 5 ml/kg body weight was used <strong>for</strong><br />
each group. <strong>Food</strong> consumption <strong>and</strong> body weights of the animals<br />
were recorded regularly throughout the study period. On day 20<br />
p.c., blood was taken from all females, then sacrificed <strong>and</strong> assessed<br />
by gross pathology (including weight determinations of the unopened<br />
uterus, the liver, the kidneys, the spleen <strong>and</strong> the placentae).<br />
For each dam, corpora lutea were counted <strong>and</strong> number <strong>and</strong> distribution<br />
of implantation sites (differentiated as resorptions, live <strong>and</strong><br />
dead fetuses) were determined. The fetuses were removed from<br />
the uterus, sexed, weighed <strong>and</strong> further investigated <strong>for</strong> any external<br />
findings soft tissue <strong>and</strong> skeletal findings. In the 750 mg/kg body<br />
weight/day dose: transient salivation was noted in all rats between<br />
treatment days 7–19 p.c.; urine-smeared fur in 4 females on gestation<br />
days 10–13 <strong>and</strong> 17–20 p.c.; statistically significant reduction<br />
of food consumption on days 6–10 p.c. (up to about 11% below<br />
the corresponding control value); statistically significant increased<br />
alanine aminotransferase values; statistically significant increased<br />
triglycerides <strong>and</strong> relative liver weights (about 14% or 18%, respectively<br />
above control values) were noted; statistically significant decreased<br />
total protein <strong>and</strong> globulin concentrations; no substancerelated<br />
effects on gestational parameters or fetuses. Substance related<br />
findings in the 250 mg/kg body weight/day group included:<br />
transient salivation in 17/25 rats immediately after gavaging between<br />
treatment days 12–19 p.c.; no substance-related effects on<br />
gestational parameters or fetuses were noted. No substance-related<br />
effects on dams, gestational parameters or fetuses were<br />
noted the 60 mg/kg body weight/day group.<br />
Under the conditions of this prenatal developmental toxicity<br />
study, the oral administration of isotridecan-1-ol (isomeric mixture)<br />
to pregnant Wistar rats from implantation to one day prior<br />
to the expected day of parturition (days 6–19 p.c.) elicited some<br />
signs of maternal toxicity at 750 mg/kg body weight/day. Placental<br />
<strong>and</strong> fetal body weights, the external, soft tissue <strong>and</strong>/or skeletal<br />
(including cartilage) examinations of the fetuses revealed no biologically<br />
relevant differences between the control <strong>and</strong> the substance-treated<br />
groups. Based on these results, the no observed<br />
adverse effect level (NOAEL) <strong>for</strong> maternal toxicity is 250 mg/kg<br />
body weight/day, while it is 750 mg/kg body weight/day <strong>for</strong> prenatal<br />
developmental toxicity (RIFM, 2003c).<br />
4.9. Genotoxicity<br />
4.9.1. In vitro studies<br />
4.9.1.1. Bacterial test systems. Isotridecan-1-ol (isomeric mixture)<br />
in DMSO was tested <strong>for</strong> mutagenicity in the Ames test (Ames<br />
et al., 1975) (st<strong>and</strong>ard plate test <strong>and</strong> preincubation test) at doses<br />
up to 5000 lg/plate both in the presence <strong>and</strong> absence of a metabolizing<br />
system obtained from rat liver (S-9 mix) using Salmonella<br />
typhimurium strains TA1537, TA 1535, TA100, <strong>and</strong> TA98. No mutagenicity<br />
was observed (RIFM, 1989).<br />
4.9.1.2. Studies in mammalian cells. No data available.<br />
4.9.2. In vivo studies<br />
No data available.<br />
4.10. Carcinogenicity<br />
No data available.<br />
This individual <strong>Fragrance</strong> Material Review is not intended as a<br />
st<strong>and</strong>-alone document. Please refer to A Safety Assessment of<br />
Branched Chain Saturated Alcohols When Used as <strong>Fragrance</strong> Ingredients<br />
(Belsito et al., 2010) <strong>for</strong> an overall assessment of this<br />
material.<br />
Conflict of interest statement<br />
This research was supported by the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong><br />
Materials, an independent research institute that is funded<br />
by the manufacturers of fragrances <strong>and</strong> consumer products containing<br />
fragrances. The authors are all employees of the <strong>Research</strong><br />
<strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials.<br />
References<br />
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Greim, H. (ed.), 2000. iso-Tridecanol (Isomerengemisch verzweigter primärer C10-<br />
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Contents lists available at ScienceDirect<br />
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong><br />
journal homepage: www.elsevier.com/locate/foodchemtox<br />
Review<br />
<strong>Fragrance</strong> material review on isononyl alcohol<br />
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api<br />
<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA<br />
article<br />
Keywords:<br />
Review<br />
<strong>Fragrance</strong><br />
info<br />
abstract<br />
A toxicologic <strong>and</strong> dermatologic review of isononyl alcohol when used as a fragrance ingredient is presented.<br />
Isononyl alcohol is a member of the fragrance structural group branched chain saturated alcohols.<br />
The common characteristic structural elements of the alcohols with saturated branched chain are one<br />
hydroxyl group per molecule, <strong>and</strong> a C 4 –C 12 carbon chain with one or several methyl side chains. This<br />
review contains a detailed summary of all available toxicology <strong>and</strong> dermatology papers that are related<br />
to this individual fragrance ingredient <strong>and</strong> is not intended as a st<strong>and</strong>-alone document. A safety assessment<br />
of the entire branched chain saturated alcohol group will be published simultaneously with this<br />
document; please refer to Belsito et al. (2010) <strong>for</strong> an overall assessment of the safe use of this material<br />
<strong>and</strong> all other branched chain saturated alcohols in fragrances.<br />
Ó 2010 Published by Elsevier Ltd.<br />
Contents<br />
Introduction . . . ..................................................................................................... S79<br />
1. Identification . . ..................................................................................................... S80<br />
2. Physical properties . . . . . . . . . . . . . . . . . .................................................................................. S80<br />
3. Usage. . . . . . . . . ..................................................................................................... S80<br />
4. <strong>Toxicology</strong> data ..................................................................................................... S81<br />
4.1. Acute toxicity. ................................................................................................ S81<br />
4.2. Skin irritation. ................................................................................................ S81<br />
4.3. Mucous membrane (eye) irritation. ............................................................................... S81<br />
4.4. Skin sensitization. ............................................................................................. S81<br />
4.5. Phototoxicity <strong>and</strong> photoallergy. . ................................................................................. S81<br />
4.6. Absorption, distribution, <strong>and</strong> metabolism .......................................................................... S81<br />
4.7. Repeated dose toxicity . . ....................................................................................... S81<br />
4.8. Reproductive <strong>and</strong> developmental toxicity .......................................................................... S81<br />
4.9. Genotoxicity. ................................................................................................. S81<br />
4.10. Carcinogenicity . . ............................................................................................. S81<br />
Conflict of interest statement . . . . . . . . .................................................................................. S81<br />
References . . . . ..................................................................................................... S81<br />
Introduction<br />
This document provides a summary of the toxicologic review,<br />
including all human health endpoints, of isononyl alcohol when used<br />
as a fragrance ingredient. Isononyl alcohol (see Fig. 1; CAS Number<br />
27458-94-2) is a fragrance ingredient used in cosmetics, fine fragrances,<br />
shampoos, toilet soaps <strong>and</strong> other toiletries as well as in<br />
non-cosmetic products such as household cleaners <strong>and</strong> detergents.<br />
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.<br />
E-mail address: dmcginty@RIFM.org (D. McGinty).<br />
In 2006, a complete literature search was conducted on isononyl<br />
alcohol. On-line toxicological databases were searched including<br />
those from the <strong>Chemical</strong> Abstract Services [e.g., ToxCenter<br />
(which in itself contains 18 databases including <strong>Chemical</strong> Abstracts)],<br />
<strong>and</strong> the National Library of Medicine [e.g., Medline, Toxnet<br />
(which contains 14 databases)] as well as 26 additional sources<br />
(e.g., BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance<br />
companies were asked to submit all test data.<br />
The safety data on this material has never been reviewed be<strong>for</strong>e<br />
by RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.). All relevant<br />
references are included in this document. More details have<br />
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.<br />
doi:10.1016/j.fct.2010.05.034
S80<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S79–S81<br />
3. Usage<br />
been provided <strong>for</strong> unpublished data. The number of animals, sex<br />
<strong>and</strong> strain are always provided unless they are not given in the original<br />
report or paper. Any papers in which the vehicles <strong>and</strong>/or the<br />
doses are not given have not been included in this review. In addition,<br />
diagnostic patch test data with fewer than 100 consecutive<br />
patients have been omitted.<br />
1. Identification<br />
1.1 Synonyms: isononanol; 7-methyloctan-1-ol<br />
1.2 CAS registry number: 27458-94-2<br />
1.3 EINECS number: 248-471-3<br />
1.4 Formula: C 9 H 20 O<br />
1.5 Molecular weight: 144.58<br />
2. Physical properties<br />
Fig. 1. Isononyl alcohol.<br />
2.1 Physical <strong>for</strong>m: no in<strong>for</strong>mation available<br />
2.2 Boiling point (calculated; EPA, 2010): 208.49<br />
2.3 Flash point: no in<strong>for</strong>mation available<br />
2.4 Henry’s law (calculated; EPA, 2010): 0.0000412 atm m 3 /mol<br />
25 °C<br />
2.5 Log K ow (calculated; EPA, 2010): 3.22<br />
2.6 Refractive index: no in<strong>for</strong>mation available<br />
2.7 Specific gravity: no in<strong>for</strong>mation available<br />
2.8 Vapor pressure (calculated; EPA, 2010): 0.0198 mm Hg;<br />
2.63 Pa (25 °C)<br />
2.9 Water solubility (calculated; EPA, 2010): 459.7 mg/l (25 °C)<br />
2.10 UV spectra not available at RIFM<br />
Isononyl alcohol is a fragrance ingredient used in many fragrance<br />
compounds. It may be found in fragrances used in decorative<br />
cosmetics, fine fragrances, shampoos, toilet soaps <strong>and</strong> other<br />
toiletries as well as in non-cosmetic products such as household<br />
cleaners <strong>and</strong> detergents. Its use worldwide is in the region of 1–<br />
10 metric tons per annum (IFRA, 2004). The reported volume of<br />
use is <strong>for</strong> isononyl alcohol as used in fragrance compounds (mixtures)<br />
in all finished consumer product categories. The volume of<br />
use is surveyed by IFRA approximately every four years through<br />
a comprehensive survey of IFRA <strong>and</strong> RIFM member companies.<br />
As such the volume of use data from this survey provides volume<br />
of use of fragrance ingredients <strong>for</strong> the majority of the fragrance<br />
industry.<br />
The dermal systemic exposure in cosmetic products (see<br />
Table 1) is calculated based on the concentrations of the same fragrance<br />
ingredient in ten types of the most frequently used personal<br />
care <strong>and</strong> cosmetic products (anti-perspirant, bath products, body<br />
lotion, eau de toilette, face cream, fragrance cream, hair spray,<br />
shampoo, shower gel, <strong>and</strong> toilet soap). The concentration of the<br />
fragrance ingredient in fine fragrances is obtained from examination<br />
of several thous<strong>and</strong> commercial <strong>for</strong>mulations. The upper<br />
97.5 percentile concentration is calculated from the data obtained.<br />
This upper 97.5 percentile concentration is then used <strong>for</strong> all 10<br />
consumer products. These concentrations are multiplied by the<br />
amount of product applied, the number of applications per day<br />
<strong>for</strong> each product type, <strong>and</strong> a ‘‘retention factor” (ranging from<br />
0.001 to 1.0) to account <strong>for</strong> the length of time a product may remain<br />
on the skin <strong>and</strong>/or likelihood of the fragrance ingredient<br />
being removed by washing. The resultant calculation represents<br />
the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford<br />
et al., 2000).<br />
This is a conservative calculation of dermal systemic exposure<br />
because it makes the unlikely assumption that a consumer will<br />
use these 10 products containing; which are all perfumed with<br />
the upper 97.5 percentile level of the fragrance ingredient from a<br />
fine fragrance type of product (Cadby et al., 2002; Ford et al.,<br />
2000). The 97.5 percentile use level in <strong>for</strong>mulae <strong>for</strong> use in cosmetics<br />
in general has been reported to be 4.46% (IFRA, 2007), which<br />
would result in a maximum daily exposure on the skin of<br />
0.1137 mg/kg <strong>for</strong> high end users.<br />
A maximum skin level is then determined <strong>for</strong> consideration of<br />
potential sensitization. The exposure is calculated as the percent<br />
concentration of the fragrance ingredient applied to the skin based<br />
on the use of 20% of the fragrance mixture in the fine fragrance<br />
consumer product (IFRA, 2007). The average maximum use level<br />
in <strong>for</strong>mulae that go into fine fragrances has been reported to be<br />
Table 1<br />
Calculation of the total human skin exposure from the use of multiple cosmetic products containing isononyl alcohol.<br />
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient (mg/kg/day) b<br />
Anti-perspirant 0.5 1 1 0.01 4.46 0.0037<br />
Bath products 17 0.29 0.001 0.02 4.46 0.0001<br />
Body lotion 8 0.71 1 0.004 4.46 0.0169<br />
Eau de toilette 0.75 1 1 0.08 4.46 0.0446<br />
Face cream 0.8 2 1 0.003 4.46 0.0036<br />
<strong>Fragrance</strong> cream 5 0.29 1 0.04 4.46 0.0431<br />
Hair spray 5 2 0.01 0.005 4.46 0.0004<br />
Shampoo 8 1 0.01 0.005 4.46 0.0003<br />
shower gel 5 1.07 0.01 0.012 4.46 0.0005<br />
Toilet soap 0.8 6 0.01 0.015 4.46 0.0005<br />
Total 0.1136<br />
a<br />
b<br />
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.<br />
Based on a 60-kg adult.
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S79–S81 S81<br />
0.30% (IFRA, 2007), assuming use of the fragrance oil at levels up to<br />
20% of the final product.<br />
4. <strong>Toxicology</strong> data<br />
4.1. Acute toxicity<br />
No available in<strong>for</strong>mation.<br />
4.2. Skin irritation<br />
No available in<strong>for</strong>mation.<br />
4.3. Mucous membrane (eye) irritation<br />
No available in<strong>for</strong>mation.<br />
4.4. Skin sensitization<br />
No available in<strong>for</strong>mation.<br />
4.5. Phototoxicity <strong>and</strong> photoallergy<br />
No available in<strong>for</strong>mation.<br />
4.6. Absorption, distribution, <strong>and</strong> metabolism<br />
No available in<strong>for</strong>mation.<br />
4.7. Repeated dose toxicity<br />
No available in<strong>for</strong>mation.<br />
4.8. Reproductive <strong>and</strong> developmental toxicity<br />
In a comparative developmental toxicity (OECD TG 414) two<br />
different isomeric mixes of isononyl alcohol were administered<br />
by gavage to Wistar rats (10 per group) at 144, 720, 1080, <strong>and</strong><br />
1440 mg/kg/d (0, 1, 5, 7.5, <strong>and</strong> 10 mmol/kg/d) on gestation days<br />
6–15. The 1080 mg/kg group was a supplemental group with supplemental<br />
control due to high maternal mortality at 1440 mg/kg/d<br />
in the original study. Both types of isononyl alcohols exhibited a<br />
marked degree of maternal <strong>and</strong> fetal toxicity at 1080, <strong>and</strong><br />
1440 mg/kg/d <strong>and</strong> slight effects at 720 mg/kg. Maternal mortality<br />
was 10/10 <strong>for</strong> mixture 1 <strong>and</strong> 3/10 <strong>for</strong> mixture 2 at 1440 mg/kg/d.<br />
Fetal observations <strong>for</strong> the 1080 mg/kg groups showed increases<br />
in resorptions, post-implantation loss, <strong>and</strong> the number/percent of<br />
fetuses/litters with mal<strong>for</strong>mations or retardations. At 720 mg/kg,<br />
the maternal clinical signs included reduced body weight gain,<br />
apathy, <strong>and</strong> nasal discharge. Fetal observations included an increased<br />
number of skeletal variations <strong>and</strong> delayed ossifications.<br />
There were no significant differences from control at 144 mg/kg<br />
in either maternal or fetal parameters (Hellwig <strong>and</strong> Jackh, 1997,<br />
<strong>and</strong> EPA, 1991).<br />
4.9. Genotoxicity<br />
No available in<strong>for</strong>mation.<br />
4.10. Carcinogenicity<br />
No available in<strong>for</strong>mation.<br />
This individual <strong>Fragrance</strong> Material Review is not intended as a<br />
st<strong>and</strong>-alone document. Please refer to A Toxicologic <strong>and</strong> Dermatologic<br />
Assessment of Alcohols Branched Chain Saturated When Used<br />
as <strong>Fragrance</strong> Ingredients (Belsito et al., 2010) <strong>for</strong> an overall assessment<br />
of this material.<br />
Conflict of interest statement<br />
This research was supported by the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong><br />
<strong>Fragrance</strong> Materials, an independent research institute that is<br />
funded by the manufacturers of fragrances <strong>and</strong> consumer products<br />
containing fragrances. The authors are all employees of the<br />
<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials.<br />
References<br />
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,<br />
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A toxicologic <strong>and</strong> dermatologic<br />
assessment of alcohols branched chain saturated when used as fragrance<br />
ingredients. <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (S4), S1–S46.<br />
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:<br />
providing estimates <strong>for</strong> safety evaluation. Regulatory <strong>Toxicology</strong> <strong>and</strong><br />
Pharmacology 36, 246–252.<br />
EPA (Environmental Protection Agency), 1991. Study of the prenatal toxicity of<br />
isononylalcohol 1 <strong>and</strong> isononylalcohol 2 in rats after oral administration<br />
(gavage). Unpublished report. Report number 34403 (RIFM, Woodcliff Lake, NJ,<br />
USA).<br />
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface<br />
Suite <strong>for</strong> Microsoft Ò Windows, v 4.00 or insert version used]. United States<br />
Environmental Protection Agency, Washington, DC, USA.<br />
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria <strong>for</strong><br />
development of a database <strong>for</strong> safety evaluation of fragrance ingredients.<br />
Regulatory <strong>Toxicology</strong> <strong>and</strong> Pharmacology 31, 166–181.<br />
Hellwig, J., Jackh, R., 1997. Differential prenatal toxicity of one straight-chain <strong>and</strong><br />
five branched-chain primary alcohols in rats. <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 35<br />
(5), 489–500.<br />
IFRA (International <strong>Fragrance</strong> Association), 2004. Use level survey, August 2004.<br />
IFRA (International <strong>Fragrance</strong> Association), 2007. Volume of use survey, February<br />
2007.
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S82–S84<br />
Contents lists available at ScienceDirect<br />
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong><br />
journal homepage: www.elsevier.com/locate/foodchemtox<br />
Review<br />
<strong>Fragrance</strong> material review on 6,8-dimethylnonan-2-ol<br />
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api<br />
<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA<br />
article<br />
Keywords:<br />
Review<br />
<strong>Fragrance</strong><br />
info<br />
abstract<br />
A toxicologic <strong>and</strong> dermatologic review of 6,8-dimethylnonan-2-ol when used as a fragrance ingredient is<br />
presented. 6,8-Dimethylnonan-2-ol is a member of the fragrance structural group branched chain saturated<br />
alcohols. The common characteristic structural elements of the alcohols with saturated branched<br />
chain are one hydroxyl group per molecule, <strong>and</strong> a C 4 –C 12 carbon chain with one or several methyl side<br />
chains. This review contains the in<strong>for</strong>mation available on this individual fragrance ingredient <strong>and</strong> is<br />
not intended as a st<strong>and</strong>-alone document. A safety assessment of the entire branched chain saturated alcohol<br />
group will be published simultaneously with this document; please refer to Belsito et al. (2010) <strong>for</strong> an<br />
overall assessment of the safe use of this material <strong>and</strong> all other branched chain saturated alcohols in<br />
fragrances.<br />
Ó 2010 Published by Elsevier Ltd.<br />
Contents<br />
Introduction ........................................................................................................ S82<br />
1. Identification . . . . . . . . . . . . . . . ........................................................................................ S82<br />
2. Physical properties . . . . . . . . . . . ........................................................................................ S83<br />
3. Usage. . . . . . ........................................................................................................ S83<br />
4. <strong>Toxicology</strong> data . . . . . . . . . . . . . ........................................................................................ S83<br />
Conflict of interest statement . . ........................................................................................ S83<br />
References . ........................................................................................................ S84<br />
Introduction<br />
* Corresponding author. Tel.: +1 201 689 8089; fax: +1 201 689 8088.<br />
E-mail address: dmcginty@RIFM.org (D. McGinty).<br />
This document provides a summary of the toxicologic review,<br />
all human health endpoints, of 6,8-dimethylnonan-2-ol when used<br />
as a fragrance ingredient. 6,8-Dimethylnonan-2-ol (see Fig. 1; CAS<br />
Number 70214-77-6) is a fragrance ingredient used in cosmetics,<br />
fine fragrances, shampoos, toilet soaps <strong>and</strong> other toiletries as well<br />
as in non-cosmetic products such as household cleaners <strong>and</strong><br />
detergents.<br />
In 2006, a complete literature search was conducted on 6,8-<br />
dimethylnonan-2-ol. On-line toxicological databases were<br />
searched including those from the <strong>Chemical</strong> Abstract Services<br />
[e.g. ToxCenter (which in itself contains 18 databases including<br />
<strong>Chemical</strong> Abstracts], <strong>and</strong> the National Library of Medicine [e.g.<br />
Medline, Toxnet (which contains 14 databases)] as well as 26 additional<br />
sources (e.g. BIOSIS, Embase, RTECS, OSHA <strong>and</strong> ESIS). In addition,<br />
fragrance companies were asked to submit all test data.<br />
The safety data on this material has never been reviewed be<strong>for</strong>e<br />
by RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials Inc.). All relevant<br />
references are included in this document. More details have<br />
been provided <strong>for</strong> unpublished data. The number of animals, sex<br />
<strong>and</strong> strain are always provided unless they are not given in the original<br />
report or paper. Any papers in which the vehicles <strong>and</strong>/or the<br />
doses are not given have not been included in this review. In addition,<br />
diagnostic patch test data with fewer than 100 consecutive<br />
patients have been omitted.<br />
1. Identification<br />
1.1. Synonyms: 2-Nonanol, 6,8-dimethyl-; Nonadyl.<br />
1.2. CAS Registry number: 70214-77-6.<br />
1.3. EINECS number: 274-447-7.<br />
1.4. Formula: C 11 H 24 O.<br />
1.5. Molecular weight: 172.12.<br />
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.<br />
doi:10.1016/j.fct.2010.05.035
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S82–S84 S83<br />
Table 1<br />
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 6,8-dimethylnonan-2-ol.<br />
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient mg/kg/day b<br />
Anti-perspirant 0.5 1 1 0.01 0.05 0.000001<br />
Bath products 17 0.29 0.001 0.02 0.05 0.000001<br />
Body lotion 8 0.71 1 0.004 0.05 0.000200<br />
Eau de toilette 0.75 1 1 0.08 0.05 0.000500<br />
Face cream 0.8 2 1 0.003 0.05 0.000001<br />
<strong>Fragrance</strong> cream 5 0.29 1 0.04 0.05 0.000500<br />
Hair spray 5 2 0.01 0.005 0.05 0.000001<br />
Shampoo 8 1 0.01 0.005 0.05 0.000001<br />
Shower gel 5 1.07 0.01 0.012 0.05 0.000001<br />
Toilet soap 0.8 6 0.01 0.015 0.05 0.000001<br />
Total 0.0012<br />
a<br />
b<br />
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.<br />
Based on a 60-kg adult.<br />
2. Physical properties<br />
2.1. Physical <strong>for</strong>m: no in<strong>for</strong>mation available.<br />
2.2. Boiling point (calculated; EPA, 2010): 217.59.<br />
2.3. Flash point: no in<strong>for</strong>mation available.<br />
2.4. Henry’s law (calculated; EPA, 2010): 0.0000726 atm m 3 /<br />
mole.<br />
2.5. Log K ow (calculated; EPA, 2010): 4.06.<br />
2.6. Refractive index: no in<strong>for</strong>mation available.<br />
2.7. Specific gravity: 0.827 g/ml at 20 °C.<br />
2.8. Vapor pressure (calculated; EPA, 2010): 0.0252 mm Hg;<br />
3.36 Pa (25 °C).<br />
2.9. Water solubility (calculated; EPA, 2010): no in<strong>for</strong>mation<br />
available.<br />
2.10. UV spectra available at RIFM, peaks at 200–210 nm <strong>and</strong><br />
returns to baseline 230–240 nm. Minor absorption from<br />
260 to 320 nm.<br />
3. Usage<br />
Fig. 1. 6,8-Dimethylnonan-2-ol.<br />
OH<br />
6,8-Dimethylnonan-2-ol is a fragrance ingredient used in many<br />
fragrance compounds. It may be found in fragrances used in decorative<br />
cosmetics, fine fragrances, shampoos, toilet soaps <strong>and</strong> other<br />
toiletries as well as in non-cosmetic products such as household<br />
cleaners <strong>and</strong> detergents. Its use worldwide is in the region of 1–<br />
10 metric tons per annum (IFRA, 2004). The reported volume of<br />
use is <strong>for</strong> 6,8-dimethylnonan-2-ol as used in fragrance compounds<br />
(mixtures) in all finished consumer product categories. The volume<br />
of use is surveyed by IFRA approximately every 4 years through a<br />
comprehensive survey of IFRA <strong>and</strong> RIFM member companies. As<br />
such the volume of use data from this survey provides volume of<br />
use of fragrance ingredients <strong>for</strong> the majority of the fragrance<br />
industry.<br />
The dermal systemic exposure in cosmetic products (see<br />
Table 1) is calculated based on the concentrations of the same<br />
fragrance ingredient in 10 types of the most frequently used<br />
personal care <strong>and</strong> cosmetic products (anti-perspirant, bath products,<br />
body lotion, eau de toilette, face cream, fragrance cream, hair<br />
spray, shampoo, shower gel <strong>and</strong> toilet soap). The concentration of<br />
the fragrance ingredient in fine fragrances is obtained from examination<br />
of several thous<strong>and</strong> commercial <strong>for</strong>mulations. The upper<br />
97.5 percentile concentration is calculated from the data obtained.<br />
This upper 97.5 percentile concentration is then used <strong>for</strong> all 10<br />
consumer products. These concentrations are multiplied by the<br />
amount of product applied, the number of applications per day<br />
<strong>for</strong> each product type, <strong>and</strong> a ‘‘retention factor” (ranging from<br />
0.001 to 1.0) to account <strong>for</strong> the length of time a product may remain<br />
on the skin <strong>and</strong>/or likelihood of the fragrance ingredient<br />
being removed by washing. The resultant calculation represents<br />
the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford<br />
et al., 2000).<br />
This is a conservative calculation of dermal systemic exposure<br />
because it makes the unlikely assumption that a consumer will<br />
use these 10 products containing; which are all perfumed with<br />
the upper 97.5 percentile level of the fragrance ingredient from a<br />
fine fragrance type of product (Cadby et al. 2002, Ford et al.<br />
2000). The 97.5% percentile use level in <strong>for</strong>mulae <strong>for</strong> use in cosmetics<br />
in general has been reported to be 0.5% (IFRA, 2007), which<br />
would result in a maximum daily exposure on the skin of<br />
0.0012 mg/kg <strong>for</strong> high end users (see Table 1).<br />
A maximum skin level is then determined <strong>for</strong> consideration of<br />
potential sensitization. The exposure is calculated as the percent<br />
concentration of the fragrance ingredient applied to the skin based<br />
on the use of 20% of the fragrance mixture in the fine fragrance<br />
consumer product (IFRA, 2007). The average maximum use level<br />
in <strong>for</strong>mulae that go into fine fragrances has been reported to be<br />
0.009% (IFRA, 2007), assuming use of the fragrance oil at levels<br />
up to 20% in the final product.<br />
4. <strong>Toxicology</strong> data<br />
No available in<strong>for</strong>mation.<br />
This individual <strong>Fragrance</strong> Material Review is not intended as a<br />
st<strong>and</strong>-alone document. Please refer to A Safety Assessment of<br />
Branched Chain Saturated Alcohols When Used as <strong>Fragrance</strong> Ingredients<br />
Belsito et al. (2010) <strong>for</strong> an overall assessment of this<br />
material.<br />
Conflict of interest statement<br />
This research was supported by the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong><br />
<strong>Fragrance</strong> Materials, an independent research institute that is<br />
funded by the manufacturers of fragrances <strong>and</strong> consumer products<br />
containing fragrances. The authors are all employees of the<br />
<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials.
S84<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S82–S84<br />
References<br />
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,<br />
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A toxicologic <strong>and</strong> dermatologic<br />
assessment of Alcohols Branched Chain Saturated when used as fragrance<br />
ingredients. <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (S4), S1–S46.<br />
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:<br />
providing estimates <strong>for</strong> safety evaluation. Regulatory <strong>Toxicology</strong> <strong>and</strong><br />
Pharmacology 36, 246–252.<br />
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface<br />
Suite <strong>for</strong> Microsoft Ò Windows, v 4.00 or Insert Version Used. United States<br />
Environmental Protection Agency, Washington, DC, USA.<br />
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria <strong>for</strong><br />
development of a database <strong>for</strong> safety evaluation of fragrance ingredients.<br />
Regulatory <strong>Toxicology</strong> <strong>and</strong> Pharmacology 31, 166–181.<br />
IFRA (International <strong>Fragrance</strong> Association), 2004. Use Level Survey, August 2004.<br />
IFRA (International <strong>Fragrance</strong> Association), 2007. Volume of Use Survey, February<br />
2007.
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S85–S88<br />
Contents lists available at ScienceDirect<br />
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong><br />
journal homepage: www.elsevier.com/locate/foodchemtox<br />
Review<br />
<strong>Fragrance</strong> material review on 2-ethyl-1-butanol<br />
D. McGinty * , C.S. Letizia, A.M. Api<br />
<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA<br />
article<br />
Keywords:<br />
Review<br />
<strong>Fragrance</strong><br />
info<br />
abstract<br />
A toxicologic <strong>and</strong> dermatologic review of 2-ethyl-1-butanol when used as a fragrance ingredient is presented.<br />
2-Ethyl-1-butanol is a member of the fragrance structural group branched chain saturated alcohols.<br />
The common characteristic structural elements of the alcohols with saturated branched chain are<br />
one hydroxyl group per molecule, <strong>and</strong> a C 4 –C 12 carbon chain with one or several methyl side chains. This<br />
review contains a detailed summary of all available toxicology <strong>and</strong> dermatology papers that are related to<br />
this individual fragrance ingredient <strong>and</strong> is not intended as a st<strong>and</strong>-alone document. A safety assessment<br />
of the entire branched chain saturated alcohol group will be published simultaneously with this document;<br />
please refer to Belsito et al. (2010) <strong>for</strong> an overall assessment of the safe use of this material <strong>and</strong><br />
all other branched chain saturated alcohols in fragrances.<br />
Ó 2010 Published by Elsevier Ltd.<br />
Contents<br />
Introduction . . . ..................................................................................................... S86<br />
1. Identification . . ..................................................................................................... S86<br />
2. Physical properties . . . . . . . . . . . . . . . . . .................................................................................. S86<br />
3. Usage. . . . . . . . . ..................................................................................................... S86<br />
4. <strong>Toxicology</strong> data ..................................................................................................... S87<br />
4.1. Acute toxicity. ................................................................................................ S87<br />
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87<br />
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87<br />
4.1.3. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87<br />
4.1.4. Other studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87<br />
4.2. Skin irritation. ................................................................................................ S87<br />
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87<br />
4.2.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87<br />
4.3. Mucous membrane (eye) irritation. ............................................................................... S87<br />
4.4. Skin densitization ............................................................................................. S87<br />
4.5. Phototoxicity <strong>and</strong> photoallergy. . ................................................................................. S87<br />
4.6. Absorption, distribution <strong>and</strong> metabolism .......................................................................... S87<br />
4.6.1. Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87<br />
4.6.2. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87<br />
4.6.3. Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87<br />
4.7. Repeated dose toxicity . . ....................................................................................... S87<br />
4.8. Reproductive <strong>and</strong> developmental toxicity .......................................................................... S87<br />
4.9. Genotoxicity. ................................................................................................. S87<br />
4.10. Carcinogenicity . . ............................................................................................. S88<br />
Conflict of interest statement . . . . . . . . .................................................................................. S88<br />
References . . . . ..................................................................................................... S88<br />
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.<br />
E-mail address: dmcginty@RIFM.org (D. McGinty).<br />
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.<br />
doi:10.1016/j.fct.2010.05.036
S86<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S85–S88<br />
Introduction<br />
This document provides a comprehensive summary of the toxicologic<br />
review of 2-ethyl-1-butanol when used as a fragrance<br />
ingredient including all human health endpoints. 2-Ethyl-1-butanol<br />
(see Fig. 1; CAS Number 97-95-0) is a fragrance ingredient used<br />
in cosmetics, fine fragrances, shampoos, toilet soaps <strong>and</strong> other toiletries<br />
as well as in non-cosmetic products such as household<br />
cleaners <strong>and</strong> detergents. This material has been reported to occur<br />
in nature, with highest quantities observed in mushrooms (VCF,<br />
2009).<br />
In 2006, a complete literature search was conducted on isoamyl<br />
alcohol. On-line toxicological databases were searched including<br />
those from the <strong>Chemical</strong> Abstract Services [e.g. ToxCenter [which<br />
in itself contains 18 databases including <strong>Chemical</strong> Abstracts)] <strong>and</strong><br />
the National Library of Medicine [e.g. Medline, Toxnet (which contains<br />
14 databases)] as well as 26 additional sources (e.g. BIOSIS,<br />
Embase, RTECS, OSHA, ESIS). In addition, fragrance companies were<br />
asked to submit all test data.<br />
The safety data on this material has never been reviewed be<strong>for</strong>e<br />
by RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.). All relevant<br />
references are included in this document. More details have<br />
been provided <strong>for</strong> unpublished data. The number of animals, sex<br />
<strong>and</strong> strain are always provided unless they are not given in the original<br />
report or paper. Any papers in which the vehicles <strong>and</strong>/or the<br />
doses are not given have not been included in this review. In addition,<br />
diagnostic patch test data with fewer than 100 consecutive<br />
patients have been omitted.<br />
1. Identification<br />
1.1. Synonyms: 1-butanol, 2-ethyl-, 2-ethylbutyl alcohol, 2-ethylbutan-1-ol.<br />
1.2. CAS Registry Number: 97-95-0.<br />
1.3. EINECS Number: 202-621-4.<br />
Fig. 1. 2-Ethyl-1-butanol.<br />
1.4. Formula: C 6 H 14 O.<br />
1.5. Molecular weight: 102.18.<br />
1.6. Council of Europe (2000): 2-ethyl-1-butanol was included<br />
by the Council of Europe in the list of substances granted B<br />
– in<strong>for</strong>mation required – 28 day oral study (COE No. 543).<br />
2. Physical properties<br />
2.1. Physical <strong>for</strong>m: no in<strong>for</strong>mation available.<br />
2.2. Boiling point (calculated; EPA, 2010): 145.86 °C.<br />
2.3. Flash point: no in<strong>for</strong>mation available.<br />
2.4. Henry’s law (calculated; EPA, 2010): 0.0000176 atm m 3 /mol<br />
25 °C.<br />
2.5. Log K ow (calculated; EPA, 2010): 1.75.<br />
2.6. Refractive index: no in<strong>for</strong>mation available.<br />
2.7. Specific gravity: no in<strong>for</strong>mation available.<br />
2.8. Vapor pressure (calculated; EPA, 2010): 1.0 mm Hg (20 °C);<br />
1.6 mm Hg (25 °C); 213 Pa (25 °C).<br />
2.9. Water solubility (calculated; EPA, 2010): 11950 mg/l (25 °C).<br />
2.10. UV spectra not available at RIFM.<br />
3. Usage<br />
2-Ethyl-1-butanol is a fragrance ingredient used in many fragrance<br />
compounds. It may be found in fragrances used in decorative<br />
cosmetics, fine fragrances, shampoos, toilet soaps <strong>and</strong> other<br />
toiletries as well as in non-cosmetic products such as household<br />
cleaners <strong>and</strong> detergents. Its use worldwide is in the region of less<br />
than 0.01 metric tons per annum (IFRA, 2004). The reported volume<br />
of use is <strong>for</strong> 2-ethyl-1-butanol as used in fragrance compounds<br />
(mixtures) in all finished consumer product categories.<br />
The volume of use is surveyed by IFRA approximately every four<br />
years through a comprehensive survey of IFRA <strong>and</strong> RIFM member<br />
companies. As such the volume of use data from this survey provides<br />
volume of use of fragrance ingredients <strong>for</strong> the majority of<br />
the fragrance industry.<br />
The dermal systemic exposure in cosmetic products (see Table<br />
1) is calculated based on the concentrations of the same fragrance<br />
ingredient in 10 types of the most frequently used<br />
personal care <strong>and</strong> cosmetic products (anti-perspirant, bath products,<br />
body lotion, eau de toilette, face cream, fragrance cream, hair<br />
spray, shampoo, shower gel, <strong>and</strong> toilet soap). The concentration of<br />
the fragrance ingredient in fine fragrances is obtained from examination<br />
of several thous<strong>and</strong> commercial <strong>for</strong>mulations. The upper<br />
97.5 percentile concentration is calculated from the data obtained.<br />
This upper 97.5 percentile concentration is then used <strong>for</strong> all 10<br />
consumer products. These concentrations are multiplied by the<br />
amount of product applied, the number of applications per day<br />
Table 1<br />
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2-ethyl-1-butanol.<br />
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient b (mg/kg/day)<br />
Anti-perspirant 0.5 1 1 0.01 0.0003 0.000001<br />
Bath products 17 0.29 0.001 0.02 0.0003 0.000001<br />
Body lotion 8 0.71 1 0.004 0.0003 0.000100<br />
Eau de toilette 0.75 1 1 0.08 0.0003 0.000200<br />
Face cream 0.8 2 1 0.003 0.0003 0.000001<br />
<strong>Fragrance</strong> cream 5 0.29 1 0.04 0.0003 0.000200<br />
Hair spray 5 2 0.01 0.005 0.0003 0.000001<br />
Shampoo 8 1 0.01 0.005 0.0003 0.000001<br />
Shower gel 5 1.07 0.01 0.012 0.0003 0.000001<br />
Toilet soap 0.8 6 0.01 0.015 0.0003 0.000001<br />
Total 0.0005<br />
a<br />
b<br />
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.<br />
Based on a 60-kg adult.
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S85–S88 S87<br />
<strong>for</strong> each product type, <strong>and</strong> a ‘‘retention factor” (ranging from 0.001<br />
to 1.0) to account <strong>for</strong> the length of time a product may remain on<br />
the skin <strong>and</strong>/or likelihood of the fragrance ingredient being removed<br />
by washing. The resultant calculation represents the total<br />
consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford et al.,<br />
2000).<br />
This is a conservative calculation of dermal systemic exposure<br />
because it makes the unlikely assumption that a consumer will<br />
use these 10 products containing; which are all perfumed with<br />
the upper 97.5 percentile level of the fragrance ingredient from a<br />
fine fragrance type of product (Cadby et al. 2002; Ford et al.,<br />
2000). The 97.5 percentile use level in <strong>for</strong>mulae <strong>for</strong> use in cosmetics<br />
<strong>for</strong> 2-ethyl-1-hexanol has been reported to be 0.02% (IFRA,<br />
2007), which would result in a maximum daily exposure on the<br />
skin of 0.0005 mg/kg <strong>for</strong> high end users (see Table 1).<br />
A maximum skin level is then determined <strong>for</strong> consideration of<br />
potential sensitization. The exposure is calculated as the percent<br />
concentration of the fragrance ingredient applied to the skin based<br />
on the use of 20% of the fragrance mixture in the fine fragrance<br />
consumer product (IFRA, 2007). The maximum skin level that results<br />
from the use of 2-ethyl-1-butanol in <strong>for</strong>mulae that go into<br />
fine fragrances has been not been reported.<br />
4. <strong>Toxicology</strong> data<br />
4.1. Acute toxicity<br />
Summary of acute toxicity studies is given in Table 2.<br />
4.1.1. Oral studies<br />
The acute oral LD 50 of 2-ethyl-1-butanol in Carworth-Wistar<br />
male or female rats (5/group) was reported to be 1.85 (1.52–<br />
2.24) g/kg. Observations were made <strong>for</strong> 14 days. No additional details<br />
were reported (Smyth et al., 1954).<br />
The acute oral LD 50 of 2-ethyl-1-butanol in rats was reported to<br />
be 1.85 g/kg. No additional details were reported (Bar <strong>and</strong> Griepentrog,<br />
1967; Nishimura et al., 1994).<br />
The acute oral LD 50 of 2-ethyl-1-butanol in rabbits was reported<br />
to be 1.2 ml/kg (1.2 g/kg). No additional details were reported<br />
(Draize et al., 1944).<br />
4.1.2. Dermal studies<br />
The acute dermal LD 50 of 2-ethyl-1-butanol in rabbits (4/group)<br />
was reported to be 1.26 (0.85–1.87) g/kg. Observations were made<br />
<strong>for</strong> 14 days. No additional details were reported (Smyth et al.,<br />
1954).<br />
The acute dermal LD 50 of 2-ethyl-1-butanol in rabbits was reported<br />
to be 2.0 ml/kg (2.0 g/kg). No additional details were reported<br />
(Draize et al., 1944).<br />
4.1.3. Inhalation studies<br />
In an acute inhalation study of 2-ethyl-1-butanol in male rats<br />
(6/group), the maximum time to death of exposure to concentrated<br />
Table 2<br />
Summary of acute toxicity studies.<br />
Route Species No. animals/<br />
dose group<br />
LD 50<br />
(g/kg)<br />
References<br />
Oral Rat 5 1.85 Smyth et al. (1954)<br />
Oral Rat N/A 1.85 Nishimura et al. (1994)<br />
Bar <strong>and</strong> Griepentrog (1967)<br />
Oral Rabbit N/A 1.2 Draize et al. (1944)<br />
Dermal Rabbit 4 1.26 Smyth et al. (1954)<br />
Dermal Rabbit N/A 2.0 Draize et al. (1944)<br />
vapors was reported to be 8 h. No additional details were reported<br />
(Smyth et al., 1954).<br />
4.1.4. Other studies<br />
The acute intraperitoneal ED3 <strong>for</strong> induction of pronounced<br />
ataxia in rats was reported to be 2.3 mmol/kg (0.24 g/kg) (McCreery<br />
<strong>and</strong> Hunt, 1978).<br />
4.2. Skin irritation<br />
4.2.1. Human studies<br />
No available in<strong>for</strong>mation.<br />
4.2.2. Animal studies<br />
In a group of 5 rabbits (giant albino, New Zeal<strong>and</strong> rabbits) dermal<br />
irritation study <strong>for</strong> 24 h uncovered neat 2-ethyl-1-butanol was<br />
applied at 0.1 ml to clipped skin. Slight to moderate irritation<br />
(grade 2) was reported (Smyth et al., 1954).<br />
4.3. Mucous membrane (eye) irritation<br />
In a rabbit eye irritation study, a 1% of 2-ethyl-1-butanol solution<br />
was reported to produce necrosis of the eye (Smyth et al.,<br />
1954).<br />
4.4. Skin densitization<br />
No available in<strong>for</strong>mation.<br />
4.5. Phototoxicity <strong>and</strong> photoallergy<br />
No available in<strong>for</strong>mation.<br />
4.6. Absorption, distribution <strong>and</strong> metabolism<br />
4.6.1. Absorption<br />
No available in<strong>for</strong>mation.<br />
4.6.2. Distribution<br />
No available in<strong>for</strong>mation.<br />
4.6.3. Metabolism<br />
4.6.3.1. In vivo studies in animals. Kamil et al. (1953a) reported that<br />
when 25 mmol (2.55 g) of 2-ethyl-1-butanol was administered by<br />
oral gavage to 3.0 kg rabbits (n = 3), 40% of the administered dose<br />
was excreted in the urine as the glucuronide within 24 h.<br />
Furthermore, Kamil et al. (1953b) reported that 2-ethyl-1-butanol,<br />
2.55 g (3.1 ml), administered by oral gavage to a rabbit was excreted<br />
in the urine (24 h) as diethylacetylglucuronide. A small<br />
amount of methyl-n-propyl ketone was also excreted.<br />
4.6.3.2. In vitro studies in animals. No available in<strong>for</strong>mation.<br />
4.7. Repeated dose toxicity<br />
No available in<strong>for</strong>mation.<br />
4.8. Reproductive <strong>and</strong> developmental toxicity<br />
No available in<strong>for</strong>mation.<br />
4.9. Genotoxicity<br />
No available in<strong>for</strong>mation.
S88<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S85–S88<br />
4.10. Carcinogenicity<br />
No available in<strong>for</strong>mation.<br />
This individual <strong>Fragrance</strong> Material Review is not intended as a<br />
st<strong>and</strong>-alone document. Please refer to A Safety Assessment of<br />
Branched Chain Saturated Alcohols When Used as <strong>Fragrance</strong> Ingredients<br />
(Belsito et al., 2010) <strong>for</strong> an overall assessment of this<br />
material.<br />
Conflict of interest statement<br />
This research was supported by the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong><br />
Materials, an independent research institute that is funded<br />
by the manufacturers of fragrances <strong>and</strong> consumer products containing<br />
fragrances. The authors are all employees of the <strong>Research</strong><br />
<strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials.<br />
References<br />
Bar, V.F., Griepentrog, F., 1967. Die Situation in der gesundheitlichen Beurteilung<br />
der Aromatisierungsmittel fur Lebensmittel (where we st<strong>and</strong> concerning the<br />
evaluation of flavoring substances from the viewpoint of health). Medizin<br />
Ernährung 8, 244–251.<br />
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,<br />
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chain<br />
saturated alcohols when used as fragrance ingredients. <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong><br />
<strong>Toxicology</strong> 48 (S4), S1–S46.<br />
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:<br />
providing estimates <strong>for</strong> safety evaluation. Regulatory <strong>Toxicology</strong> <strong>and</strong><br />
Pharmacology 36, 246–252.<br />
Council of Europe, 2000. Partial Agreement in the Social <strong>and</strong> Public Health Field.<br />
<strong>Chemical</strong>ly-defined flavouring substances. Group 2.1.3 Aliphatic Alcohols,<br />
branched chain. p. 59, number 543. Council of Europe Publishing, Strasbourg.<br />
Draize, J.H., Woodard, G., Calvery, H.O., 1944. Methods <strong>for</strong> the study of irritation <strong>and</strong><br />
toxicity of substances applied topically to the skin <strong>and</strong> mucous membranes.<br />
Journal of Pharmacology <strong>and</strong> Experimental Therapeutics 82 (2), 377–390.<br />
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface<br />
Suite <strong>for</strong> Microsoft Ò Windows, v 4.00 or Insert Version used. United States<br />
Environmental Protection Agency, Washington, DC, USA.<br />
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria <strong>for</strong><br />
development of a database <strong>for</strong> safety evaluation of fragrance ingredients.<br />
Regulatory <strong>Toxicology</strong> <strong>and</strong> Pharmacology 31, 166–181.<br />
IFRA (International <strong>Fragrance</strong> Association), 2004. Use Level Survey, August 2004.<br />
IFRA (International <strong>Fragrance</strong> Association), 2007. Volume of Use Survey, February<br />
2007.<br />
Kamil, I.A., Smith, J.N., Williams, R.T., 1953a. Studies in detoxication. 46. The<br />
metabolism of aliphatic alcohols. The glucuronic acid conjugation of acyclic<br />
aliphatic alcohols. Biochemical Journal 53, 129–136.<br />
Kamil, I.A., Smith, J.N., Williams, R.T., 1953b. Studies in detoxication. 47. The<br />
<strong>for</strong>mation of ester glucuronides of aliphatic acids during the metabolism of 2-<br />
ethylbutanol <strong>and</strong> 2-ethylhexanol. Biochemical Journal 53 (1), 137–140.<br />
McCreery, M.J., Hunt, W.A., 1978. Physico-chemical correlates of alcohol<br />
intoxication. Neuropharmacology 17, 451–461.<br />
Nishimura, H., Saito, S., Kishida, F., Matsuo, M., 1994. Analysis of acute toxicity<br />
(LD 50 -value) of organic chemicals to mammals by solubility parameter (delta).<br />
1. Acute oral toxicity to rats. Sangyo Igaku 36 (5), 314–323 (Japanese Journal<br />
Industrial Health).<br />
Smyth, H.F., Carpenter, C.P., Weil, C.S., Pozzani, U.C., 1954. Range-finding toxicity<br />
data. List V. Archives of Industrial Hygiene 10, 61–68.<br />
VCF, 2009. Volatile Compounds in <strong>Food</strong>: Database/Nijssen, L.M., van Ingen-Visscher,<br />
C.A., Donders, J.J.H. (Eds.) – Version 11.1.1. TNO Quality of Life, Zeist, The<br />
Netherl<strong>and</strong>s, 1963–2009.
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S89–S92<br />
Contents lists available at ScienceDirect<br />
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong><br />
journal homepage: www.elsevier.com/locate/foodchemtox<br />
Review<br />
<strong>Fragrance</strong> material review on 2,6-dimethyl-4-heptanol<br />
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api<br />
<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA<br />
article<br />
Keywords:<br />
Review<br />
<strong>Fragrance</strong><br />
info<br />
abstract<br />
A toxicologic <strong>and</strong> dermatologic review of 2,6-dimethyl-4-heptanol when used as a fragrance ingredient is<br />
presented. 2,6-Dimethyl-4-heptanol is a member of the fragrance structural group branched chain saturated<br />
alcohols. The common characteristic structural elements of the alcohols with saturated branched<br />
chain are one hydroxyl group per molecule, <strong>and</strong> a C 4 –C 12 carbon chain with one or several methyl side<br />
chains. This review contains a detailed summary of all available toxicology <strong>and</strong> dermatology papers that<br />
are related to this individual fragrance ingredient <strong>and</strong> is not intended as a st<strong>and</strong>-alone document. A safety<br />
assessment of the entire branched chain saturated alcohol group will be published simultaneously with<br />
this document; please refer to Belsito et al. (2010) <strong>for</strong> an overall assessment of the safe use of this material<br />
<strong>and</strong> all other branched chain saturated alcohols in fragrances.<br />
Ó 2010 Published by Elsevier Ltd.<br />
Contents<br />
Introduction . . . ..................................................................................................... S90<br />
1. Identification . . ..................................................................................................... S90<br />
2. Physical properties . . . . . . . . . . . . . . . . . .................................................................................. S90<br />
3. Usage. . . . . . . . . ..................................................................................................... S90<br />
4. <strong>Toxicology</strong> data ..................................................................................................... S91<br />
4.1. Acute toxicity (see Table 2). ..................................................................................... S91<br />
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S91<br />
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S91<br />
4.1.3. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S91<br />
4.2. Skin irritation. ................................................................................................ S91<br />
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S91<br />
4.2.2. Animal studies (see Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S91<br />
4.3. Mucous membrane (eye) irritation (see Table 4) .................................................................... S92<br />
4.4. Skin sensitization. ............................................................................................. S92<br />
4.5. Phototoxicity <strong>and</strong> photoallergy. . ................................................................................. S92<br />
4.6. Absorption, distribution <strong>and</strong> metabolism .......................................................................... S92<br />
4.7. Repeated dose toxicity . . ....................................................................................... S92<br />
4.7.1. Two to 30-day studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S92<br />
4.7.2. Subchronic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S92<br />
4.7.3. Chronic (90+ days) studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S92<br />
4.8. Reproductive <strong>and</strong> developmental toxicity .......................................................................... S92<br />
4.9. Genotoxicity. ................................................................................................. S92<br />
4.10. Carcinogenicity . . ............................................................................................. S92<br />
Conflict of interest statement . . . . . . . . .................................................................................. S92<br />
References . . . . ..................................................................................................... S92<br />
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.<br />
E-mail address: dmcginty@RIFM.org (D. McGinty).<br />
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.<br />
doi:10.1016/j.fct.2010.05.037
S90<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S89–S92<br />
1. Identification<br />
1.1. Synonyms: diisobutylcarbinol; 4-heptanol, 2,6-dimethyl-;<br />
2,6-dimethylheptan-4-ol.<br />
1.2. CAS registry number: 108-82-7.<br />
1.3. EINECS number: 203-619-6.<br />
1.4. Formula: C 9 H 20 O.<br />
1.5. Molecular weight: 144.26.<br />
1.6. JECFA (2003): The Joint FAO/WHP Expert Committee on<br />
<strong>Food</strong> Additives (JECFA No. 303) concluded that the substance<br />
does not present a safety concern at current levels of intake<br />
when used as a flavouring agent.<br />
1.7. FEMA (1970): Flavor <strong>and</strong> Extract Manufacturers’ Association<br />
states: generally Recognized as Safe as a flavor ingredient –<br />
GRAS 4. (3140) Hall, 1970.<br />
Introduction<br />
Fig. 1. 2,6,-Dimethyl-4-heptanol.<br />
This document provides a summary of the toxicologic review,<br />
including all human health endpoints, of 2,6-dimethyl-4-heptanol<br />
when used as a fragrance ingredient. 2,6-Dimethyl-4-heptanol (see<br />
Fig. 1; CAS No. 108-82-7) is a fragrance ingredient used in cosmetics,<br />
fine fragrances, shampoos, toilet soaps <strong>and</strong> other toiletries as<br />
well as in non-cosmetic products such as household cleaners <strong>and</strong><br />
detergents.<br />
In 2006, a complete literature search was conducted on 2,6-dimethyl-4-heptanol.<br />
On-line toxicological databases were searched<br />
including those from the <strong>Chemical</strong> Abstract Services, e.g. ToxCenter<br />
[which in itself contains 18 databases including <strong>Chemical</strong> Abstracts)],<br />
<strong>and</strong> the National Library of Medicine [e.g. Medline, Toxnet<br />
(which contains 14 databases)] as well as 26 additional sources<br />
(e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance<br />
companies were asked to submit all test data.<br />
The safety data on this material has never been reviewed be<strong>for</strong>e<br />
by RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.). All relevant<br />
references are included in this document. More details have<br />
been provided <strong>for</strong> unpublished data. The number of animals, sex<br />
<strong>and</strong> strain are always provided unless they are not given in the original<br />
report or paper. Any papers in which the vehicles <strong>and</strong>/or the<br />
doses are not given have not been included in this review. In addition,<br />
diagnostic patch test data with fewer than 100 consecutive<br />
patients have been omitted.<br />
2. Physical properties<br />
2.1. Physical <strong>for</strong>m: no in<strong>for</strong>mation available.<br />
2.2. Boiling point (calculated; EPA, 2010): 177.59 °C.<br />
2.3. Flash point: no in<strong>for</strong>mation available.<br />
2.4. Henry’s law (calculated; EPA, 2010): 0.0000412 atm m 3 /mol<br />
25 °C.<br />
2.5. Log K ow (calculated; EPA, 2010): 3.08.<br />
2.6. Refractive index: no in<strong>for</strong>mation available.<br />
2.7. Specific gravity: no in<strong>for</strong>mation available.<br />
2.8. Vapor pressure: (calculated; EPA, 2010): 0.334 mm Hg;<br />
44.5 Pa (25 °C).<br />
2.9. Water solubility (calculated; EPA, 2010): 613.8 mg/l @ 25 °C.<br />
2.10. UV spectra available at RIFM, does not absorb UV light.<br />
3. Usage<br />
2,6-Dimethyl-4-heptanol is a fragrance ingredient used in many<br />
fragrance compounds. It may be found in fragrances used in decorative<br />
cosmetics, fine fragrances, shampoos, toilet soaps <strong>and</strong> other<br />
toiletries as well as in non-cosmetic products such as household<br />
cleaners <strong>and</strong> detergents. Its use worldwide is in the region of 10–<br />
100 metric tons per annum (IFRA, 2004). The reported volume of<br />
use is <strong>for</strong> 2,6-dimethyl-4-heptanol as used in fragrance compounds<br />
(mixtures) in all finished consumer product categories. The volume<br />
of use is surveyed by IFRA approximately every four years through<br />
a comprehensive survey of IFRA <strong>and</strong> RIFM member companies. As<br />
such the volume of use data from this survey provides volume of<br />
use of fragrance ingredients <strong>for</strong> the majority of the fragrance<br />
industry.<br />
Table 1<br />
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2,6-dimethyl-4-heptanol.<br />
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient (mg/kg/day) b<br />
Anti-perspirant 0.5 1 1 0.01 .02 0.000001<br />
Bath products 17 0.29 0.001 0.02 .02 0.000001<br />
Body lotion 8 0.71 1 0.004 .02 0.000100<br />
Eau de toilette 0.75 1 1 0.08 .02 0.000200<br />
Face cream 0.8 2 1 0.003 .02 0.000001<br />
<strong>Fragrance</strong> cream 5 0.29 1 0.04 .02 0.000200<br />
Hair spray 5 2 0.01 0.005 .02 0.000001<br />
Shampoo 8 1 0.01 0.005 .02 0.000001<br />
Shower gel 5 1.07 0.01 0.012 .02 0.000001<br />
Toilet soap 0.8 6 0.01 0.015 .02 0.000001<br />
Total 0.0005<br />
a<br />
b<br />
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.<br />
Based on a 60 kg adult.
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S89–S92 S91<br />
Table 2<br />
Summary of acute toxicity studies.<br />
Route Species No. animals/<br />
dose group<br />
The dermal systemic exposure in cosmetic products (see Table<br />
1) is calculated based on the concentrations of the same fragrance<br />
ingredient in ten types of the most frequently used<br />
personal care <strong>and</strong> cosmetic products (anti-perspirant, bath products,<br />
body lotion, eau de toilette, face cream, fragrance cream, hair<br />
spray, shampoo, shower gel, <strong>and</strong> toilet soap). The concentration of<br />
the fragrance ingredient in fine fragrances is obtained from examination<br />
of several thous<strong>and</strong> commercial <strong>for</strong>mulations. The upper<br />
97.5 percentile concentration is calculated from the data obtained.<br />
This upper 97.5 percentile concentration is then used <strong>for</strong> all 10<br />
consumer products. These concentrations are multiplied by the<br />
amount of product applied, the number of applications per day<br />
<strong>for</strong> each product type, <strong>and</strong> a ‘‘retention factor” (ranging from<br />
0.001 to 1.0) to account <strong>for</strong> the length of time a product may remain<br />
on the skin <strong>and</strong>/or likelihood of the fragrance ingredient<br />
being removed by washing. The resultant calculation represents<br />
the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford<br />
et al., 2000).<br />
This is a conservative calculation of dermal systemic exposure<br />
because it makes the unlikely assumption that a consumer will<br />
use these 10 products containing; which are all perfumed with<br />
the upper 97.5 percentile level of the fragrance ingredient from a<br />
fine fragrance type of product (Cadby et al., 2002; Ford et al.,<br />
2000). The 97.5% percentile use level in <strong>for</strong>mulae <strong>for</strong> use in cosmetics<br />
in general has not been reported. As such the default value of<br />
0.02% is used to calculate the maximum daily exposure on the skin<br />
of 0.0005 mg/kg <strong>for</strong> high end users of these products.<br />
A maximum skin level is then determined <strong>for</strong> consideration of<br />
potential sensitization. The exposure is calculated as the percent<br />
concentration of the fragrance ingredient applied to the skin based<br />
on the use of 20% of the fragrance mixture in the fine fragrance<br />
consumer product (IFRA, 2007). The maximum skin level that results<br />
from the use of 2,6-dimethyl-4-heptanol in <strong>for</strong>mulae that<br />
go into fine fragrances has not been reported. A default value of<br />
0.02% is used, assuming use of the fragrance oil at levels up to<br />
20% in the final product.<br />
4. <strong>Toxicology</strong> data<br />
4.1. Acute toxicity (see Table 2)<br />
LD 50<br />
(g/kg)<br />
References<br />
Oral Rats 5 3.56 Smyth et al. (1949)<br />
Oral Rats 32 4.35 Posternak <strong>and</strong> Vodoz (1975)<br />
Oral Rats 5,6 or 11 6.5 McOmie <strong>and</strong> Anderson (1949)<br />
Oral Mice 6 or 14 5 McOmie <strong>and</strong> Anderson (1949)<br />
Dermal Rabbit 5 5.66 Smyth et al. (1949)<br />
4.1.1. Oral studies<br />
Five rats per dose were given a single dose of 2,6-dimethyl-4-<br />
heptanol at 1, 2, 4, <strong>and</strong> 8 g/kg. Observations <strong>for</strong> mortality <strong>and</strong> or<br />
systemic effects were made <strong>for</strong> 14 days. The acute oral LD 50 in rats<br />
was calculated to be 3.56 g/kg (95% CI 1.43–8.86) (Smyth et al.,<br />
1949).<br />
Sixteen male <strong>and</strong> sixteen female rats of the Wistar CF/Gif Carworth<br />
strain were given 2,6-dimethyl-4-heptanol with food.<br />
Observations <strong>for</strong> mortality <strong>and</strong> or systemic effects were made.<br />
The acute oral LD 50 in rats was calculated to be 4.35 g/kg. Necropsy<br />
results done at week 12 showed organ weights <strong>and</strong> organ histopathology<br />
to be within normal limits (Posternak <strong>and</strong> Vodoz, 1975).<br />
Rats (5, 6, or 11/dose) were dosed intra-gastrically with 2.5, 3.7,<br />
5.0, 7.5, 10, <strong>and</strong> 12.5 g/kg in 1% aqueous Tergitol. Observations <strong>for</strong><br />
mortality <strong>and</strong> or systemic effects were made. The acute oral LD 50 in<br />
rats was calculated to be 6.5 ml/kg (6.5 g/kg) (McOmie <strong>and</strong> Anderson,<br />
1949).<br />
In the same study as above, mice (6 or 14/dose) were dosed intra-gastrically<br />
with 2.5, 5.0, <strong>and</strong> 10 g/kg in 1% Tergitol. Observations<br />
<strong>for</strong> mortality <strong>and</strong> systemic effects were made. The LD 50 in<br />
mice was calculated to be 5.0 g/kg (95% CI 2.5–7.5) (McOmie <strong>and</strong><br />
Anderson, 1949).<br />
4.1.2. Dermal studies<br />
Five rabbits received a single dermal application of 1, 2, 4 or 8 g/<br />
kg 2,6-dimethyl-4-heptanol. Observations <strong>for</strong> mortality <strong>and</strong>/or systemic<br />
effects were made <strong>for</strong> 14 days. The acute dermal LD 50 in rabbits<br />
was calculated to be 5.66 g/kg (95% CI 2.51–12.80) (Smyth<br />
et al., 1949).<br />
4.1.3. Inhalation studies<br />
A group of male <strong>and</strong> female subjects (n = 12) were exposed by<br />
inhalation to 2,6-dimethyl-4-heptanol <strong>for</strong> 15 min. The sensory response<br />
limit <strong>and</strong> the concentration that produced irritation of the<br />
mucus membranes of the eyes, nose, or throat were determined.<br />
Less than 5 ppm produced eye irritation in the majority of subjects.<br />
At 10 ppm nose <strong>and</strong> throat were irritated as well (Silverman et al.,<br />
1946).<br />
Groups of an unspecified number of rats were exposed to a saturated<br />
vapor of two samples of 2,6-dimethyl-4-heptanol. The maximum<br />
period of exposure to both samples one <strong>and</strong> two that did not<br />
result in any deaths was 8 h (Smyth et al., 1949).<br />
Ten mice were exposed by inhalation to 2 mg/l of 2,6-dimethyl-<br />
4-heptanol as a saturated vapor-air mixture. No deaths were reported<br />
after the 12-h exposure (McOmie <strong>and</strong> Anderson, 1949).<br />
4.2. Skin irritation<br />
4.2.1. Human studies<br />
No available in<strong>for</strong>mation.<br />
4.2.2. Animal studies (see Table 3)<br />
The primary skin irritation of neat 2,6-dimethyl-4-heptanol was<br />
evaluated on groups of five rabbits. Scoring similar to the Draize<br />
method was used, with grades ranging from 1 to 10. A grade of 1<br />
was observed; this indicates there was no irritation from the undiluted<br />
material (Smyth et al., 1949).<br />
Seven 5 h applications of neat 2,6-dimethyl-4-heptanol were<br />
made to the intact skin of two rabbits over a period of 21 days.<br />
Observations included definite erythema after the 2nd exposure,<br />
areas of flaking after the 4th exposure, <strong>and</strong> cracking of the skin<br />
with bleeding fissures after the 7th exposure (McOmie <strong>and</strong><br />
Anderson, 1949).<br />
Table 3<br />
Summary of animal irritation studies.<br />
Method Dose (%) Species Reactions References<br />
Dermal application 100% Rabbit 0/5 No irritation Smyth et al. (1949)<br />
Dermal application 100% Rabbit Definite erythema, flaking, <strong>and</strong> bleeding fissures McOmie <strong>and</strong> Anderson (1949)<br />
Dermal application 100% Rabbit 2/5 erythema <strong>and</strong> slight edema McOmie <strong>and</strong> Anderson (1949)
S92<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S89–S92<br />
Table 4<br />
Summary of eye irritation studies.<br />
Dose (%) Vehicle Reactions References<br />
100% NA Irritation observed Smyth et al. (1949)<br />
NA NA Irritation observed McOmie <strong>and</strong> Anderson (1949)<br />
The cuff method was used <strong>for</strong> acute dermal exposure in five rabbits.<br />
Animals were given 4 h semi-occlusive applications of neat<br />
2,6-dimethyl-4-heptanol from 3.9–9.4 ml/kg. Two of the five rabbits<br />
showed some erythema <strong>and</strong> slight edema (McOmie <strong>and</strong><br />
Anderson, 1949).<br />
4.3. Mucous membrane (eye) irritation (see Table 4)<br />
An ocular irritation study was conducted with two samples of<br />
neat 2,6-dimethyl-4-heptanol. Groups of five rabbits per dose were<br />
used, <strong>and</strong> the test material was applied to the corneas. The retracted<br />
eyelids were released approximately 1 min after the instillation,<br />
<strong>and</strong> the eyes were stained with fluorescein 18–24 h later.<br />
The eyes were examined <strong>and</strong> scored according to a 10-point scale.<br />
Both samples of 2,6-dimethyl-4-heptanol were assigned a score of<br />
2, which was equivalent to 0.5 ml of the neat material producing<br />
injury of 1–5 points. Prior to the fluorescein staining, an injury of<br />
one point was equivalent to iritis <strong>and</strong> five points was equivalent<br />
to corneal opacity. After fluorescein staining, one point was equivalent<br />
to necrosis on less than 5% of the cornea <strong>and</strong> five points was<br />
equivalent to necrosis on 63–87% of the cornea (Smyth et al.,<br />
1949).<br />
2,6-Dimethyl-4-heptanol was tested in one rabbit. Moderate<br />
Irritation was observed within the first 24 h, but returned to normal<br />
by the 72nd hour (McOmie <strong>and</strong> Anderson, 1949).<br />
4.4. Skin sensitization<br />
No available in<strong>for</strong>mation.<br />
4.5. Phototoxicity <strong>and</strong> photoallergy<br />
No available in<strong>for</strong>mation.<br />
4.6. Absorption, distribution <strong>and</strong> metabolism<br />
No available in<strong>for</strong>mation.<br />
4.7. Repeated dose toxicity<br />
4.7.1. Two to 30-day studies<br />
No available in<strong>for</strong>mation.<br />
4.7.2. Subchronic studies<br />
No available in<strong>for</strong>mation.<br />
4.7.3. Chronic (90+ days) studies<br />
A 12-week oral study was conducted on groups of 32 Wistar CF/<br />
Gif Carworth strain rats (16 per sex), <strong>and</strong> the treated animals were<br />
fed a diet containing 2,6-dimethyl-4-heptanol mixed with microcrystalline<br />
cellulose. The controls were only fed the basic diet,<br />
but both the test <strong>and</strong> control animals were allowed access to food<br />
ad libitum. The daily intake of the test material was estimated to<br />
be 11 mg/kg bodyweight per day. Individual body weights were recorded<br />
prior to the test <strong>and</strong> weekly thereafter. Observations of<br />
physical appearance <strong>and</strong> behavior were made daily. <strong>Food</strong> consumption<br />
was measured on a weekly basis, <strong>and</strong> efficiency of food<br />
utilization (EFU) was calculated <strong>for</strong> pairs of rats (as housed). Hematological<br />
examinations <strong>and</strong> blood urea determinations were carried<br />
out on 50% of the animals at week seven, <strong>and</strong> on all the<br />
animals at the end of the treatment period. All animals were sacrificed<br />
at the end of the study, <strong>and</strong> a gross necropsy was conducted<br />
at that time. The liver <strong>and</strong> kidneys were weighed, <strong>and</strong> a histological<br />
examination was conducted. No adverse effects were observed,<br />
<strong>and</strong> no changes of any biological significance were observed (Posternak<br />
<strong>and</strong> Vodoz, 1975).<br />
4.8. Reproductive <strong>and</strong> developmental toxicity<br />
No available in<strong>for</strong>mation.<br />
4.9. Genotoxicity<br />
No available in<strong>for</strong>mation.<br />
4.10. Carcinogenicity<br />
No available in<strong>for</strong>mation.<br />
This individual <strong>Fragrance</strong> Material Review is not intended as a<br />
st<strong>and</strong>-alone document. Please refer to A Safety Assessment of Alcohols<br />
Branched Chain Saturated when used as fragrance ingredients<br />
(Belsito et al., 2010) <strong>for</strong> an overall assessment of this material.<br />
Conflict of interest statement<br />
This research was supported by the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong><br />
Materials, an independent research institute that is funded<br />
by the manufacturers of fragrances <strong>and</strong> consumer products containing<br />
fragrances. The authors are all employees of the <strong>Research</strong><br />
<strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials.<br />
References<br />
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,<br />
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chain<br />
saturated alcohols when used as fragrance ingredients. <strong>Food</strong> <strong>and</strong> Chemistry<br />
<strong>Toxicology</strong> 48 (S4), S1–46.<br />
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:<br />
providing estimates <strong>for</strong> safety evaluation. Regulatory <strong>Toxicology</strong> <strong>and</strong><br />
Pharmacology 36, 246–252.<br />
EPA (Environmental Protection Agency), 2010. Estimation programs interface<br />
suite <strong>for</strong> Microsoft Ò Windows, v 4.00 or insert version used. United States<br />
Environmental Protection Agency, Washington, DC, USA.<br />
FEMA (Flavor <strong>and</strong> Extract Manufacturers Association), 1970. Recent progress in the<br />
consideration of flavoring ingredients under the food additives amendment 4.<br />
GRAS substances. <strong>Food</strong> Technology, 24(5), 25–34.<br />
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria <strong>for</strong><br />
development of a database <strong>for</strong> safety evaluation of fragrance ingredients.<br />
Regulatory <strong>Toxicology</strong> <strong>and</strong> Pharmacology 31, 166–181.<br />
IFRA (International <strong>Fragrance</strong> Association), 2004. Use level survey, August 2004.<br />
IFRA (International <strong>Fragrance</strong> Association), 2007. Volume of use survey, February<br />
2007.<br />
JECFA (Joint Expert Committee on <strong>Food</strong> Additives), 2003. Safety evaluation of<br />
certain food additives. Who <strong>Food</strong> Additives Series:42. Prepared by the Fifty-First<br />
Meeting of the Joint FAO/WHO Expert Committee on <strong>Food</strong> Additives (JECFA).<br />
World Health Organization, Geneva 1999.<br />
McOmie, W.A., Anderson, H.H., 1949. Comparative toxicologic effects of some<br />
isobutyl carbinols <strong>and</strong> ketones. University Cali<strong>for</strong>nia Publications Pharmacology<br />
2 (17), 217–230.<br />
Posternak, J.M., Vodoz, C.A., 1975. <strong>Toxicology</strong> tests on flavouring matters. II.<br />
Pyrazines <strong>and</strong> other compounds. <strong>Food</strong> <strong>and</strong> Cosmetics <strong>Toxicology</strong> 13, 487–490.<br />
Silverman, L., Schultz, H.F., First, M.W., 1946. Further studies on sensory response to<br />
certain industrial solvent vapors. The Journal of Industrial Hygiene <strong>and</strong><br />
Toxicolology 28, 262–266.<br />
Smyth, H.F., Carpenter, C.P., Weil, C.S., 1949. Range-finding toxicity data, list III. The<br />
Journal of Industrial Hygiene <strong>and</strong> Toxicolology 31 (1), 60–62.
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S93–S96<br />
Contents lists available at ScienceDirect<br />
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong><br />
journal homepage: www.elsevier.com/locate/foodchemtox<br />
Review<br />
<strong>Fragrance</strong> material review on 3-methyl-1-pentanol<br />
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api<br />
<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA<br />
article<br />
Keywords:<br />
Review<br />
<strong>Fragrance</strong><br />
info<br />
abstract<br />
A toxicologic <strong>and</strong> dermatologic review of 3-methyl-1-pentanol when used as a fragrance ingredient is<br />
presented. 3-Methyl-1-pentanol is a member of the fragrance structural group branched chain saturated<br />
alcohols. The common characteristic structural elements of the alcohols with saturated branched chain<br />
are one hydroxyl group per molecule, <strong>and</strong> a C 4 to C 12 carbon chain with one or several methyl side chains.<br />
This review contains a detailed summary of all available toxicology <strong>and</strong> dermatology papers that are<br />
related to this individual fragrance ingredient <strong>and</strong> is not intended as a st<strong>and</strong>-alone document. A safety<br />
assessment of the entire branched chain saturated alcohol group will be published simultaneously with<br />
this document; please refer to Belsito et al. (2010) <strong>for</strong> an overall assessment of the safe use of this material<br />
<strong>and</strong> all other branched chain saturated alcohols in fragrances.<br />
Ó 2010 Published by Elsevier Ltd.<br />
Contents<br />
Introduction . . . ..................................................................................................... S94<br />
1. Identification . . ..................................................................................................... S94<br />
2. Physical properties . . . . . . . . . . . . . . . . . .................................................................................. S94<br />
3. Usage. . . . . . . . . ..................................................................................................... S94<br />
4. <strong>Toxicology</strong> data ..................................................................................................... S95<br />
4.1. Acute toxicity (see Table 2). ..................................................................................... S95<br />
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95<br />
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95<br />
4.1.3. Other studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95<br />
4.2. Skin irritation. ................................................................................................ S95<br />
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95<br />
4.2.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95<br />
4.3. Mucous membrane (eye) irritation. ............................................................................... S95<br />
4.4. Skin sensitization. ............................................................................................. S95<br />
4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95<br />
4.4.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95<br />
4.5. Phototoxicity <strong>and</strong> photoallergy. . ................................................................................. S95<br />
4.6. Absorption, distribution <strong>and</strong> metabolism .......................................................................... S95<br />
4.7. Repeated dose toxicity . . ....................................................................................... S95<br />
4.8. Reproductive <strong>and</strong> developmental toxicity .......................................................................... S95<br />
4.9. Genotoxicity. ................................................................................................. S95<br />
4.10. Carcinogenicity . . ............................................................................................. S95<br />
Conflict of interest statement . . . . . . . . .................................................................................. S96<br />
References . . . . ..................................................................................................... S96<br />
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.<br />
E-mail address: dmcginty@RIFM.org (D. McGinty).<br />
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.<br />
doi:10.1016/j.fct.2010.05.038
S94<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S93–S96<br />
1.6. JECFA (1998): The Joint FAO/WHP Expert Committee on<br />
<strong>Food</strong> Additives (JECFA No. 263) concluded that the substance<br />
does not present a safety concern at current levels of intake<br />
when used as a flavoring agent.<br />
1.7. FEMA (1990): Flavor <strong>and</strong> Extract Manufacturers’ Association<br />
states: Generally Recognized as Safe as a flavor ingredient –<br />
GRAS 15 (3762).<br />
Introduction<br />
This document provides a summary of the toxicologic review,<br />
including all human health endpoints, of 3-methyl-1-pentanol<br />
when used as a fragrance ingredient. 3-Methyl-1-pentanol (see<br />
Fig. 1; CAS Number 589-35-5) is a fragrance ingredient used in cosmetics,<br />
fine fragrances, shampoos, toilet soaps <strong>and</strong> other toiletries<br />
as well as in non-cosmetic products such as household cleaners<br />
<strong>and</strong> detergents. This material has been reported to occur in nature,<br />
with quantities observed in the mangifera species of mango (VCF,<br />
2009).<br />
In 2006, a complete literature search was conducted on 3-<br />
methyl-1-pentanol. On-line toxicological databases were searched<br />
including those from the <strong>Chemical</strong> Abstract Services [e.g. ToxCenter<br />
[which in itself contains 18 databases including <strong>Chemical</strong> Abstracts)]<br />
<strong>and</strong> the National Library of Medicine [e.g. Medline,<br />
Toxnet (which contains 14 databases)] as well as 26 additional<br />
sources (e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance<br />
companies were asked to submit all test data.<br />
The safety data on this material has never been reviewed be<strong>for</strong>e<br />
by RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.). All relevant<br />
references are included in this document. More details have<br />
been provided <strong>for</strong> unpublished data. The number of animals, sex<br />
<strong>and</strong> strain are always provided unless they are not given in the original<br />
report or paper. Any papers in which the vehicles <strong>and</strong>/or the<br />
doses are not given have not been included in this review. In addition,<br />
diagnostic patch test data with fewer than 100 consecutive<br />
patients have been omitted.<br />
1. Identification<br />
Fig. 1. 3-Methyl-1-pentanol.<br />
1.1. Synonyms: 2-ethyl-4-butanol; 1-pentanol, 3-methyl;<br />
methyl pentanol-3.<br />
1.2. CAS Registry Number: 589-35-5.<br />
1.3. EINECS Number: 209-644-9.<br />
1.4. Formula: C 6 H 14 O.<br />
1.5. Molecular weight: 102.18.<br />
2. Physical properties<br />
2.1. Physical <strong>for</strong>m: no in<strong>for</strong>mation available.<br />
2.2. Boiling point (calculated; EPA, 2010): 145.86 °C.<br />
2.3. Flash point: no in<strong>for</strong>mation available.<br />
2.4. Henry’s law (calculated; EPA, 2010): 0.0000176 atm m 3 /mol<br />
25 °C.<br />
2.5. Log K ow (calculated; EPA, 2010): 1.75.<br />
2.6. Refractive index: no in<strong>for</strong>mation available.<br />
2.7. Specific gravity: no in<strong>for</strong>mation available.<br />
2.8. Vapor pressure (calculated; EPA, 2010): 0.7 mm Hg (20 °C);<br />
1.7 mm Hg (25 °C); 227 Pa (25 °C).<br />
2.9. Water solubility (calculated; EPA, 2010): 11950 mg/l (25 °C).<br />
2.10. UV spectra available at RIFM, peaks at 200–210 nm <strong>and</strong><br />
returns to baseline at 280–290 nm.<br />
3. Usage<br />
3-Methyl-1-pentanol is a fragrance ingredient used in many fragrance<br />
compounds. It may be found in fragrances used in decorative<br />
cosmetics, fine fragrances, shampoos, toilet soaps <strong>and</strong> other<br />
toiletries as well as in non-cosmetic products such as household<br />
cleaners <strong>and</strong> detergents. Its use worldwide is in the region of less<br />
than 0.01 metric tons per annum (IFRA, 2004). The reported volume<br />
of use is <strong>for</strong> 3-methyl-1-pentanol as used in fragrance compounds<br />
(mixtures) in all finished consumer product categories.<br />
The volume of use is surveyed by IFRA approximately every four<br />
years through a comprehensive survey of IFRA <strong>and</strong> RIFM member<br />
companies. As such the volume of use data from this survey provides<br />
volume of use of fragrance ingredients <strong>for</strong> the majority of<br />
the fragrance industry.<br />
The dermal systemic exposure in cosmetic products (see Table 1)<br />
is calculated based on the concentrations of the same fragrance<br />
ingredient in 10 types of the most frequently used personal care<br />
<strong>and</strong> cosmetic products (anti-perspirant, bath products, body lotion,<br />
eau de toilette, face cream, fragrance cream, hair spray, shampoo,<br />
shower gel, <strong>and</strong> toilet soap). The concentration of the fragrance<br />
ingredient in fine fragrances is obtained from examination of several<br />
thous<strong>and</strong> commercial <strong>for</strong>mulations. The upper 97.5 percentile<br />
concentration is calculated from the data obtained. This upper 97.5<br />
Table 1<br />
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 3-methyl-1-pentanol.<br />
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient b (mg/kg/day)<br />
Anti-perspirant 0.5 1 1 0.01 0.0006 0.000001<br />
Bath products 17 0.29 0.001 0.02 0.0006 0.000001<br />
Body lotion 8 0.71 1 0.004 0.0006 0.000001<br />
Eau de toilette 0.75 1 1 0.08 0.0006 0.000010<br />
Face cream 0.8 2 1 0.003 0.0006 0.000001<br />
<strong>Fragrance</strong> cream 5 0.29 1 0.04 0.0006 0.000010<br />
Hair spray 5 2 0.01 0.005 0.0006 0.000001<br />
Shampoo 8 1 0.01 0.005 0.0006 0.000001<br />
Shower gel 5 1.07 0.01 0.012 0.0006 0.000001<br />
Toilet soap 0.8 6 0.01 0.015 0.0006 0.000001<br />
Total 0.00002<br />
a<br />
b<br />
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.<br />
Based on a 60-kg adult.
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S93–S96 S95<br />
percentile concentration is then used <strong>for</strong> all 10 consumer products.<br />
These concentrations are multiplied by the amount of product applied,<br />
the number of applications per day <strong>for</strong> each product type,<br />
<strong>and</strong> a ‘‘retention factor” (ranging from 0.001 to 1.0) to account <strong>for</strong><br />
the length of time a product may remain on the skin <strong>and</strong>/or likelihood<br />
of the fragrance ingredient being removed by washing. The<br />
resultant calculation represents the total consumer exposure (mg/<br />
kg/day) (Cadby et al., 2002; Ford et al., 2000).<br />
This is a conservative calculation of dermal systemic exposure<br />
because it makes the unlikely assumption that a consumer will<br />
use these 10 products containing; which are all perfumed with<br />
the upper 97.5 percentile level of the fragrance ingredient from a<br />
fine fragrance type of product (Cadby et al., 2002; Ford et al.,<br />
2000). The 97.5 percentile use level in <strong>for</strong>mulae <strong>for</strong> use in cosmetics<br />
in general has been reported to be 0.0006 (IFRA, 2007), which<br />
would result in a maximum daily exposure on the skin of<br />
0.00002 mg/kg <strong>for</strong> high end users of these products (Table 1).<br />
A maximum skin level is then determined <strong>for</strong> consideration of<br />
potential sensitization. The exposure is calculated as the percent<br />
concentration of the fragrance ingredient applied to the skin based<br />
on the use of 20% of the fragrance mixture in the fine fragrance<br />
consumer product (IFRA, 2007). The maximum skin level in <strong>for</strong>mulae<br />
that go into fine fragrances has been reported to be 0.0002%<br />
(IFRA, 2007), assuming use of the fragrance oil at levels up to<br />
20% in the final product.<br />
4. <strong>Toxicology</strong> data<br />
4.1. Acute toxicity (see Table 2)<br />
4.1.1. Oral studies<br />
The acute oral LD 50 of 3-methyl-1-pentanol in mice was reported<br />
to be >2 g/kg. Mortality was 0, 0, 1, <strong>and</strong> 10 of 10 mice at<br />
0.5, 1.0, 2.0, <strong>and</strong> 4.0 g/kg. At the top dose 8/10 animals died within<br />
24 h. Surviving animals were observed <strong>for</strong> 14 days post-dosing<br />
(RIFM, 1982).<br />
4.1.2. Dermal studies<br />
No in<strong>for</strong>mation available.<br />
4.1.3. Other studies<br />
The acute intraperitoneal LD 50 of 3-methyl-1-pentanol in mice<br />
was reported to be >0.25 g/kg. Mortality was 0, 0, 8, 9, 10, <strong>and</strong> 10<br />
of 10 mice at 0.125, 0.25, 0.5, 1.0, 2.0, <strong>and</strong> 4.0 g/kg. At the 0.5,<br />
1.0, 2.0, <strong>and</strong> 4.0 g/kg, 7, 9, 10, <strong>and</strong> 10 animals, respectively, died<br />
within 24 h. Surviving animals were observed <strong>for</strong> 14 days postdosing<br />
(RIFM, 1982).<br />
4.2. Skin irritation<br />
4.2.1. Human studies<br />
Irritation was evaluated during the induction phase in a human<br />
repeated insult patch test (HRIPT). An application of 0.5 ml with<br />
0.5% 3-methyl-1-pentanol in 99.5% alcohol SDA 39C on a 1 1-<br />
inch Webril patch was administered to the upper arms of the<br />
panelists <strong>and</strong> removed after 24 h. Irritation was scored 48 h after<br />
initial application <strong>and</strong> a new patch reapplied at that time. Nine<br />
Table 2<br />
Summary of acute toxicity studies.<br />
Route Species No. animals/<br />
dose group<br />
LD 50 (g/kg)<br />
References<br />
Oral Mice 10 >2.0 RIFM (1982)<br />
Intraperitoneal Mice 10 >0.25 RIFM (1982)<br />
applications were made in a three week period. Little or no irritation<br />
was found in all 41 male <strong>and</strong> female volunteers (RIFM, 1973).<br />
4.2.2. Animal studies<br />
A group of three albino rabbits were given 0.5 ml of 0.5% 3-<br />
methyl-1-pentanol in 99.5% Alcohol SDA 39C <strong>and</strong> observed at the<br />
end of the 24 h contact period <strong>and</strong> again 48 h later. Erythema<br />
<strong>and</strong> edema were not observed in any of the three rabbits tested<br />
<strong>and</strong> there<strong>for</strong>e 3-methyl-1-pentanol cannot be considered a primary<br />
irritant (RIFM, 1972).<br />
4.3. Mucous membrane (eye) irritation<br />
No in<strong>for</strong>mation available.<br />
4.4. Skin sensitization<br />
4.4.1. Human studies<br />
4.4.1.1. Induction studies. A repeated insult patch test was conducted<br />
to determine if 3-methyl-1-pentanol would induce dermal<br />
sensitization in human volunteers. During the induction phase<br />
0.5 ml was applied onto a Webril swatch <strong>and</strong> applied to the upper<br />
arms of each volunteer <strong>for</strong> 24 h. Induction applications were made<br />
<strong>for</strong> a total of 9 applications during 3 week period. Following a two<br />
week rest period, a challenge patch was applied to the original site<br />
as well as a fresh site. Patches were applied as in the induction<br />
phase <strong>and</strong> kept in place <strong>for</strong> 24 h after which time they were removed.<br />
Reactions to the challenge were scored at 48 <strong>and</strong> 72 h after<br />
application. There was no sensitization reactions observed during<br />
the challenge phase (RIFM, 1973).<br />
4.4.1.2. Cross-sensitization. No in<strong>for</strong>mation available.<br />
4.4.1.3. Diagnostic studies. No in<strong>for</strong>mation available.<br />
4.4.2. Animal studies<br />
No in<strong>for</strong>mation available.<br />
4.5. Phototoxicity <strong>and</strong> photoallergy<br />
No in<strong>for</strong>mation available.<br />
4.6. Absorption, distribution <strong>and</strong> metabolism<br />
No in<strong>for</strong>mation available.<br />
4.7. Repeated dose toxicity<br />
No in<strong>for</strong>mation available.<br />
4.8. Reproductive <strong>and</strong> developmental toxicity<br />
No in<strong>for</strong>mation available.<br />
4.9. Genotoxicity<br />
No in<strong>for</strong>mation available.<br />
4.10. Carcinogenicity<br />
No in<strong>for</strong>mation available.<br />
This individual <strong>Fragrance</strong> Material Review is not intended as a<br />
st<strong>and</strong>-alone document. Please refer to A Safety Assessment of<br />
Branched Chain Saturated Alcohols When Used as <strong>Fragrance</strong>
S96<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S93–S96<br />
Ingredients (Belsito et al., 2010) <strong>for</strong> an overall assessment of this<br />
material.<br />
Conflict of interest statement<br />
This research was supported by the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong><br />
Materials, an independent research institute that is funded<br />
by the manufacturers of fragrances <strong>and</strong> consumer products containing<br />
fragrances. The authors are all employees of the <strong>Research</strong><br />
<strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials.<br />
References<br />
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,<br />
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chain<br />
saturated alcohols when used as fragrance ingredients. <strong>Food</strong> Chem. Toxicol. 48<br />
(S4), S1–S46.<br />
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:<br />
providing estimates <strong>for</strong> safety evaluation. Regul. Toxicol. Pharma. 36, 246–252.<br />
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface<br />
Suite <strong>for</strong> Microsoft Ò Windows, v 4.00 or Insert Version used. United States<br />
Environmental Protection Agency, Washington, DC, USA.<br />
FEMA (Flavor <strong>and</strong> Extract Manufacturers Association), 1990. Recent progress in the<br />
consideration of flavoring ingredients under the food additives amendment. 15.<br />
GRAS substances. <strong>Food</strong> Technol. 44 (2). 78, 80, 82, 84, 86.<br />
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria <strong>for</strong><br />
Development of a database <strong>for</strong> safety evaluation of fragrance ingredients. Regul.<br />
Toxicol. Pharm. 31, 166–181.<br />
IFRA (International <strong>Fragrance</strong> Association), 2004. Use Level Survey, August 2004.<br />
IFRA (International <strong>Fragrance</strong> Association), 2007. Volume of Use Survey, February<br />
2007.<br />
JECFA (Joint Expert Committee on <strong>Food</strong> Additives), 1998. Safety Evaluation of<br />
Certain <strong>Food</strong> Additives. Who <strong>Food</strong> Additives Series: 40. Prepared by the Fortyninth<br />
Meeting of the Joint FAO/WHO Expert Committee on <strong>Food</strong> Additives<br />
(JECFA). World Health Organization, Geneva.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1972. Skin Irritation Study<br />
with 3-Methyl-1-pentanol in Rabbits. Unpublished Report from International<br />
Flavors <strong>and</strong> <strong>Fragrance</strong>s. Report Number 53594. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1973. Repeated Insult Patch<br />
Test with 3-Methyl-1-pentanol. Unpublished Report from International Flavors<br />
<strong>and</strong> <strong>Fragrance</strong>s. Report Number 53593 RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1982. 14-Day LD50 Study on<br />
3-Methyl-1-pentanolin Mice. Private Communication to FEMA. Unpublished<br />
Report from H.W. Engler B. Bahler. Report Number 9019. RIFM, Woodcliff Lake,<br />
NJ, USA.<br />
VCF, 2009. (Volatile Compounds in <strong>Food</strong>): Database/Nijssen, L.M., van Ingen-<br />
Visscher, C.A., Donders, J.J.H. (Eds.), – Version 11.1.1. TNO Quality of Life, Zeist,<br />
The Netherl<strong>and</strong>s, 1963–2009.
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S97–S101<br />
Contents lists available at ScienceDirect<br />
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong><br />
journal homepage: www.elsevier.com/locate/foodchemtox<br />
Review<br />
<strong>Fragrance</strong> material review on 2-methylbutanol<br />
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api<br />
<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA<br />
article<br />
Keywords:<br />
Review<br />
<strong>Fragrance</strong><br />
info<br />
abstract<br />
A toxicologic <strong>and</strong> dermatologic review of 2-methylbutanol when used as a fragrance ingredient is presented.<br />
2-Methylbutanol is a member of the fragrance structural group branched chain saturated alcohols.<br />
The common characteristic structural elements of the alcohols with saturated branched chain are<br />
one hydroxyl group per molecule, <strong>and</strong> a C 4 –C 12 carbon chain with one or several methyl side chains. This<br />
review contains a detailed summary of all available toxicology <strong>and</strong> dermatology papers that are related to<br />
this individual fragrance ingredient <strong>and</strong> is not intended as a st<strong>and</strong>-alone document. A safety assessment<br />
of the entire branched chain saturated alcohol group will be published simultaneously with this document;<br />
please refer to Belsito et al., 2010 <strong>for</strong> an overall assessment of the safe use of this material <strong>and</strong><br />
all other branched chain saturated alcohols in fragrances.<br />
Ó 2010 Published by Elsevier Ltd.<br />
Contents<br />
Introduction . . . ..................................................................................................... S98<br />
1. Identification . . ..................................................................................................... S98<br />
2. Physical properties . . . . . . . . . . . . . . . . . .................................................................................. S98<br />
3. Usage. . . . . . . . . ..................................................................................................... S99<br />
4. <strong>Toxicology</strong> data ..................................................................................................... S99<br />
4.1. Acute toxicity (see Table 2). ..................................................................................... S99<br />
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S99<br />
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S99<br />
4.1.3. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S99<br />
4.1.4. Intraperitoneal studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S99<br />
4.1.5. Other studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S99<br />
4.2. Skin irritation. ................................................................................................ S99<br />
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S99<br />
4.2.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S100<br />
4.3. Mucous membrane (eye) irritation. ............................................................................... S100<br />
4.4. Skin sensitization. ............................................................................................. S100<br />
4.5. Phototoxicity <strong>and</strong> photoallergy. . ................................................................................. S100<br />
4.6. Absorption, distribution <strong>and</strong> metabolism .......................................................................... S100<br />
4.6.1. Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S100<br />
4.6.2. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S100<br />
4.6.3. Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S100<br />
4.7. Repeated dose toxicity . . ....................................................................................... S100<br />
4.8. Reproductive <strong>and</strong> developmental toxicity .......................................................................... S100<br />
4.9. Genotoxicity. ................................................................................................. S100<br />
* Corresponding author. Tel.: +1 201 689 8089; fax: +1 201 689 8088.<br />
E-mail address: dmcginty@RIFM.org (D. McGinty).<br />
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.<br />
doi:10.1016/j.fct.2010.05.039
S98<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S97–S101<br />
4.9.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S100<br />
4.9.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S100<br />
4.10. Carcinogenicity . . ............................................................................................. S100<br />
Conflict of interest statement . . ........................................................................................ S100<br />
References . ........................................................................................................ S101<br />
Introduction<br />
This document provides a comprehensive summary of the toxicologic<br />
review, including all human health endpoints, of 2-methylbutanol<br />
when used as a fragrance ingredient. 2-Methylbutanol<br />
(see Fig. 1; CAS Number 137-32-6) is a fragrance ingredient used<br />
in cosmetics, fine fragrances, shampoos, toilet soaps <strong>and</strong> other<br />
toiletries as well as in non-cosmetic products such as household<br />
cleaners <strong>and</strong> detergents. This material has been reported to occur<br />
in nature, with highest quantities observed in hop oil (VCF,<br />
2009).<br />
In 2006, a complete literature search was conducted on 2-methylbutanol.<br />
On-line toxicological databases were searched including<br />
those from the <strong>Chemical</strong> Abstract Services, [e.g., ToxCenter (which<br />
in itself contains 18 databases including <strong>Chemical</strong> Abstracts)], <strong>and</strong><br />
the National Library of Medicine [e.g., Medline, Toxnet (which contains<br />
14 databases)] as well as 26 additional sources (e.g., BIOSIS,<br />
Embase, RTECS, OSHA, ESIS). In addition, fragrance companies were<br />
asked to submit all test data.<br />
The safety data on this material has never been reviewed by<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.). All relevant<br />
references are included in this document. More details have been<br />
provided <strong>for</strong> unpublished data. The number of animals, sex <strong>and</strong><br />
strain are always provided unless they are not given in the original<br />
report or paper. Any papers in which the vehicles <strong>and</strong>/or the doses<br />
are not given have not been included in this review. In addition,<br />
Fig. 1. 2-Methylbutanol.<br />
diagnostic patch test data with fewer than 100 consecutive patients<br />
have been omitted.<br />
1. Identification<br />
1.1. Synonyms: active amyl alcohol; 1-butanol, 2-methyl-; secbutylcarbinol;<br />
(±) 2-methyl-1-butanol; 2-methylbutyl alcohol;<br />
2-methylbutan-1-ol.<br />
1.2. CAS registry number: 137-32-6.<br />
1.3. EINECS number: 205-289-9.<br />
1.4. Formula: C 5 H 12 O.<br />
1.5. Molecular weight: 88.15.<br />
1.6. Council of Europe (2000): 2-methylbutanol was included<br />
by the Council of Europe in the list of substances granted<br />
B – in<strong>for</strong>mation required – 28 day oral study (COE No. 2346).<br />
1.7. FEMA (2001): Flavor <strong>and</strong> Extract Manufacturers’ Association<br />
states: Generally Recognized as Safe as a flavor ingredient –<br />
GRAS 20.<br />
1.8. JECFA (2004): The Joint FAO/WHO Expert Committee on<br />
<strong>Food</strong> Additives (JECFA No. 1199) concluded that the substance<br />
does not present a safety concern at current levels<br />
of intake when used as a flavouring agent.<br />
2. Physical properties<br />
2.1. Physical <strong>for</strong>m: no in<strong>for</strong>mation available.<br />
2.2. Boiling point (calculated; EPA, 2010): 123.17 °C.<br />
2.3. Flash point: no in<strong>for</strong>mation available.<br />
2.4. Henry’s law (calculated; EPA, 2010): 0.0000133 atm m 3 /mol<br />
(25 °C).<br />
2.5. Log K ow (calculated; EPA, 2010): 1.26.<br />
2.6. Refractive index: no in<strong>for</strong>mation available.<br />
2.7. Specific gravity: no in<strong>for</strong>mation available.<br />
2.8. Vapor pressure (calculated; EPA, 2010): 2.5 mm Hg (20 °C);<br />
4.54 mm Hg (25 °C); 606 Pa (25 °C).<br />
2.9. Water solubility (calculated; EPA, 2010): 32,200 mg/l<br />
(25 °C).<br />
2.10. UV spectra available at RIFM, peaked at 200–215 nm range<br />
<strong>and</strong> returns to baseline at 220–225 nm.<br />
Table 1<br />
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2-methylbutanol.<br />
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient mg/kg/day b<br />
Anti-perspirant 0.5 1 1 0.01 0.007 0.000010<br />
Bath products 17 0.29 0.001 0.02 0.007 0.000001<br />
Body lotion 8 0.71 1 0.004 0.007 0.000030<br />
Eau de toilette 0.75 1 1 0.08 0.007 0.000070<br />
Face cream 0.8 2 1 0.003 0.007 0.000010<br />
<strong>Fragrance</strong> cream 5 0.29 1 0.04 0.007 0.000070<br />
Hair spray 5 2 0.01 0.005 0.007 0.000001<br />
Shampoo 8 1 0.01 0.005 0.007 0.000001<br />
Shower gel 5 1.07 0.01 0.012 0.007 0.000001<br />
Toilet soap 0.8 6 0.01 0.015 0.007 0.000001<br />
Total 0.0002<br />
a<br />
b<br />
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.<br />
Based on a 60-kg adult.
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S97–S101 S99<br />
3. Usage<br />
2-Methylbutanol is a fragrance ingredient used in many fragrance<br />
compounds. It may be found in fragrances used in decorative<br />
cosmetics, fine fragrances, shampoos, toilet soaps <strong>and</strong> other toiletries<br />
as well as in non-cosmetic products such as household cleaners<br />
<strong>and</strong> detergents. Its use worldwide is in the region of 0.01–0.1 metric<br />
tons per annum (IFRA, 2004). The reported volume of use is <strong>for</strong> 2-<br />
methylbutanol as used in fragrance compounds (mixtures) in all<br />
finished consumer product categories. The volume of use is surveyed<br />
by IFRA approximately every 4 years through a comprehensive<br />
survey of IFRA <strong>and</strong> RIFM member companies. As such the<br />
volume of use data from this survey provides volume of use of fragrance<br />
ingredients <strong>for</strong> the majority of the fragrance industry.<br />
The dermal systemic exposure in cosmetic products (see Table<br />
1) is calculated based on the concentrations of the same fragrance<br />
ingredient in ten types of the most frequently used personal care<br />
<strong>and</strong> cosmetic products (anti-perspirant, bath products, body lotion,<br />
eau de toilette, face cream, fragrance cream, hair spray, shampoo,<br />
shower gel, <strong>and</strong> toilet soap). The concentration of the fragrance<br />
ingredient in fine fragrances is obtained from examination of several<br />
thous<strong>and</strong> commercial <strong>for</strong>mulations. The upper 97.5 percentile<br />
concentration is calculated from the data obtained. This upper 97.5<br />
percentile concentration is then used <strong>for</strong> all 10 consumer products.<br />
These concentrations are multiplied by the amount of product applied,<br />
the number of applications per day <strong>for</strong> each product type,<br />
<strong>and</strong> a ‘‘retention factor” (ranging from 0.001 to 1.0) to account<br />
<strong>for</strong> the length of time a product may remain on the skin <strong>and</strong>/or<br />
likelihood of the fragrance ingredient being removed by washing.<br />
The resultant calculation represents the total consumer exposure<br />
(mg/kg/day) (Cadby et al., 2002, Ford et al., 2000).<br />
This is a conservative calculation of dermal systemic exposure<br />
because it makes the unlikely assumption that a consumer will<br />
use these 10 products containing; which are all perfumed with<br />
the upper 97.5 percentile level of the fragrance ingredient from a<br />
fine fragrance type of product (Cadby et al., 2002, Ford et al.,<br />
2000). The 97.5% percentile use level in <strong>for</strong>mulae <strong>for</strong> use in cosmetics<br />
in general has been reported to be 0.007% (IFRA, 2007), which<br />
would result in a maximum daily exposure on the skin of<br />
0.0002 mg/kg <strong>for</strong> high end users.<br />
A maximum skin level is then determined <strong>for</strong> consideration of<br />
potential sensitization. The exposure is calculated as the percent<br />
concentration of the fragrance ingredient applied to the skin based<br />
on the use of 20% of the fragrance mixture in the fine fragrance<br />
consumer product (IFRA, 2007). The average maximum use level<br />
in <strong>for</strong>mulae that go into fine fragrances has been reported to be<br />
0.001% (IFRA, 2007), assuming use of the fragrance oil at levels<br />
up to 20% in the final product.<br />
4. <strong>Toxicology</strong> data<br />
4.1. Acute toxicity (see Table 2)<br />
4.1.1. Oral studies<br />
The acute oral LD 50 of 2-methylbutanol in rats (n = 5) was<br />
reported to be 4.92 (3.75–6.46) ml/kg (4.92 g/kg). No additional<br />
details were reported (Smyth et al., 1962).<br />
The acute oral LD 50 of 2-methylbutanol in rats (not specified)<br />
was reported to be 1000 mg/kg. No additional details were reported<br />
(Nishimura et al., 1994).<br />
The acute oral LD 50 of 2-methylbutanol in rats (not specified)<br />
was reported to be 4.01 g/kg. No additional details were reported<br />
(Rowe <strong>and</strong> McCollister, 1982).<br />
2-Methylbutanol was given to Sprague dawley rats (5/sex) at<br />
doses of 1.47, 2.15, 3.16, or 5.0 g/kg <strong>and</strong> observed <strong>for</strong> 14 days.<br />
Table 2<br />
Summary of acute toxicity studies.<br />
Route Species NO. animals/<br />
dose group<br />
The acute oral LD 50 was reported to be 4.17 g/kg based on mortality<br />
(1/10) at 3.16 g/kg <strong>and</strong> (8/10) at 5.0 g/kg (RIFM, 1979).<br />
Wistar rats (5/sex) were given a single oral dose 3.0 or 5.0 g/kg<br />
of 2-methylbutanol by gavage <strong>and</strong> observed <strong>for</strong> 14 days. No animals<br />
died, <strong>and</strong> the LD 50 was determined to be greater than 5.0 g/<br />
kg (RIFM, 1985).<br />
4.1.2. Dermal studies<br />
The acute dermal LD 50 of 2-methylbutanol in rabbits (n = 4) was<br />
reported to be 3.54 ml/kg (3.54 g/kg). Contact time was 24 h <strong>and</strong><br />
observation time was 14 days. No additional details were reported<br />
(Smyth et al., 1962; RIFM, 1979).<br />
An acute dermal LD 50 value was reported to be 2.89 <strong>for</strong> 2-<br />
methyl-1-butanol (Rowe <strong>and</strong> McCollister, 1982).<br />
4.1.3. Inhalation studies<br />
The maximum time <strong>for</strong> exposure of rats (6/dose) to concentrated<br />
vapors of 2-methylbutanol without mortality was 8 h. The<br />
chemical was administered undiluted, unless a lesser concentration<br />
was necessary. Then the solution was made in water, or corn<br />
oil (Smyth et al., 1962).<br />
Rats were exposed to 2-methylbutanol by inhalation of saturated<br />
atmosphere at 20 °C <strong>for</strong> 7 h. Mortality was not observed,<br />
but escape behavior <strong>and</strong> intermittent respiration was noted (RIFM,<br />
1979).<br />
No mortality was observed when six rats were exposed to 2-<br />
methylbutanol by inhalation of saturated vapors <strong>for</strong> 8 h. No further<br />
in<strong>for</strong>mation available (Rowe <strong>and</strong> McCollister, 1982).<br />
4.1.4. Intraperitoneal studies<br />
Mice were given 2-methylbutanol at doses of 200, 700, or<br />
2000 mg/kg by intraperitoneal injection <strong>and</strong> observed <strong>for</strong> 14 days.<br />
All animals in the 2000 mg/kg <strong>and</strong> 9/10 at 700 mg/kg died. The<br />
LD 50 was estimated to be greater than 200 mg/kg but less than<br />
700 mg/kg (RIFM, 1979).<br />
Rats were given 2-methylbutanol at doses of 1000, or 2000 mg/<br />
kg by intraperitoneal injection <strong>and</strong> observed <strong>for</strong> 14 days. Animals<br />
in the 2000 mg/kg showed respiratory arrest <strong>and</strong> death. At<br />
1000 mg/kg the rats showed sedation, irritation of the peritoneum<br />
<strong>and</strong> injury of the lungs (Haggard et al., 1945 as cited in Greim,<br />
2008).<br />
4.1.5. Other studies<br />
In isolated perfused livers of rats, 65.1 mmol 2-methylbutanol/l<br />
were cytotoxic as evidenced by the release of liver enzymes into<br />
the perfusate. The alcohols decreased the content of ATP in the liver.<br />
The content of oxidized glutathione was increased. Lipid peroxidation<br />
was not observed (Strubelt et al., 1999).<br />
4.2. Skin irritation<br />
4.2.1. Human studies<br />
No available in<strong>for</strong>mation.<br />
LD 50<br />
(g/kg)<br />
References<br />
Oral Rat 5 4.92 Smyth et al. (1962)<br />
Oral Rat N/A 1.00 Nishimura et al. (1994)<br />
Oral Rat N/A 4.01 Rowe <strong>and</strong> McCollister (1982)<br />
Oral Rat 10 (5/sex) 4.17 RIFM (1979)<br />
Oral Rat 10 (5/sex) >5.0 RIFM (1985)<br />
Dermal Rabbit 4 3.54 Smyth et al. (1962)<br />
Dermal Rabbit N/A 3.54 RIFM (1979)
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D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S97–S101<br />
4.2.2. Animal studies<br />
In a rabbit dermal irritation study (n = 5) undiluted 2-methylbutanol<br />
resulted in Grade 2 irritation defined as the least visible<br />
capillary injection from the undiluted material (Smyth et al., 1962).<br />
In a rabbit dermal irritation study with two rabbits, undiluted<br />
2-methylbutanol resulted in Grade 4.7 or moderate irritation with<br />
some necrosis observed (RIFM, 1979).<br />
4.3. Mucous membrane (eye) irritation<br />
In a rabbit eye irritation study, 2-methylbutanol resulted in<br />
Grade 8 injury where corneal necrosis was observed (Smyth<br />
et al., 1962).<br />
In a rabbit eye irritation study (n = 6), undiluted 2-methylbutanol<br />
resulted in some turbidity at the cornea, inflammation on the<br />
iris, <strong>and</strong> redness of the conjunctivae after observations <strong>for</strong> 72 h<br />
(RIFM, 1979).<br />
When a 0.005 ml of undiluted 2-methylbutanol (or an excess of<br />
a 15% solution in propylene glycol; not specified) was instilled into<br />
the eyes of rabbits moderate to severe burns <strong>and</strong> corneal necrosis<br />
was observed (Rowe <strong>and</strong> McCollister, 1982).<br />
4.4. Skin sensitization<br />
No available in<strong>for</strong>mation.<br />
4.5. Phototoxicity <strong>and</strong> photoallergy<br />
No available in<strong>for</strong>mation.<br />
4.6. Absorption, distribution <strong>and</strong> metabolism<br />
4.6.1. Absorption<br />
No available in<strong>for</strong>mation.<br />
4.6.2. Distribution<br />
No available in<strong>for</strong>mation.<br />
4.6.3. Metabolism<br />
4.6.3.1. In vivo studies in animals (see Table 3). Following intraperitoneal<br />
administration of 1 g/kg undiluted 2-methylbutanol to rats;<br />
blood was drawn <strong>for</strong> analysis 1 h after the first administration <strong>and</strong><br />
at subsequent intervals. There was total elimination of 7.6%, 5.6%<br />
was recovered unchanged in the expired air <strong>and</strong> 2.0% unchanged<br />
in the urine. Disappearance from blood was rapid, with neither<br />
alcohol nor aldehyde detected after 10 h (Haggard et al., 1945).<br />
Oxidation to the aldehyde <strong>and</strong> glucuronidation was demonstrated<br />
<strong>for</strong> 2-methylbutanol with microsomes from rats pre-treated<br />
with ethanol (Iwersen <strong>and</strong> Schmoldt, 1995).<br />
2-Methylbutanol was administered to large chinchilla rabbits<br />
(n = 3) by oral gavage at 25 m-mol/rabbit. Collected urine did not<br />
Table 3<br />
Summary of in vivo animal studies.<br />
Route Species Results References<br />
Intraperitoneal Rat 5.6% was recovered unchanged in<br />
the expired air <strong>and</strong> 2.0%<br />
unchanged in the urine<br />
Oral (drinking<br />
water)<br />
Rat<br />
Oxidation to the aldehyde <strong>and</strong><br />
glucuronidation was<br />
demonstrated<br />
Oral (gavage) Rabbit Excess glucuronide excretion<br />
represented 9.6% of the<br />
administered dose<br />
Haggard<br />
et al. (1945)<br />
Iwersen <strong>and</strong><br />
Schmoldt<br />
(1995)<br />
Kamil et al.<br />
(1953)<br />
contain aldehydes or ketones, but did yield 9.6% of non-reducing<br />
glucuronide (Kamil et al., 1953).<br />
4.6.3.2. In vitro studies in animals. Rat liver microsomes metabolized<br />
2-methylbutanol to yield approximately 8 nmol aldehyde<br />
per minute per mg protein <strong>and</strong> 13 nmol glucuronide per min per<br />
mg protein. The k m <strong>and</strong> V max <strong>for</strong> glucuronidation were 2 mmol/l<br />
<strong>and</strong> 18 nmol/min/mg protein, respectively. The k m <strong>and</strong> V max <strong>for</strong><br />
microsomal oxidation were 4.6 mmol/l <strong>and</strong> 3.6 nmol/min/mg protein,<br />
respectively. The microsomes were obtained from male Sprague–Dawley<br />
rats that had been pre-treated <strong>for</strong> 2 weeks with 10%<br />
ethanol in the drinking water (Iwersen <strong>and</strong> Schmoldt, 1995).<br />
4.7. Repeated dose toxicity<br />
No available in<strong>for</strong>mation.<br />
4.8. Reproductive <strong>and</strong> developmental toxicity<br />
No available in<strong>for</strong>mation.<br />
4.9. Genotoxicity<br />
4.9.1. In vitro studies<br />
4.9.1.1. Bacterial test systems. Light absorption <strong>and</strong> luminescent<br />
umu tests were used to investigate the genotoxicity of 2-methylbutanol<br />
with Salmonella typhimurium TA1535/pSK1002 <strong>and</strong> TA1535/<br />
pTL210. Results showed the umu test <strong>for</strong> light absorption of<br />
TA1535/pSK102 to be negative, where as the umu test <strong>for</strong> luminescent<br />
TA1535/pTL210 to be positive (Nakajima et al., 2006).<br />
4.9.1.2. Studies in mammalian cells. In a study of the cytotoxic <strong>and</strong><br />
genotoxic effects of a number of alcohols <strong>and</strong> ketones, 2-methylbutanol<br />
had an IC 50 (Inhibitory concentration resulting in 50% reduction<br />
in colony <strong>for</strong>mation) of 31 mM <strong>for</strong> human lung carcinoma cell<br />
line A549. At 45 <strong>and</strong> 90 mM concentration of 2-methylbutanol,<br />
there was no difference from controls in alkaline comet assay tail<br />
moment in either A549 cells or Chinese hamster V79 cells. The comet<br />
assay could not be per<strong>for</strong>med in human peripheral blood cells<br />
due to cytotoxicity. At methylbutanol concentrations of 23 <strong>and</strong><br />
45 mM, there was no difference, in the micronucleus test, from<br />
controls in induction of micronuclei in V79 cells with or without<br />
the addition of hepatic S-9 from Aroclor induced rats. Finally an<br />
HPRT with Chinese hamster V70 fibroblast cells at concentrations<br />
up to 46 mM (the highest non-toxic concentration) mutagenicity<br />
was not observed (Kreja <strong>and</strong> Seidel, 2001, 2002a,b).<br />
4.9.2. In vivo studies<br />
No available in<strong>for</strong>mation.<br />
4.10. Carcinogenicity<br />
No available in<strong>for</strong>mation.<br />
This individual <strong>Fragrance</strong> Material Review is not intended as a<br />
st<strong>and</strong>-alone document. Please refer to A Safety Assessment of<br />
Branched Chain Saturated Alcohols When Used as <strong>Fragrance</strong> Ingredients<br />
(Belsito et al., 2010) <strong>for</strong> an overall assessment of this<br />
material.<br />
Conflict of interest statement<br />
This research was supported by the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong><br />
Materials, an independent research institute that is funded<br />
by the manufacturers of fragrances <strong>and</strong> consumer products con-
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S97–S101 S101<br />
taining fragrances. The authors are all employees of the <strong>Research</strong><br />
<strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials.<br />
References<br />
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,<br />
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched<br />
chain saturated alcohols when used as fragrance ingredients. <strong>Food</strong> Chem<br />
Toxicol. 48 (S4), S1–S46.<br />
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:<br />
providing estimates <strong>for</strong> safety evaluation. Regul.Toxicol. Pharm. 36, 246–252.<br />
Council of Europe, 2000. Partial Agreement in the Social <strong>and</strong> Public Health Field.<br />
<strong>Chemical</strong>ly-defined flavouring substances. Group 2.1.3 Aliphatic alcohols,<br />
branched chain. p. 60, number 2346. Council of Europe Publishing, Strasbourg.<br />
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface<br />
Suite <strong>for</strong> Microsoft Ò Windows, v 4.00 or insert version used]. United States<br />
Environmental Protection Agency, Washington, DC, USA.<br />
FEMA (Flavor <strong>and</strong> Extract Manufacturers Association), 2001. GRAS flavoring<br />
substances 20. <strong>Food</strong> Technol. 55 (12), 1-17.<br />
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria <strong>for</strong><br />
development of a database <strong>for</strong> safety evaluation of fragrance ingredients. Regul.<br />
Toxicol. Pharm. 31, 166–181.<br />
Greim, H. (Ed.), 2008. Pentanol-Isomeren. Toxikologisch-arbeitsmedizinische<br />
Begründungen von MAK-Werten, Lieferung 44. Wiley-VCH, Weinheim.<br />
Haggard, H.W., Miller, D.P., Greenberg, L.A., 1945. The amyl alcohols <strong>and</strong> their<br />
ketones: their metabolic fates <strong>and</strong> comparative toxicities. J. Ind. Hyg. Toxicol. 27<br />
(1), 1–14.<br />
IFRA (International <strong>Fragrance</strong> Association), 2004. Use Level Survey, August 2004.<br />
IFRA (International <strong>Fragrance</strong> Association), 2007. Volume of Use Survey, February<br />
2007.<br />
Iwersen, S., Schmoldt, A., 1995. ADH Independent metabolism of aliphatic alcohols:<br />
comparison of oxidation <strong>and</strong> glucuronidation. Adv. Forensic Sci. 13 (4), 19–22.<br />
JECFA, 2004. Safety evaluation of certain food additives. Aliphatic branched-chain<br />
saturated <strong>and</strong> unsaturated alcohols, aldehydes, acids, <strong>and</strong> related esters.<br />
Prepared by the Joint FAO/WHO Expert Committee on <strong>Food</strong> Additives (JECFA).<br />
WHO <strong>Food</strong> Additives Series: 52. IPCS, WHO, Geneva.<br />
Kamil, I.A., Smith, J.N., Williams, R.T., 1953. Studies in detoxication. 46. The<br />
metabolism of aliphatic alcohols. The glucuronic acid conjugation of acyclic<br />
aliphatic alcohols. Biochem. J. 53, 129–136.<br />
Kreja, L., Seidel, H.J., 2001. <strong>Toxicology</strong> study of some often detected microbial<br />
volatile organic compounds (MVOC). Umweltmed Forsch Prax. 6 (3), 159–163.<br />
Kreja, L., Seidel, H.J., 2002a. Evaluation of the genotoxic potential of some microbial<br />
volatile organic compounds (MVOC) with the comet assay, the micronucleus<br />
assay <strong>and</strong> the HPRT gene mutation assay. Mutat. Res. 513 (1–2), 143–150.<br />
Kreja, L., Seidel, H.J., 2002b. On the cytotoxicity of some microbial volatile organic<br />
compounds as studied in the human lung cell line A549. Chemosphere 49 (1),<br />
105–110.<br />
Nakajima, D., Ishii, R., Kageyama, S., Onji, Y., Mineki, S., Morooka, N., Takatori, K.,<br />
Goto, S., 2006. Genotoxicity of microbial volatile organic compounds. J. Health<br />
Sci. 52 (2), 148–153.<br />
Nishimura, H., Saito, S., Kishida, F., Matsuo, M., 1994. Analysis of acute toxicity<br />
(LD50-value) of organic chemicals to mammals by solubility parameter (delta).<br />
1. Acute oral toxicity to rats. Sangyo Igaku 36 (5), 314–323 (Japanese Journal<br />
Industrial Health).<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1979. Acute toxicity studies<br />
on 2-methylbutanol. Unpublished report from BASF, Report number 55366.<br />
RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1985. Report on the acute<br />
oral toxicity of 2-methylbutanol in rats. Unpublished report from BASF, Report<br />
number 55365. RIFM, Woodcliff Lake, NJ, USA.<br />
Rowe, V.K., McCollister, S.B, 1982. Alcohols. In: Industrial Hygiene <strong>and</strong> <strong>Toxicology</strong>,<br />
third ed., vol. 11C, pp. 4527–4708 (Chapter 55).<br />
Smyth, H.F., Carpenter, C.P., Weil, C.S., Pozzani, U.C., Striegel, J.A., 1962. Rangefinding<br />
toxicity data: list VI. Am. Ind. Hyg. Assoc. J. (AIHAJ) 23, 95–107.<br />
Strubelt, O., Deters, M., Pentz, R., Siegers, C.P., Younes, M., 1999. The toxic <strong>and</strong><br />
metabolic effects of 23 aliphatic alcohols in the isolated perfused rat liver.<br />
Toxicol. Sci. (<strong>for</strong>merly Fundam. Appl. Toxicol.) 49 (1), 133–142.<br />
VCF, 2009. Volatile compounds in food: database. In: Nijssen, L.M., Ingen-Visscher,<br />
C.A. van., Donders, J.J.H. (Eds.), Version 11.1.1 – Zeist. TNO Quality of Life, The<br />
Netherl<strong>and</strong>s, pp. 1963–2009.
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S102–S109<br />
Contents lists available at ScienceDirect<br />
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong><br />
journal homepage: www.elsevier.com/locate/foodchemtox<br />
Review<br />
<strong>Fragrance</strong> materials review on isoamyl alcohol<br />
D. McGinty * , A. Lapczynski, J. Scognamiglio, C.S. Letizia, A.M. Api<br />
<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA<br />
article<br />
Keywords:<br />
Review<br />
Frangrance<br />
info<br />
abstract<br />
A toxicologic <strong>and</strong> dermatologic review of isoamyl alcohol when used as a fragrance ingredient is presented.<br />
Isoamyl alcohol is a member of the fragrance structural group branched chain saturated alcohols.<br />
The common characteristic structural elements of the alcohols with saturated branched chain are one<br />
hydroxyl group per molecule, <strong>and</strong> a C 4 –C 12 carbon chain with one or several methyl side chains. This<br />
review contains a detailed summary of all available toxicology <strong>and</strong> dermatology papers that are related<br />
to this individual fragrance ingredient <strong>and</strong> is not intended as a st<strong>and</strong>-alone document. A safety assessment<br />
of the entire branched chain saturated alcohol group will be published simultaneously with this<br />
document; please refer to Belsito et al. (2010) <strong>for</strong> an overall assessment of the safe use of this material<br />
<strong>and</strong> all other branched chain saturated alcohols in fragrances.<br />
Ó 2010 Published by Elsevier Ltd.<br />
Contents<br />
Introduction ....................................................................................................... S103<br />
1. Identification . . . . . . . . . . . . . . . ....................................................................................... S103<br />
2. Physical properties . . . . . . . . . . . ....................................................................................... S103<br />
3. Usage. . . . . . ....................................................................................................... S103<br />
4. <strong>Toxicology</strong> data . . . . . . . . . . . . . ....................................................................................... S104<br />
4.1. Acute toxicity (see Table 2). ................................................................................... S104<br />
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S104<br />
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105<br />
4.1.3. Intravenous studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105<br />
4.1.4. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105<br />
4.2. Skin irritation . . . ............................................................................................ S105<br />
4.2.1. Human studies (see Table 3). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105<br />
4.2.2. Animal studies (see Table 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105<br />
4.3. Mucous membrane (eye) irritation. ............................................................................. S105<br />
4.4. Skin sensitization ............................................................................................ S105<br />
4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105<br />
4.4.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105<br />
4.5. Phototoxicity <strong>and</strong> photoallergy. ................................................................................ S105<br />
4.6. Absorption, distribution, <strong>and</strong> metabolism ........................................................................ S105<br />
4.6.1. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105<br />
4.6.2. Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S106<br />
4.7. Repeated dose toxicity. . ...................................................................................... S106<br />
4.7.1. Subchronic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S106<br />
4.7.2. Chronic studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S106<br />
4.8. Reproductive <strong>and</strong> developmental ............................................................................... S107<br />
4.9. Genotoxicity ................................................................................................ S107<br />
4.9.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S107<br />
4.9.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S107<br />
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.<br />
E-mail address: dmcginty@RIFM.org (D. McGinty).<br />
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.<br />
doi:10.1016/j.fct.2010.05.040
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S102–S109 S103<br />
4.10. Carcinogenicity . . ............................................................................................ S107<br />
4.11. Neurotoxicity. ............................................................................................... S108<br />
Conflict of interest statement . . . . . . . . ................................................................................. S108<br />
References . . . . .................................................................................................... S108<br />
Introduction<br />
This document provides a comprehensive summary of the toxicologic<br />
review of isoamyl alcohol when used as a fragrance ingredient<br />
including all human health endpoints. Isoamyl alcohol (see<br />
Fig. 1; CAS Number 123-51-3) is a fragrance ingredient used in cosmetics,<br />
fine fragrances, shampoos, toilet soaps, <strong>and</strong> other toiletries<br />
as well as in non-cosmetic products such as household cleaners<br />
<strong>and</strong> detergents. It is a colorless liquid with a disagreeable alcohol<br />
odor only becoming a pleasant fruity-winey odor at high dilutions<br />
(Arct<strong>and</strong>er, 1969). This material has been reported to occur in nature,<br />
with the highest quantities observed in the brassica species of<br />
mustard (VCF, 2009).<br />
In 2006, a complete literature search was conducted on isoamyl<br />
alcohol. On-line toxicological databases were searched including<br />
those from the <strong>Chemical</strong> Abstract Services [e.g. ToxCenter (which<br />
in itself contains 18 databases including <strong>Chemical</strong> Abstracts)],<br />
<strong>and</strong> the National Library of Medicine [e.g. Medline, Toxnet (which<br />
contains 14 databases)] as well as 26 additional sources (e.g. BIO-<br />
SIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance companies<br />
were asked to submit all test data.<br />
The safety data on this material was last reviewed by Opdyke<br />
(1979). All relevant references are included in this document. More<br />
details have been provided <strong>for</strong> unpublished data. The number of<br />
animals, sex, <strong>and</strong> strain are always provided unless they are not given<br />
in the original report or paper. Any papers in which the vehicles<br />
<strong>and</strong>/or the doses are not given have not been included in this<br />
review. In addition, diagnostic patch test data with fewer than 100<br />
consecutive patients have been omitted.<br />
Fig. 1. Isoamyl alcohol.<br />
1. Identification<br />
1.1. Synonyms: 1-butanol, 3-methyl-; isobutyl carbinol; isopentanol;<br />
isopentyl alcohol; 3-methyl-1-butanol; 3-methylbutan-1-ol.<br />
1.2. CAS Registry Number: 123-51-3.<br />
1.3. EINECS Number: 204-633-5.<br />
1.4. Formula: C 5 H 12 O.<br />
1.5. Molecular weight: 88.15.<br />
1.6. Council of Europe (2000): isoamyl alcohol was included by<br />
the Council of Europe in the list of substances granted A –<br />
may be used in foodstuffs (COE Number 51).<br />
1.7. FDA: isoamyl alcohol was approved by the FDA as flavor (21<br />
CFR 172.515).<br />
1.8. FEMA (1965): Flavor <strong>and</strong> Extract Manufacturers’ Association<br />
states: Generally Recognized as Safe as a flavor ingredient –<br />
GRAS 3 (2057).<br />
1.9. JECFA (1996): the Joint FAO/WHO Expert Committee on<br />
<strong>Food</strong> Additives (JECFA) concluded that the substance does<br />
not present a safety concern at current levels of intake when<br />
used as a flavoring agent (52).<br />
1.10. OSHA: isoamyl alcohol was listed by the Occupational Safety<br />
<strong>and</strong> Health Administration as PEL-TWA 100 ppm, 360 mg/<br />
m 3 (<strong>for</strong> primary <strong>and</strong> secondary).<br />
2. Physical properties<br />
2.1. Physical <strong>for</strong>m: colorless liquid with a disagreeable alcohol<br />
odor <strong>and</strong> pungent, repulsive taste.<br />
2.2. Flash point: 109 °F; CC.<br />
2.3. Boiling point: 132 °C.<br />
2.4. Henry’s law (calculated; EPA, 2010): 0.0000133 atm m 3 /mol<br />
(25 °C).<br />
2.5. Log K ow (measured; EPA, 2010): 1.16.<br />
2.6. Specific gravity: 0.81.<br />
2.7. Refractive index: 1.4.<br />
2.8. Vapor pressure (calculated; EPA, 2010): 3.84 mm Hg at<br />
(25 °C); 512 Pa (25 °C).<br />
2.9. Water solubility (calculated; EPA, 2010): 41,580 mg/l at<br />
25 °C.<br />
2.10. UV spectra available at RIFM. Does not absorb UV light.<br />
Table 1<br />
Calculation of the total human skin exposure from the use of multiple cosmetic products containing isoamyl alcohol.<br />
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient (mg/kg/day) b<br />
Anti-perspirant 0.5 1 1 0.01 0.01 0.000001<br />
Bath products 17 0.29 0.001 0.02 0.01 0.000001<br />
Body lotion 8 0.71 1 0.004 0.01 0.000001<br />
Eau de toilette 0.75 1 1 0.08 0.01 0.000100<br />
Face cream 0.8 2 1 0.003 0.01 0.000001<br />
<strong>Fragrance</strong> cream 5 0.29 1 0.04 0.01 0.000100<br />
Hair spray 5 2 0.01 0.005 0.01 0.000001<br />
Shampoo 8 1 0.01 0.005 0.01 0.000001<br />
Shower gel 5 1.07 0.01 0.012 0.01 0.000001<br />
Toilet soap 0.8 6 0.01 0.015 0.01 0.000001<br />
Total 0.0002<br />
a<br />
b<br />
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.<br />
Based on a 60-kg adult.
S104<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S102–S109<br />
Table 2<br />
Summary of acute toxicity studies.<br />
Route Species Number<br />
of animals/<br />
dose group<br />
3. Usage<br />
LD 50 (g/kg)<br />
References<br />
Oral Mice 4 >2.0 RIFM (2008)<br />
Oral Rat N/A 4.36 Golovinskaya (1976)<br />
Oral Rat N/A 1.3 Nishimura et al. (1994)<br />
Oral Rat 4 1.3 (male) Purchase (1969)<br />
4.0 (female)<br />
Oral Rat 5 7.1 Smyth et al. (1969)<br />
Oral Rat N/A >5.0 RIFM (1979)<br />
Oral Rabbit 10–35 3.44 Munch (1972)<br />
Dermal Rabbit 10 >5.0 RIFM (1976a)<br />
Dermal Rabbit 4 3.97 Smyth et al. (1969)<br />
Dermal Rabbit 6 4.0 RIFM (1979)<br />
Intravenous Mice N/A 0.23 Chvapil et al. (1962)<br />
Isoamyl alcohol is a fragrance ingredient used in decorative cosmetics,<br />
fine fragrances, shampoos, toilet soaps, <strong>and</strong> other toiletries<br />
as well as in non-cosmetic products such as household cleaners<br />
<strong>and</strong> detergents. Its use worldwide is in the region 0.1–1.0 metric<br />
tons/annum (IFRA, 2004). The reported volume of use is <strong>for</strong> isoamyl<br />
alcohol as used in fragrance compounds (mixtures) in all finished<br />
consumer product categories. The volume of use is surveyed<br />
by IFRA approximately every four years through a comprehensive<br />
survey of IFRA <strong>and</strong> RIFM member companies. As such the volume<br />
of use data from this survey provides volume of use of fragrance<br />
ingredients <strong>for</strong> the majority of the fragrance industry.<br />
The dermal systemic exposure in cosmetic products (see Table 1)<br />
is calculated based on the concentrations of the same fragrance<br />
ingredient in 10 types of the most frequently used personal care<br />
<strong>and</strong> cosmetic products (anti-perspirant, bath products, body lotion,<br />
eau de toilette, face cream, fragrance cream, hair spray, shampoo,<br />
shower gel, <strong>and</strong> toilet soap). The concentration of the fragrance<br />
ingredient in fine fragrances is obtained from examination of several<br />
thous<strong>and</strong> commercial <strong>for</strong>mulations. The upper 97.5 percentile concentration<br />
is calculated from the data obtained. This upper 97.5 percentile<br />
concentration is then used <strong>for</strong> all 10 consumer products.<br />
These concentrations are multiplied by the amount of product applied,<br />
the number of applications per day <strong>for</strong> each product type,<br />
<strong>and</strong> a ‘‘retention factor” (ranging from 0.001 to 1.0) to account <strong>for</strong><br />
the length of time a product may remain on the skin <strong>and</strong>/or likelihood<br />
of the fragrance ingredient being removed by washing. The<br />
resultant calculation represents the total consumer exposure (mg/<br />
kg/day) (Cadby et al., 2002; Ford et al., 2000).<br />
This is a conservative calculation of dermal systemic exposure<br />
because it makes the unlikely assumption that a consumer will<br />
use these 10 products containing; which are all perfumed with<br />
the upper 97.5 percentile level of the fragrance ingredient from a<br />
fine fragrance type of product (Cadby et al., 2002; Ford et al.,<br />
2000). The 97.5 percentile use level in <strong>for</strong>mulae <strong>for</strong> use in cosmetics<br />
in general has been reported to be 0.01% (IFRA, 2007), which<br />
would result in a conservative calculated maximum daily exposure<br />
on the skin of 0.0002 mg/kg <strong>for</strong> high end users of these products<br />
(see Table 1).<br />
A maximum skin level is then determined <strong>for</strong> consideration of<br />
potential sensitization. The exposure is calculated as the percent<br />
concentration of the fragrance ingredient applied to the skin based<br />
on the use of 20% of the fragrance mixture in the fine fragrance<br />
consumer product (IFRA, 2007). The maximum skin level that results<br />
from the use of isoamyl alcohol in <strong>for</strong>mulae that go into fine<br />
fragrances has been reported to be 0.012% (IFRA, 2007), assuming<br />
use of the fragrance oil at levels up to 20% in the final product.<br />
4. <strong>Toxicology</strong> data<br />
4.1. Acute toxicity (see Table 2)<br />
4.1.1. Oral studies<br />
As a preliminary study <strong>for</strong> a mouse micronucleus test, acute oral<br />
toxicity was evaluated with four (2/sex) animals. The NMRI mice<br />
were treated orally with the 0.1, 0.5, 1.0, or 2.0 g/kg of isoamyl<br />
alcohol <strong>and</strong> examined <strong>for</strong> acute toxic symptoms at intervals of<br />
around 1, 2–4, 6, 24, 30, <strong>and</strong> 48 h after administration. At the highest<br />
dose of 2.0 g/kg bodyweight the toxic effects observed were a<br />
reduction in spontaneous activity, eyelid closure, <strong>and</strong> ruffled fur.<br />
No mortality was observed at the highest dose which indicated<br />
the LD 50 to be greater than 2.0 g/kg (RIFM, 2008).<br />
The acute oral LD 50 of isoamyl alcohol in rats was reported to be<br />
4.36 g/kg (no further details provided) (Golovinskaya, 1976).<br />
The oral LD 50 of isoamyl alcohol in rats was reported to be 1.3 g/<br />
kg (no further details provided) (Nishimura et al., 1994).<br />
The acute oral (gavage) LD 50 was evaluated in groups of 4 rats<br />
with isoamyl alcohol at a dose range of 0.325–4.95 <strong>and</strong> 0.81–<br />
12.0 g/kg (concentration not reported) in polyethylene glycol 200<br />
<strong>for</strong> male <strong>and</strong> female, respectively. Deaths in female rats occurred<br />
4 h after high doses (4.95 <strong>and</strong> 12.0 g/kg); none died in the 10 days<br />
after the lower doses (0.81 <strong>and</strong> 2.0 g/kg). Males receiving the highest<br />
doses of 4.95 g/kg <strong>and</strong> a group receiving 12.0 g/kg died within<br />
4 h, <strong>and</strong> several at the lower doses of 0.81 <strong>and</strong> 2.0 g/kg died<br />
1–5 days later. Histological examination of the liver revealed<br />
hyperemia but very few degenerative changes. Females receiving<br />
4.95 g/kg showed cloudy swelling <strong>and</strong> cast <strong>for</strong>mation in the cortex<br />
Table 3<br />
Summary of human skin irritation studies.<br />
Method Concentration Results References<br />
Reactions Frequency (%)<br />
48 h closed patch test 8% in petrolatum 0/25 0 RIFM (1976b)<br />
5 min, occlusive patch test 75% in water 12/12 100 Wilkin <strong>and</strong> Fortner (1985a)<br />
5 min, occlusive patch test 75% in water 3/3 100 Wilkin <strong>and</strong> Fortner (1985b)<br />
5 min, occlusive patch test 75% in a hydrophilic ointment 12/12 100 Wilkin <strong>and</strong> Stewart (1987)<br />
Table 4<br />
Summary of animal irritation studies.<br />
Method Dose (%) Species Reactions References<br />
Single application of 5.0 g/kg 100 Rabbit Marked erythema <strong>and</strong> moderate edema RIFM (1976)<br />
0.01 ml aliquot applied to the clipped skin 100 Rabbit Irritation observed Smyth et al. (1969)<br />
Single application 100 Rabbit Very irritating RIFM (1979)
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<strong>and</strong> a few pyknotic tubular cells in the medulla section of the kidney.<br />
In females receiving 12.0 g/kg, the cortex showed signs of<br />
necrosis with some tubular cells showing pyknosis. In males pyknosis<br />
<strong>and</strong> hyperemia were seen in the outer zone of the medulla<br />
in all groups, <strong>and</strong> tubular necrosis was seen in the cortex after<br />
the two highest doses (2.0 <strong>and</strong> 4.95 g/kg). The calculated LD 50<br />
was 4.0 g/kg (95% limits: 2.45–6.17 g/kg) <strong>for</strong> female <strong>and</strong> 1.3 g/kg<br />
(95% limits: 0.67–2.41 g/kg) <strong>for</strong> male (Purchase, 1969).<br />
Groups of five Carworth-Wistar male rats were administered a<br />
single dose of undiluted isoamyl alcohol by gavage. The oral LD 50<br />
of was reported to be 7.1 g/kg with limits of 4.82–10.4 g/kg (Smyth<br />
et al., 1969).<br />
Isoamyl alcohol was reported to have an LD 50 greater than 5.0 g/<br />
kg in Sprague Dawley rats. The animals were given doses of 2.15 or<br />
5.0 g/kg <strong>and</strong> observed <strong>for</strong> 14 days (RIFM, 1979).<br />
The acute oral (gavage) LD 50 of isoamyl alcohol was reported to<br />
be 39 mmol/kg (3.45 g/kg). Administration was via stomach tube<br />
from a 50 ml syringe to groups of 10–35 rabbits (Munch, 1972).<br />
4.1.2. Dermal studies<br />
The acute dermal LD 50 of isoamyl alcohol was evaluated in 10<br />
rabbits. Each animal received a single dermal application of undiluted<br />
isoamyl alcohol at a dose of 5.0 g/kg. Clinical signs <strong>and</strong>/or<br />
mortality were observed over a 14 day period. No deaths were observed.<br />
Clinical signs included flaccidity, ataxia, loss of righting reflex<br />
<strong>and</strong> diarrhea. The LD 50 was reported to be greater than 5.0 g/kg<br />
(RIFM, 1976a).<br />
The acute dermal LD 50 was evaluated in groups of four male albino<br />
New Zeal<strong>and</strong> rabbits. Undiluted isoamyl alcohol at 0.1 ml was<br />
applied to the clipped trunk, <strong>and</strong> kept in place beneath an impervious<br />
plastic film <strong>for</strong> 24 h (doses <strong>and</strong> skin area not provided). The<br />
LD 50 was reported to be 3.97 g/kg with limits of 2.93–5.37 g/kg<br />
(Smyth et al., 1969).<br />
Isoamyl alcohol was reported to have a dermal LD 50 of 4 ml/kg<br />
(4 g/kg) in rabbits. The animals were given undiluted doses of<br />
isoamyl alcohol <strong>and</strong> observed <strong>for</strong> 8 days (RIFM, 1979).<br />
4.1.3. Intravenous studies<br />
The intravenous LD 50 of isoamyl alcohol in water was determined<br />
in female white H strain mice. Using an approximate graphic<br />
probit method, the LD 50 was calculated to be 2.64 mmol/kg<br />
(233 mg/kg; no further details provided) (Chvapil et al., 1962).<br />
The hemodynamic effects of isoamyl alcohol were studied in 56<br />
anesthetized, open chest dogs. The material was administered i.v.<br />
at a constant rate <strong>for</strong> 40–150 min. The infusion of 20 mg/kg/min<br />
decreased heart rate, systemic arterial pressure, <strong>and</strong> myocardial<br />
contraction <strong>for</strong>ce progressively <strong>and</strong> markedly. All dogs died during<br />
the first hour of infusion (Nakano <strong>and</strong> Kessinger, 1972).<br />
Isoamyl alcohol was injected into the vein of cat, under a light<br />
ether anesthesia, to determine the lethal dose. In terms of the pure<br />
alcohol of 0.26 ml/kg (260 mg/kg) was determined to be lethal<br />
(Macht, 1920).<br />
4.1.4. Inhalation studies<br />
Smyth et al. (1969) reported no death up to 8 h when concentrated<br />
vapors of isoamyl alcohol were exposed to rats by<br />
inhalation.<br />
Sensory irritation was evaluated in four Swiss male mice via<br />
measurement of changes in respiratory rate during a 10 min exposure<br />
to isoamyl alcohol. The concentration of isoamyl alcohol that<br />
caused a 50% decrease in the respiratory rate (RD 50 ) of mice was<br />
4452 ppm with 95% confidence limits of 2885–12,459 (Kane<br />
et al., 1980).<br />
Rats inhaled isoamyl alcohol as a steam vapor in an enriched<br />
atmosphere at 20 °C. After a 7 h exposure, no animals died (RIFM,<br />
1979).<br />
4.2. Skin irritation<br />
4.2.1. Human studies (see Table 3)<br />
In a pre-test <strong>for</strong> a human maximization study, a 48 h closed<br />
patch test was conducted on the volar <strong>for</strong>earms or backs of 25 volunteers<br />
with 8% isoamyl alcohol in petrolatum. No irritation was<br />
observed (RIFM, 1976b).<br />
Patch tests were conducted on 27 (groups of 12, 12, <strong>and</strong> 3)<br />
healthy volunteers with 75% aqueous solution of isoamyl alcohol.<br />
Patches were applied to the subjects’ <strong>for</strong>earms, <strong>and</strong> were removed<br />
after being occluded <strong>for</strong> 5 min. Irritation reactions were observed<br />
in all volunteers (Wilkin <strong>and</strong> Fortner, 1985a,b; Wilkin <strong>and</strong> Stewart,<br />
1987).<br />
4.2.2. Animal studies (see Table 4)<br />
Irritation was evaluated during a dermal LD 50 study. A single<br />
application of 5.0 g/kg of neat isoamyl alcohol was made to 10 rabbits.<br />
Marked or moderate edema were observed in 10/10 rabbits<br />
(RIFM, 1976a).<br />
Primary skin irritation was determined using groups of five albino<br />
rabbits. A 0.01 ml aliquot of isoamyl alcohol was applied to<br />
the clipped skin of the animals undiluted or as a solution in water,<br />
propylene glycol or acetone. Irritation reactions were observed<br />
(Smyth et al., 1969).<br />
Isoamyl alcohol was reported to be very irritating when applied<br />
undiluted to the skin of six rabbits. Irritation resolved after 8 days<br />
(RIFM, 1979).<br />
4.3. Mucous membrane (eye) irritation<br />
An eye irritation test was conducted in five rabbits per dose. Isoamyl<br />
alcohol (0.5 ml aliquot) was tested undiluted or as a solution<br />
in propylene glycol <strong>and</strong> water. Irritant effects were observed<br />
(Smyth et al., 1969).<br />
An eye irritation test was conducted in two rabbits with undiluted<br />
isoamyl alcohol. Irritation was observed up to 8 days in one<br />
rabbit (RIFM, 1979).<br />
4.4. Skin sensitization<br />
4.4.1. Human studies<br />
A maximization study was conducted on 25 (5 male, 20 female)<br />
volunteers. Isoamyl alcohol at 8% in petrolatum was applied under<br />
occlusion to the volar <strong>for</strong>earms or backs <strong>for</strong> five alternate days,<br />
48 h periods. The sites were pre-treated <strong>for</strong> 24 h with 2.5% aqueous<br />
sodium lauryl sulfate (SLS) under occlusion. The challenge phase<br />
was conducted after a rest period of 10–14 days at sites pre-treated<br />
<strong>for</strong> 1 h with 5–10% SLS. The challenge patch was removed after<br />
48 h, <strong>and</strong> the site was read at the patch removal <strong>and</strong> 24 h after<br />
the patch removal. No reactions were observed (RIFM, 1976b).<br />
4.4.2. Animal studies<br />
No data available.<br />
4.5. Phototoxicity <strong>and</strong> photoallergy<br />
No data available.<br />
4.6. Absorption, distribution, <strong>and</strong> metabolism<br />
4.6.1. Distribution<br />
4.6.1.1. Human studies. Respiratory uptake of isoamyl alcohol was<br />
investigated in four healthy volunteers. Test air concentration<br />
was 25–200 ppm <strong>and</strong> it was inhaled <strong>for</strong> 10 min. The mean uptake<br />
(determined using calculations based on exhalation percentages of<br />
isoamyl alcohol to mixed exhaled air) <strong>for</strong> the last 5 min of the test
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respiration was 63% <strong>and</strong> the mean respiratory rate was 15.3 min 1<br />
(Kumagai et al., 1998).<br />
4.6.1.2. Animal studies. Groups of 10 rats per dose received 600 mg<br />
of 20% isoamyl alcohol/l solution (either in ethanol or water) by<br />
intraperitoneal injection in four equally divided portions of<br />
2.5 ml/100 g of bodyweight, at 15 min intervals. Two hours after<br />
administration, the blood concentration of isoamyl alcohol with<br />
ethanol was maximal. It declined thereafter <strong>and</strong> was still detectable<br />
at 10 h but not at 12 h. When isoamyl alcohol was administered<br />
in water, its presence in the blood was discernible 2 h after<br />
administration but not thereafter (Greenberg, 1970).<br />
A single dose of 2.0 g/kg of isoamyl alcohol, in an aqueous solution<br />
of 20%, was given orally to fasted six Wistar WAG rats. Blood<br />
<strong>and</strong> urine were collected <strong>for</strong> up to 8 h <strong>for</strong> measurement of test<br />
material levels. The blood level in mg/100 ml was 7 at 15 min, 9<br />
at 30 min, 17 at 1 h, 8 at 1.5 h, 7 at 2 h, 3 at 4 h, <strong>and</strong> 1 at 8 h. Urinary<br />
excretion was 0 (Gaillard <strong>and</strong> Derache, 1965).<br />
After intraperitoneal administration of 1000 mg bodyweight,<br />
the concentration of isoamyl alcohol in blood declined within 5 h<br />
to non-detectable levels. An elimination half-life was not calculated.<br />
For isoamyl alcohol 1.2% was excreted via urine <strong>and</strong> expired<br />
air. Compared to other amyl alcohols tested by the authors, primary<br />
alcohols were eliminated from the blood more quickly than<br />
secondary <strong>and</strong> tertiary alcohols (Haggard et al., 1945).<br />
4.6.2. Metabolism<br />
4.6.2.1. Human studies. The glucuronidation of isoamyl alcohol <strong>and</strong><br />
other short-chained aliphatic alcohols was investigated in vitro<br />
with human liver microsomes. The V max value was 3.3 nmol/min/<br />
mg protein <strong>and</strong> the Km was determined as 13.3 mM. The glucuronidation<br />
increased with chain length (C 2 –C 5 ) of the alcohols studied<br />
(Jurowich et al., 2004).<br />
The rate of oxidation of isoamyl alcohol by human skin alcohol<br />
dehydrogenase was 183.3 nM/mg protein/min (Wilkin <strong>and</strong> Stewart,<br />
1987).<br />
4.6.2.2. Animal studies. A single oral (gavage) dose of 25 mmol/3 kg<br />
rabbit (734.6 mg/kg) of isoamyl alcohol in water was given to<br />
three chinchilla rabbits. Increases in the urinary excretion of glucuronides<br />
were monitored. Of the dose, 9% was excreted in the urine<br />
(at 24 h) as the glucuronide. The urine did not contain aldehydes or<br />
ketones (Kamil et al., 1953).<br />
In isolated perfused livers of rats, 65.1 mmol isoamyl alcohol/l<br />
were cytotoxic as evidenced by the release of liver enzymes into<br />
the perfusate. The alcohols decreased the content of ATP in the liver.<br />
The content of oxidized glutathione was increased. Lipid peroxidation<br />
was not observed (Strubelt et al., 1999).<br />
Age-dependent glucuronidation activity was demonstrated<br />
in vitro in the olfactory mucosa of 1 day, 1 week, 2 week, 3 month,<br />
12 month, <strong>and</strong> 24 month old male Wistar rats with isoamyl alcohol<br />
(Leclerc et al., 2002).<br />
Oxidation to the aldehyde <strong>and</strong> glucuronidation was demonstrated<br />
<strong>for</strong> isoamyl alcohol with microsomes from rats pre-treated<br />
with ethanol (Iwersen <strong>and</strong> Schmoldt, 1995).<br />
The rate of oxidative metabolism of isoamyl alcohol was about<br />
0.1 mmol/g liver in rat liver homogenate <strong>and</strong> about 0.05 mM/g perfused<br />
rat liver (Hedlund <strong>and</strong> Kiessling, 1969).<br />
The Km-values of isoamyl alcohol with alcohol dehydrogenase<br />
from human <strong>and</strong> horse liver were 0.07 <strong>and</strong> 0.08 mM, respectively<br />
(Pietruszko et al., 1973).<br />
4.7. Repeated dose toxicity<br />
4.7.1. Subchronic studies<br />
Groups of 10 Ash/CSE rats (5/sex) were administered 500 or<br />
1000 mg/kg of isoamyl alcohol dissolved in corn oil by gavage,<br />
7 days a week <strong>for</strong> 6 weeks. A group of 10 controls (5/sex) were<br />
administered corn oil alone. Observations included mortality,<br />
behavior, bodyweight, food <strong>and</strong> water consumption, renal concentration,<br />
organ weights, <strong>and</strong> gross pathology. Blood was examined<br />
<strong>for</strong> hemoglobin content, packed cell volume, <strong>and</strong> counts of erythrocytes,<br />
reticulocytes, as well as total <strong>and</strong> differential leukocytes. Serum<br />
was analyzed <strong>for</strong> the content of urea, glucose, total protein, <strong>and</strong><br />
albumin as well as activities of glutanic–oxalacetic <strong>and</strong> glutamic–<br />
pyruvic trasaminases <strong>and</strong> lactic dehydrogenase. With 500 mg/kg,<br />
a significant increase in the hemoglobin concentration <strong>and</strong> red<br />
blood cell count of test females was observed when compared to<br />
the controls, but the increases were not dose-related. With<br />
1000 mg/kg, a lower pituitary weight in males was observed, but<br />
when expressed relative to bodyweight, the decrease was not evident.<br />
At both doses, red patches on the lungs of male <strong>and</strong> female<br />
treated animals <strong>and</strong> control animals were found at the necropsy.<br />
Histopathological examination of the lungs revealed lymphocyte<br />
cuffing of the bronchi, but the incidence <strong>and</strong> severity were similar<br />
in both the test <strong>and</strong> control animals. The authors have concluded<br />
the NOAEL to be 1000 mg/kg in females <strong>and</strong> 500 mg/kg in males<br />
(Carpanini et al., 1973).<br />
Groups of 20 SPF-Wistar, Chbb:THOM rats (10/sex) were<br />
administered isoamyl alcohol in drinking water at 1000 ppm<br />
(80 mg/kg), 4000 ppm (320 mg/kg), <strong>and</strong> 16,000 ppm<br />
(1280 mg/kg) <strong>for</strong> 90 days. A group of 20 controls (10/sex) were<br />
administered drinking water alone. Parameters evaluated included<br />
bodyweight, food <strong>and</strong> water consumption, clinical signs, mortality,<br />
hematology, clinical chemistry, gross <strong>and</strong> microscopic pathology.<br />
The erythrocyte count was slightly elevated in males treated with<br />
4000 ppm (320 mg/kg). With 16,000 ppm (1280 mg/kg), an increase<br />
in the erythrocyte count, a decrease in the mean corpuscular<br />
volume, <strong>and</strong> a decrease in the mean corpuscular hemoglobin content<br />
of the blood in male rats were observed. Compared to the controls,<br />
a significant deviation from the control group leukocyte<br />
count was observed in males at 1000 ppm (80 mg/kg), <strong>and</strong> in the<br />
prothrombin time in females treated with 4000 <strong>and</strong> 16,000 ppm<br />
(320 <strong>and</strong> 1280 mg/kg). However, these observed effects did not appear<br />
to be relevant to the treatment. Ectopia of thymus tissue in<br />
the region of the thyroid gl<strong>and</strong> was observed in five males treated<br />
with 16,000 ppm (1680 mg/kg). The no-observable-adverse-effectlevel<br />
(NOAEL) of isoamyl alcohol was concluded to be 4000 ppm<br />
(320 mg/kg) in males <strong>and</strong> 16,000 ppm (1680 mg/kg) in females<br />
(Schilling et al., 1997; RIFM, 1991).<br />
4.7.2. Chronic studies<br />
Groups of 30 Ash/CSE rats (15/sex) were administered 150, 500,<br />
<strong>and</strong> 1000 mg/kg of isoamyl alcohol dissolved in corn oil by gavage,<br />
7 days a week <strong>for</strong> 17 weeks. A group of 30 controls (15/sex) were<br />
administered corn oil alone. Observations included mortality,<br />
behavior, bodyweight, food <strong>and</strong> water consumption, hematology,<br />
serum analysis, urinalysis, renal concentration, organ weights,<br />
<strong>and</strong> gross pathology. Microscopic pathology was examined <strong>for</strong><br />
the highest dose only. There were no effects associated with treatment<br />
in the results of the hematological examinations, serum analyses,<br />
urinary cell counts, renal concentration tests, or organ<br />
weights. A slight reduced rate of bodyweight gain at the highest<br />
dose level was shown to be due to a reduced food intake. Two rats<br />
in the highest dose level died, but histopathological examination<br />
showed that these deaths were due to dosing into the lungs <strong>and</strong><br />
not to any toxic effects of isoamyl alcohol. A female rat given<br />
500 mg/kg/day developed a lipoma, which was not considered to
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S102–S109 S107<br />
be due to treatment. The other histopathological changes seen<br />
were related to mild infections in the animals <strong>and</strong> not to isoamyl<br />
alcohol. The NOAEL was concluded to be 1000 mg/kg/day (Carpanini<br />
et al., 1973).<br />
Astill et al. (1996) gave 0 (water), 0 (vehicle), 50, 200, or<br />
750 mg/kg bodyweight/day in 0.005% cremophor EL to B6C3F1<br />
mice (50/sex). For 18 months, 5 days a week, animals were treated<br />
with isoamyl alcohol by gavage. Increased mortality, <strong>and</strong> decreases<br />
in bodyweight gains, <strong>and</strong> food consumption were observed at<br />
750 mg/kg as well as fatty liver <strong>and</strong> hyperplasia of the <strong>for</strong>estomach<br />
epithelium. A systemic NOAEL of 200 mg/kg bodyweight was<br />
determined.<br />
4.8. Reproductive <strong>and</strong> developmental<br />
Groups of 25 pregnant rats were exposed to a vapor–air mixture<br />
of isoamyl alcohol at concentrations of 0.5, 2.5, <strong>and</strong> 10 mg/l, 6 h/<br />
day from gestation day (GD) 6–15. In rats exposed to 10 mg/l bodyweight<br />
gain was decreased between GD 6 <strong>and</strong> 9 <strong>and</strong> increased between<br />
GD 12–15, however no biologically relevant or<br />
concentration related differences were apparent among the<br />
groups. At 0.5 mg/l fetal examination revealed skeletal changes:<br />
mal<strong>for</strong>mations of the sternebrae <strong>and</strong>/or the vertebral column. With<br />
2.5 mg/l, the observed fetal anomalies included soft tissue changes<br />
such as a globular shaped heart <strong>and</strong> dextrocardia, <strong>and</strong> skeletal<br />
changes: mal<strong>for</strong>mations of the sternebrae <strong>and</strong>/or the vertebral column.<br />
At 10 mg/l observed fetal anomalies included external<br />
changes such as polydactyly <strong>and</strong> skeletal changes: mal<strong>for</strong>mations<br />
of the sternebrae <strong>and</strong>/or the vertebral column. With all the tested<br />
concentrations, retardations such as incomplete or missing ossification<br />
of hyoid, skull bones, metacarpal or metatarsal bones, vertebral<br />
bodies, <strong>and</strong>/or sternebrae were observed. The NOAEL <strong>for</strong> dams<br />
was 2.5 <strong>and</strong> 10 mg/l <strong>for</strong> the fetuses (Klimisch <strong>and</strong> Hellwig, 1995;<br />
RIFM, 1990a).<br />
As a part of the same experiment, groups of 15 pregnant Himalayan<br />
rabbits Chbbb:HM per dose were exposed to 0.5, 2.5, <strong>and</strong><br />
10 mg/l isoamyl alcohol on gestation days 7–19. At 10 mg/l a slight<br />
retardation of bodyweight increase was observed throughout the<br />
whole exposure period <strong>and</strong> was significant on GD 7–10. Also, at<br />
10 mg/l an indication of an irritant eye effect (reddish, lid closure,<br />
or slight discharge) was also observed during the exposure period.<br />
In fetuses pseudoankylosis <strong>and</strong> soft tissue changes such as hypoplasia<br />
of the gall bladder, bipartite ovary, dilated renal pelvis,<br />
<strong>and</strong>/or separate origin of carotids were observed at all doses. However,<br />
it was noted that these findings occurred at a similar incidence<br />
rate in historical controls. Observed skeletal changes<br />
included mal<strong>for</strong>mations of the sternebrae <strong>and</strong>/or the vertebral column,<br />
the sternum <strong>and</strong> the ribs. They were seen in all groups without<br />
apparent dose relationships or statistically significant<br />
differences between the groups. The only significant differences<br />
of note were due to the increased incidence of two specific types<br />
of soft tissue variation (the separated origin of carotids <strong>and</strong> traces<br />
of interventricular <strong>for</strong>amen/septum membranaceum) which occurred<br />
without a clear concentration relationship. The NOAEL <strong>for</strong><br />
dams was 2.5 <strong>and</strong> 10 mg/l <strong>for</strong> the fetuses (Klimisch <strong>and</strong> Hellwig,<br />
1995; RIFM, 1990b).<br />
4.9. Genotoxicity<br />
4.9.1. In vitro studies<br />
4.9.1.1. Bacterial test systems. Isoamyl alcohol was negative in a<br />
umu test <strong>for</strong> light absorption in Salmonella typhimurium TA1535/<br />
pSK1002 at concentrations in which growth inhibition was 650%.<br />
However, isoamyl alcohol was positive when tested in a umu test<br />
<strong>for</strong> luminescence with S. typhimurium TA1535/pTL210 at concentrations<br />
in which growth inhibition was 650% (Nakajima et al.,<br />
2006).<br />
4.9.1.2. Studies in mammalian cells (see Table 5). A Comet assay was<br />
conducted on human lung carcinoma A549 cells <strong>and</strong> human<br />
peripheral blood pB cells. Induced DNA damage was only observed<br />
at cytotoxic concentrations of isoamyl alcohol such as 23, 46, <strong>and</strong><br />
91 mM (Kreja <strong>and</strong> Seidel, 2002).<br />
An alkaline single cell gel electrophorese assay (comet assay)<br />
was conducted on Chinese hamster V79 fibroblasts, <strong>and</strong> DNA damage<br />
induced by isoamyl alcohol was observed at cytotoxic concentrations<br />
of 23, 46, <strong>and</strong> 91 mM (Kreja <strong>and</strong> Seidel, 2002).<br />
A micronucleus assay was conducted on Chinese hamster fibroblast<br />
V79 cells, with isoamyl alcohol at concentrations of 5, 9, <strong>and</strong><br />
23 mM in the presence <strong>and</strong> absence of metabolic activation (S9).<br />
No genotoxic effects were produced at any of the tested concentrations<br />
(Kreja <strong>and</strong> Seidel, 2002).<br />
No mutagenicity was produced in a hypoxanthine–guanine<br />
phosphoribosyltransferase (HPRT) assay conducted on Chinese<br />
hamster lung fibroblast cell line V79, with 51.5 mM of isoamyl<br />
alcohol in the presence or absence of metabolic activation (S9)<br />
(Kreja <strong>and</strong> Seidel, 2002).<br />
4.9.2. In vivo studies<br />
An in vivo micronucleus assay was conducted with bone marrow<br />
cells of NMRI mice with isoamyl alcohol at doses of 500,<br />
1000, <strong>and</strong> 2000 mg/kg. Ten animals (5/sex) were evaluated at 24<br />
<strong>and</strong> 48 h after a single administration <strong>for</strong> the occurrence of micronuclei.<br />
There was no increase in the frequency of detected micronuclei.<br />
Isoamyl alcohol was determined to be non-mutagenic in<br />
the micronucleus assay (RIFM, 2008).<br />
4.10. Carcinogenicity<br />
A group of 15 Wistar rats were administered 0.1 ml/kg (0.1 g/<br />
kg) of isoamyl alcohol by gavage, twice a week up to the time of<br />
their spontaneous deaths. The average total dosage was 27 ml<br />
(27 g). The 25 controls were treated with 1 ml/kg (1 g/kg) of a<br />
0.9% NaCl solution, twice weekly. The animals were weighed at<br />
regular intervals, <strong>and</strong> most were subjected to hematological testing.<br />
At the time of spontaneous death, a necropsy, histological<br />
examinations of all organs, vertebrae, <strong>and</strong> femur, <strong>and</strong> additional<br />
hematological tests were conducted. The average survival time of<br />
the control animals was 643 days. A wide spectrum of tumors<br />
was observed from bladder carcinoma, carcinoma of the kidney<br />
pelvis, adenocarcinoma of the proventriculum to benign tumors<br />
such as papillomae <strong>and</strong> occasional incipient infiltrative growth.<br />
The number of malignant <strong>and</strong> benign tumors found was 0 <strong>and</strong> 3,<br />
Table 5<br />
Summary of studies in mammalian cells.<br />
Test system Concentration (mM) Results References<br />
Comet assay Human lung carcinoma A549 cells 23, 46, <strong>and</strong> 91 Not genotoxic Kreja <strong>and</strong> Seidel (2002)<br />
Comet assay Human lung peripheral blood pB cells 46 <strong>and</strong> 91 Not genotoxic Kreja <strong>and</strong> Seidel (2002)<br />
Comet assay Chinese hamster fibroblast V79 cells 23 <strong>and</strong> 91 Not genotoxic Kreja <strong>and</strong> Seidel (2002)<br />
Micronucleus assay Chinese hamster fibroblast V79 cells 5, 9, <strong>and</strong> 23 Not genotoxic Kreja <strong>and</strong> Seidel (2002)<br />
HPRT assay Chinese hamster lunch fibroblast V79 cells 51.5 Not genotoxic Kreja <strong>and</strong> Seidel (2002)
S108<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S102–S109<br />
respectively. The average survival time of test animals was<br />
527 days, <strong>and</strong> the number of malignant <strong>and</strong> benign tumors found<br />
was 4 <strong>and</strong> 3, respectively (Gibel et al., 1975).<br />
As a part of the same experiment group of 24 Wistar rats were<br />
subcutaneously administered 0.04 ml/kg (0.04 g/kg) of isoamyl<br />
alcohol, once a week up to the time of their spontaneous deaths.<br />
The average total dosage was 3.8 ml (3.8 g/kg). The controls were<br />
subcutaneously treated with 1 ml/kg (1 g/kg) of a 0.9% NaCl solution,<br />
twice weekly. The average survival time of the control animals<br />
was 643 days, <strong>and</strong> the number of malignant <strong>and</strong> benign<br />
tumors found was 0 <strong>and</strong> 2, respectively. The average survival time<br />
of test animals was 592 days, <strong>and</strong> the number of malignant <strong>and</strong> benign<br />
tumors found was 10 <strong>and</strong> 5, respectively. The tumors consisted<br />
of pancreas adenomas, adenomas of the proventriculus<br />
<strong>and</strong> of suprarenal gl<strong>and</strong>s, spleen fibromas to the benign small papillomas<br />
or fibroadenomas (Gibel et al., 1975).<br />
4.11. Neurotoxicity<br />
Male albino SPF rats derived from the Wistar strain, or female<br />
mice of the H strain were used to study the neurotoxicity of isoamyl<br />
alcohol. Whole body exposures were carried out in 80-l glass<br />
chambers with 1 rat or 2 mice. In total 16 rats (4/group) or 32 mice<br />
were exposed. Less than 1 min after removal from the exposure<br />
box, a short electrical impulse was applied through ear electrodes<br />
to the animals to measure the biological effect of isoamyl alcohol.<br />
Of the six time characteristics recorded, duration of toxic extension<br />
of hind limbs was measured, as this was considered the most sensitive<br />
<strong>and</strong> reproducible response measures. All animals were given<br />
three control tests at weekly intervals be<strong>for</strong>e the 1st exposure.<br />
Most animals went through 3–4 exposure to each concentration,<br />
<strong>and</strong> the interval between exposures was at least 3 weeks. The concentration<br />
that evoked a 30% depression in the recorded activity<br />
(M) was determined to be 1700 ppm in rats <strong>and</strong> 950 ppm in mice<br />
(Frantik et al., 1994).<br />
Male Sprague–Dawley rats were divided into groups of four or<br />
five <strong>and</strong> orally administered 325 mg/kg of isoamyl alcohol. Two<br />
hours after administration acetylcholine, 3,4-dihydroxyphenylalanine<br />
(DOPA), dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC),<br />
homovanillic acid (HVA), norepinephrine, 3-methoxy-4-hydroxyphenylglycol<br />
(MHPG), serotonin, <strong>and</strong> 5-hydroxyindoleacetic acid<br />
(5HIAA) contents in the small-brain regions were measured. Under<br />
the conditions of this study, a single dose of 325 mg/kg administered<br />
by gavage to rats resulted in increases in 5HIAA in the midbrain<br />
<strong>and</strong> MHPG in the medulla oblongata. Decreases occurred in<br />
norepinephrine in the midbrain <strong>and</strong> in 5HIAA in the hypothalamus<br />
(Kanada et al., 1994).<br />
This individual <strong>Fragrance</strong> Material Review is not intended as a<br />
st<strong>and</strong>-alone document. Please refer to A Safety Assessment of<br />
Branched Chain Saturated Alcohols When Used as <strong>Fragrance</strong> Ingredients<br />
(Belsito et al., 2010) <strong>for</strong> an overall assessment of this<br />
material.<br />
Conflict of interest statement<br />
This research was supported by the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong><br />
Materials, an independent research institute that is funded<br />
by the manufacturers of fragrances <strong>and</strong> consumer products containing<br />
fragrances. The authors are all employees of the <strong>Research</strong><br />
<strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials.<br />
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<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S110–S114<br />
Contents lists available at ScienceDirect<br />
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong><br />
journal homepage: www.elsevier.com/locate/foodchemtox<br />
Review<br />
<strong>Fragrance</strong> material review on 2,6-dimethyl-2-heptanol<br />
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api<br />
<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA<br />
article<br />
Keywords:<br />
Review<br />
<strong>Fragrance</strong><br />
info<br />
abstract<br />
A toxicologic <strong>and</strong> dermatologic review of 2,6-dimethyl-2-heptanol when used as a fragrance ingredient is<br />
presented. 2,6-Dimethyl-2-heptanol is a member of the fragrance structural group branched chain saturated<br />
alcohols. The common characteristic structural elements of the alcohols with saturated branched<br />
chain are one hydroxyl group per molecule, <strong>and</strong> a C 4 –C 12 carbon chain with one or several methyl side<br />
chains. This review contains a detailed summary of all available toxicology <strong>and</strong> dermatology papers that<br />
are related to this individual fragrance ingredient <strong>and</strong> is not intended as a st<strong>and</strong>-alone document. A safety<br />
assessment of the entire branched chain saturated alcohol group will be published simultaneously with<br />
this document; please refer to Belsito et al. (2010) <strong>for</strong> an overall assessment of the safe use of this material<br />
<strong>and</strong> all other branched chain saturated alcohols in fragrances.<br />
Ó 2010 Published by Elsevier Ltd.<br />
Contents<br />
Introduction ....................................................................................................... S111<br />
1. Identification . . . . . . . . . . . . . . . ....................................................................................... S111<br />
2. Physical properties . . . . . . . . . . . ....................................................................................... S111<br />
3. Usage. . . . . . ....................................................................................................... S111<br />
4. <strong>Toxicology</strong> data . . . . . . . . . . . . . ....................................................................................... S112<br />
4.1. Acute toxicity (see Table 2). .................................................................................... S112<br />
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S112<br />
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S112<br />
4.2. Skin irritation. ............................................................................................... S112<br />
4.2.1. Human studies (see Table 3). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S112<br />
4.2.2. Animal studies (see Table 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S112<br />
4.3. Mucous membrane (eye) irritation. .............................................................................. S113<br />
4.4. Skin sensitization. ............................................................................................ S113<br />
4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S113<br />
4.4.2. Maximization studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S113<br />
4.4.3. Diagnostic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S113<br />
4.4.4. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S113<br />
4.5. Phototoxicity <strong>and</strong> photoallergy. . ................................................................................ S113<br />
4.5.1. Phototoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S113<br />
4.5.2. Photoallergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S114<br />
4.6. Absorption, distribution <strong>and</strong> metabolism ......................................................................... S114<br />
4.7. Repeated dose toxicity . . ...................................................................................... S114<br />
4.8. Reproductive <strong>and</strong> developmental toxicity ......................................................................... S114<br />
4.9. Genotoxicity. ................................................................................................ S114<br />
4.10. Carcinogenicity . . ............................................................................................ S114<br />
Conflict of interest statement . . ....................................................................................... S114<br />
References . ....................................................................................................... S114<br />
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.<br />
E-mail address: dmcginty@RIFM.org (D. McGinty).<br />
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.<br />
doi:10.1016/j.fct.2010.05.041
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S110–S114 S111<br />
Introduction<br />
This document provides a summary, including all human health<br />
endpoints, of the toxicologic review of 2,6-dimethyl-2-heptanol<br />
when used as a fragrance ingredient. 2,6-Dimethyl-2-heptanol<br />
(see Fig. 1; CAS Number 13254-34-7) is a fragrance ingredient used<br />
in cosmetics, fine fragrances, shampoos, toilet soaps <strong>and</strong> other toiletries<br />
as well as in non-cosmetic products such as household<br />
cleaners <strong>and</strong> detergents. It is a colorless liquid with a fresh, woody,<br />
floral odor.<br />
In 2006, a complete literature search was conducted on 2,6-dimethyl-2-heptanol.<br />
On-line toxicological databases were searched<br />
including those from the <strong>Chemical</strong> Abstract Services, [e.g., ToxCenter<br />
(which in itself contains 18 databases including <strong>Chemical</strong> Abstracts)],<br />
<strong>and</strong> the National Library of Medicine [e.g., Medline,<br />
Toxnet (which contains 14 databases)] as well as 26 additional<br />
sources (e.g., BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance<br />
companies were asked to submit all test data.<br />
The safety data on this material was last reviewed by Ford et al.<br />
(1992). All relevant references are included in this document. More<br />
details have been provided <strong>for</strong> unpublished data. The number of<br />
animals, sex <strong>and</strong> strain are always provided unless they are not given<br />
in the original report or paper. Any papers in which the vehicles<br />
<strong>and</strong>/or the doses are not given have not been included in this<br />
review. In addition, diagnostic patch test data with fewer than 100<br />
consecutive patients have been omitted.<br />
1. Identification<br />
1.1. Synonyms: dimetol; freesiol; 2-heptanol, 2,6-dimethyl-; lolitol;<br />
2,6-dimethylheptan-2-ol.<br />
1.2. CAS Registry number: 13254-34-7.<br />
1.3. EINECS number: 236-244-1.<br />
1.4. Formula: C 9 H 20 O.<br />
1.5. Molecular weight: 144.26.<br />
HO<br />
Fig. 1. 2,6-Dimethyl-2-heptanol.<br />
2. Physical properties<br />
2.1. Physical <strong>for</strong>m: a colorless liquid with a fresh, woody, floral<br />
odor.<br />
2.2. Boiling point (calculated; EPA, 2010): 172.11 °C.<br />
2.3. Flash point: 145°F; CC.<br />
2.4. Henry’s law (calculated; EPA, 2010): 0.0000412 atm m 3 /mol<br />
25 °C.<br />
2.5. Log K ow : 3.0 at 45 °C.<br />
2.6. Refractive index: 1.4259.<br />
2.7. Specific gravity: 0.8135.<br />
2.8. Vapor pressure (calculated; EPA, 2010): 0.2 mm Hg (20 °C);<br />
0.364 mm Hg (25 °C); 48.5 Pa (25 °C).<br />
2.9. Water solubility (calculated; EPA, 2010): 572 mg/l (25 °C).<br />
2.10. UV spectra available at RIFM, does not absorb UV light.<br />
3. Usage<br />
2,6-Dimethyl-2-heptanol is a fragrance ingredient used in many<br />
fragrance compounds. It may be found in fragrances used in decorative<br />
cosmetics, fine fragrances, shampoos, toilet soaps <strong>and</strong> other<br />
toiletries as well as in non-cosmetic products such as household<br />
cleaners <strong>and</strong> detergents. Its use worldwide is in the region of 10–<br />
100 metric tons per annum (IFRA, 2004). The reported volume of<br />
use is <strong>for</strong> 2,6-dimethyl-2-heptanol as used in fragrance compounds<br />
(mixtures) in all finished consumer product categories. The volume<br />
of use is surveyed by IFRA approximately every four years through<br />
a comprehensive survey of IFRA <strong>and</strong> RIFM member companies. As<br />
such the volume of use data from this survey provides volume of<br />
use of fragrance ingredients <strong>for</strong> the majority of the fragrance<br />
industry.<br />
The dermal systemic exposure in cosmetic products (see Table 1)<br />
is calculated based on the concentrations of the same fragrance<br />
ingredient in ten types of the most frequently used personal care<br />
<strong>and</strong> cosmetic products (anti-perspirant, bath products, body lotion,<br />
eau de toilette, face cream, fragrance cream, hair spray, shampoo,<br />
shower gel, <strong>and</strong> toilet soap). The concentration of the fragrance<br />
ingredient in fine fragrances is obtained from examination of several<br />
thous<strong>and</strong> commercial <strong>for</strong>mulations. The upper 97.5 percentile concentration<br />
is calculated from the data obtained. This upper 97.5 percentile<br />
concentration is then used <strong>for</strong> all 10 consumer products.<br />
These concentrations are multiplied by the amount of product applied,<br />
the number of applications per day <strong>for</strong> each product type,<br />
<strong>and</strong> a ‘‘retention factor” (ranging from 0.001 to 1.0) to account <strong>for</strong><br />
the length of time a product may remain on the skin <strong>and</strong>/or likelihood<br />
of the fragrance ingredient being removed by washing. The<br />
resultant calculation represents the total consumer exposure (mg/<br />
kg/day) (Cadby et al., 2002; Ford et al., 2000).<br />
Table 1<br />
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2,6-dimethyl-2-heptanol.<br />
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient mg/kg/day b<br />
Anti-perspirant 0.5 1 1 0.01 2.41 0.00200<br />
Bath products 17 0.29 0.001 0.02 2.41 0.00004<br />
Body lotion 8 0.71 1 0.004 2.41 0.00910<br />
Eau de toilette 0.75 1 1 0.08 2.41 0.02410<br />
Face cream 0.8 2 1 0.003 2.41 0.00190<br />
<strong>Fragrance</strong> cream 5 0.29 1 0.04 2.41 0.02330<br />
Hair spray 5 2 0.01 0.005 2.41 0.00020<br />
Shampoo 8 1 0.01 0.005 2.41 0.00020<br />
Shower gel 5 1.07 0.01 0.012 2.41 0.00030<br />
Toilet soap 0.8 6 0.01 0.015 2.41 0.00030<br />
Total 0.0614<br />
a<br />
b<br />
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.<br />
Based on a 60-kg adult.
S112<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S110–S114<br />
This is a conservative calculation of dermal systemic exposure<br />
because it makes the unlikely assumption that a consumer will<br />
use these 10 products containing; which are all perfumed with<br />
the upper 97.5 percentile level of the fragrance ingredient from a<br />
fine fragrance type of product (Cadby et al., 2002; Ford et al.,<br />
2000). The 97.5 percentile use level in <strong>for</strong>mulae <strong>for</strong> use in cosmetics<br />
in general has been reported to be 2.41 (IFRA, 2007), which<br />
would result in a maximum daily exposure on the skin of<br />
0.0614 mg/kg <strong>for</strong> high end users (see Table 1).<br />
A maximum skin level is then determined <strong>for</strong> consideration of<br />
potential sensitization. The exposure is calculated as the percent<br />
concentration of the fragrance ingredient applied to the skin based<br />
on the use of 20% of the fragrance mixture in the fine fragrance<br />
consumer product (IFRA, 2007). The average maximum use level<br />
in <strong>for</strong>mulae that go into fine fragrances has been reported to be<br />
1.40% (IFRA, 2007), assuming use of the fragrance oil at levels up<br />
to 20% in the final product.<br />
4. <strong>Toxicology</strong> data<br />
4.1. Acute toxicity (see Table 2)<br />
4.1.1. Oral studies<br />
Ten rats were given a single dose of 2,6-dimethyl-2-heptanol at<br />
5.0 g/kg. Observations <strong>for</strong> mortality <strong>and</strong> or systemic effects were<br />
made. At 5.0 g/kg, 2/10 deaths occurred within the first day. Symptoms<br />
observed between 2 <strong>and</strong> 24 h were lethargy (in 3/8 rats),<br />
ataxia, piloerection (in 2/8 rats), <strong>and</strong> some loss of righting reflex.<br />
At necropsy two of the rats showed redness through the lungs<br />
<strong>and</strong> stomach. The acute oral LD 50 in rats was resolved to be greater<br />
than 5.0 g/kg (RIFM, 1976a).<br />
Rats were orally given 2,6-dimethyl-2-heptanol as a 31.6–50%<br />
emulsion in olive oil. Observations <strong>for</strong> mortality <strong>and</strong>/or systemic<br />
effects were made. The acute oral LD 50 in rats was calculated to<br />
be greater than 6.8 g/kg (RIFM, 1979).<br />
4.1.2. Dermal studies<br />
The acute LD 50 in rabbits exceeded 5.0 g/kg based on 0 deaths in<br />
10 animals tested at that dose. Ten rabbits received a single dermal<br />
application at a dose level of 5.0 g/kg bodyweight. Mortality <strong>and</strong>/or<br />
systemic effects were not observed (RIFM, 1976a).<br />
4.2. Skin irritation<br />
Table 2<br />
Summary of acute toxicity studies.<br />
Route Species No. animals/<br />
dose group<br />
LD 50 (g/kg)<br />
References<br />
Oral Rats 10 5.0 RIFM (1976a)<br />
Oral Rats NA 6.8 RIFM (1979)<br />
Dermal Rabbits 10 5.0 RIFM (1976a)<br />
Table 3<br />
Summary of human irritation studies.<br />
Method<br />
Dose<br />
(%)<br />
Vehicle Results References<br />
Maximization 10 Petrolatum No irritation RIFM (1976b)<br />
(pre-test)<br />
Phototoxicity 10 1:1 Ethanol/acetone No irritation RIFM (1983)<br />
(control)<br />
HRIPT (pre-test) 2 Dimethyl phthalate No irritation RIFM (1969)<br />
HRIPT (pre-test) 5 Alcohol SDA 39C No irritation RIFM (1971a)<br />
HRIPT (pre-test) 5 Alcohol SDA 39C No irritation RIFM (1972)<br />
4.2.1. Human studies (see Table 3)<br />
In an irritation screen <strong>for</strong> a maximization test, 10% 2,6-dimethyl-2-heptanol<br />
in petrolatum was applied to the <strong>for</strong>earms or<br />
backs of 25 subjects <strong>for</strong> 48 h under occlusion. No irritation was observed<br />
(RIFM, 1976b).<br />
Irritation was assessed during an associated phototoxicity<br />
study. Six healthy female volunteers, 20–40 years old were used.<br />
The vehicle was 1:1 ethanol/acetone. Prior to the application of<br />
2,6-dimethyl-2-heptanol, 36 test sites (each 2 cm 2 ) were marked<br />
on the back (1.5 cm apart). 2,6-Dimethyl-2-heptanol was then applied<br />
in a dose volume of 0.025 ml/2 cm 2 in 1:1 ethanol/acetone.<br />
The right h<strong>and</strong> test site was covered <strong>and</strong> served as an irritancy control<br />
site. No effects were observed in any of the subject’s exposed<br />
to 10% 2,6-dimethyl-2-heptanol in 1:1 ethanol/acetone without<br />
irradiation (irritancy control sites) (RIFM, 1983).<br />
A preliminary primary irritation study was conducted prior to<br />
the associated Human Repeated Insult Patch Test (HRIPT) to<br />
determine irritation potential of 2,6-dimethyl-2-heptanol. A pilot<br />
group of 10 healthy male <strong>and</strong> female subjects, ranging in age<br />
from 18 to 72 were used. The 10 subjects in the pilot group became<br />
part of the full complement of 57 subjects that started<br />
the associated HRIPT. By the end of the induction period, these<br />
10 individuals had had 11 induction applications as compared<br />
to the remaining individuals who were subjected to 10 induction<br />
applications. At 2% 2,6-dimethyl-2-heptanol no effects were observed<br />
(RIFM, 1969).<br />
Irritation was assessed with a panel of 10 volunteers during<br />
preliminary test <strong>for</strong> an HRIPT. The test patch consisted of a 1 1<br />
inch Webril swatch <strong>and</strong> 0.5 ml aliquot of 5% 2,6-dimethyl-2-heptanol<br />
in alcohol SDA 39C. A series of nine 24 h exposures over three<br />
successive weeks caused little to no irritation (RIFM, 1971a).<br />
A preliminary primary irritation study was conducted prior to<br />
the associated Repeated Insult Patch Test to determine irritation<br />
potential. Thirty-five subjects (10 males <strong>and</strong> 25 females) completed<br />
the study. The test patch was a 1 inch square of Webril<br />
swatch with 0.5 ml of 5% 2,6-dimethyl-2-heptanol in alcohol SDA<br />
39C. A series of nine 24 h exposures over three successive weeks<br />
caused little to no irritation (RIFM, 1972).<br />
4.2.2. Animal studies (see Table 4)<br />
As part of an associated acute toxicity study with a 5 g/kg neat<br />
application of 2,6-dimethyl-2-heptanol, rabbits were observed <strong>for</strong><br />
irritation. Slight redness in 2, moderate redness in 8, slight edema<br />
in 1, <strong>and</strong> moderate edema in 9 animals was observed (RIFM,<br />
1976a).<br />
2,6-Dimethyl-2-heptanol was applied to the intact <strong>and</strong> abraded<br />
skin of six rabbits. The undiluted material produced strong irritation.<br />
The Primary Irritation Index was reported as 5.13. (RIFM,<br />
1979).<br />
To determine the degree of irritation with 5% 2,6-dimethyl-2-<br />
heptanol, dermal occluded patches (0.5 ml) were applied to the<br />
clipped intact <strong>and</strong> abraded skin of three rabbits. Animals were<br />
Table 4<br />
Summary of animal irritation studies.<br />
Method<br />
Dermal<br />
application<br />
Dermal<br />
application<br />
Dermal<br />
application<br />
Phototoxicity<br />
(control)<br />
Dose<br />
(%)<br />
Species Results<br />
References<br />
100 Rabbits Slight to moderate<br />
erythema <strong>and</strong> edema<br />
RIFM (1976a)<br />
100 Rabbits Strong irritation RIFM (1979)<br />
observed<br />
5 Rabbits No irritation RIFM (1972)<br />
10 Guinea<br />
Pigs<br />
No irritation<br />
RIFM (1981a,b)
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S110–S114 S113<br />
immobilized <strong>for</strong> the 24 h exposure, <strong>and</strong> then evaluated 48 h after<br />
removal. Irritation was not observed (RIFM, 1971b).<br />
A minimum of four groups of four albino guinea pigs were patch<br />
tested to both flanks <strong>for</strong> a reaction time of 48 h. Four hours after<br />
the removal of the patches, the left flanks of the two experimental<br />
groups (A <strong>and</strong> B) were irradiated with UV-A or UV-B light. Groups C<br />
<strong>and</strong> D were controls, where C did not receive radiation <strong>and</strong> group D<br />
was not pre-treated. No reactions were observed in the control<br />
Group C where animals were treated with 10% 2,6-diemthyl-2-<br />
heptanol but not irradiated (RIFM, 1981a,b).<br />
4.3. Mucous membrane (eye) irritation<br />
Undiluted 2,6-dimethyl-2-heptanol produced strong irritation<br />
when applied to the surface of the rabbit eye. The Primary Irritation<br />
Index was reported as 29.8. Further details reported in German<br />
(RIFM, 1979).<br />
Aliquots of 0.1 ml 2,6-dimethyl-2-heptanol at 5% in alcohol SDA<br />
39C were instilled into the eyes of three healthy albino rabbits.<br />
Both the treated <strong>and</strong> control eyes were examined every 24 h <strong>for</strong><br />
4 days, then again on the 7th day. Moderate conjunctival irritation<br />
such as redness, chemosis, <strong>and</strong> discharge were observed, but returned<br />
to normal by day 7 (RIFM, 1971c).<br />
4.4. Skin sensitization<br />
4.4.1. Human studies<br />
4.4.1.1. Induction studies (see Table 5).<br />
4.4.1.2. Human repeated insult patch test. Human Repeated Insult<br />
Patch Tests (HRIPT) were conducted to determine if 2,6-dimethyl-2-heptanol<br />
would induce dermal sensitization in human<br />
volunteers. Patches were applied to the inner surface of the right<br />
<strong>and</strong> left deltoid area of each subject. Patches were occluded <strong>and</strong> remained<br />
in place <strong>for</strong> 48 h. The patches were then removed <strong>and</strong> read<br />
<strong>for</strong> any reactions. Alternating rotation of the sites was made <strong>for</strong> a<br />
total of 10 applications. A 2-week rest period followed the application<br />
of the last patch. After the rest period, the challenge patch was<br />
applied in the identical manner that the previous patches were applied,<br />
except that the test patch was applied in duplicate, one to<br />
the inner surface of each deltoid area. Patches remain in place <strong>for</strong><br />
48 h after which time they were removed <strong>and</strong> scored <strong>for</strong> reactions.<br />
Fifty-three subjects (35 female <strong>and</strong> 18 male) ranging in age<br />
from 18 to 72, completed the study. 2,6-Dimethyl-2-heptanol<br />
(0.5 cc) in dimethyl phthalate was applied to individual absorbent<br />
patches. At 72 <strong>and</strong> 144 h readings were made to detect any delayed/retarded<br />
responses. Five minor adhesive tape reactions were<br />
recorded but not repeated during the challenge tests. There were<br />
no sensitization reactions observed in any of the 53 subjects during<br />
the challenge phase of the study. Under the conditions of the study,<br />
2% 2,6-dimethyl-2-heptanol in dimethyl phthalate was not considered<br />
a sensitizer in humans subjects (RIFM, 1969).<br />
A1 1 inch Webril swatch with 0.5 ml of 5% 2,6-dimethyl-2-<br />
heptanol was applied to the upper arms of 45 subjects (33 female,<br />
12 male) ranging in age from 16 to 60. There were no sensitization<br />
reactions observed in any of the 45 subjects during the challenge<br />
Table 5<br />
Summary of human skin sensitization studies.<br />
Test method Test concentration Results References<br />
HRIPT 2 0/53 RIFM (1969)<br />
HRIPT 5 0/10 RIFM (1971)<br />
0/35 RIFM (1972)<br />
MAX 10 0/25 RIFM (1976a)<br />
phases of these studies. Under these conditions, 5% 2,6-dimethyl-<br />
2-heptanol in alcohol SDA 39C was not considered a sensitizer in<br />
humans subjects (RIFM, 1971b, 1972).<br />
4.4.2. Maximization studies<br />
A human maximization (MAX) test was conducted on 25 healthy<br />
volunteers (19 female <strong>and</strong> 6 males), ages 18–43 years old. Application<br />
was on the volar <strong>for</strong>earm or back of all subjects <strong>for</strong> five alternate<br />
days, 48 h periods. The patch site was pre-treated <strong>for</strong> 24 h with 2.5%<br />
aqueous SLS under occlusion. Following a 10-day rest period, a challenge<br />
patch of 10% 2,6-dimethyl-2-heptanol was applied to a different<br />
site <strong>for</strong> a 48 h period under occlusion. Prior to challenge, 5–10%<br />
SLS was applied to the site <strong>for</strong> one hour be<strong>for</strong>e application of 2,6-dimethyl-2-heptanol.<br />
The challenge site was read at patch removal<br />
<strong>and</strong> 24 h thereafter. There were no instances of contact sensitization<br />
by 2,6-dimethyl-2-heptanol (RIFM, 1976a).<br />
4.4.2.1. Cross-sensitization. No data available on this material.<br />
4.4.3. Diagnostic studies<br />
No data available on this material.<br />
4.4.4. Animal studies<br />
4.4.4.1. Maximization test. A guinea pig maximization test according<br />
to the Kligman (1969) method was conducted. Induction consisted<br />
of a series of six intradermal injections of 10% 2,6-<br />
dimethyl-2-heptanol with <strong>and</strong> without FCA, followed six to eight<br />
days later with a 48 h occluded patch application. Animals were<br />
challenged 12–14 days later by an occluded 24 h (20% in acetone)<br />
patch application. Reactions were read 24 <strong>and</strong> 48 h after patch removal.<br />
Positive reactions were not observed (Watanabe et al.,<br />
1988).<br />
4.4.4.2. Local Lymph Node Assay (LLNA). No data available on this<br />
material.<br />
4.5. Phototoxicity <strong>and</strong> photoallergy<br />
4.5.1. Phototoxicity<br />
4.5.1.1. Human studies. A test was per<strong>for</strong>med on six female volunteers<br />
to determine the phototoxic potential of 2,6-dimethyl-2-<br />
heptanol. The light source was a bank of four ‘blacklight’ fluorescent<br />
tubes with an emission spectrum of 320–400 mm housed in<br />
a reflector unit. Prior to the application 36 test sites (2 cm 2 ) with<br />
a 1.5 separation between each were marked on the back using a<br />
metal stamp <strong>and</strong> Gentian Violent solution. The sites were loaded<br />
by micro-pipette with the test material at a dose of 0.25 ml per<br />
2cm 2 area. Thirty minutes later the sites were exposed to UV A-<br />
irradiation. Observations were made at 4, 24, 48, <strong>and</strong> 72 h after<br />
the application. No evidence was noted to indicate that at a concentration<br />
of 10% the material will produce a phototoxic reaction<br />
in humans (RIFM, 1983).<br />
4.5.1.2. Animal studies. A minimum of four groups of four albino<br />
guinea pigs were patch tested on both flanks <strong>for</strong> a reaction time<br />
of 48 h. Four hours after the removal of the patches, the left flanks<br />
of the two experimental groups (A <strong>and</strong> B) were irradiated with UV-<br />
A or UV-B light. Groups C <strong>and</strong> D were controls, where C did not receive<br />
radiation <strong>and</strong> group D was not pre-treated. The light sources<br />
were both Westinghouse FS 40. The ‘‘black lamp” had a spectrum<br />
between 320 <strong>and</strong> 400 nm <strong>and</strong> a radiation time of 30 min; whereas<br />
the ‘‘sunlamp” had a spectrum of 280–370 nm <strong>and</strong> radiation time<br />
of 15 min. Skin reactions were measured 4, 24, <strong>and</strong> 48 h after radiation.<br />
Slight irritation was observed 4 h after application of 10%<br />
2,6-dimethyl-2-heptanol in ethanol in 1/8 animals in Group A, B<br />
<strong>and</strong> D. However, by 48 h all irritation had cleared (RIFM, 1981a).
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D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S110–S114<br />
4.5.2. Photoallergy<br />
4.5.2.1. Human studies. No data available on this material.<br />
4.5.2.2. Animal studies. Guinea pigs of both sexes, divided in groups<br />
of eight animals each, were shaved on the upper dorsal area. About<br />
one hour later, 0.1 ml of 10% 2,6-dimethyl-2-heptanol in rectified<br />
alcohol was applied to 8 cm 2 of the test area. After this pretreatment,<br />
the animals were exposed to the UV B-irradiation <strong>for</strong> 15 0<br />
<strong>and</strong> thereafter to UV A-irradiation <strong>for</strong> 4 h (Westinghouse black<br />
light tubes) from a distance of 25 cm. The application of the test<br />
material <strong>and</strong> the following irradiation were per<strong>for</strong>med every second<br />
day, a total of nine times in 18 days. Observations <strong>for</strong> irritation<br />
were made 24 h after each application. After a 10-day rest period<br />
the guinea pigs were again shaved on both flanks <strong>and</strong> the test area<br />
was marked. A 0.025 ml sample was applied to a 2 cm 2 area. Then<br />
only the left flank was irradiated. Observations were made <strong>and</strong> 24<br />
<strong>and</strong> 48 h after the challenge. At 10% 2,6-dimethyl-2-heptanol in<br />
rectified alcohol showed no photosensitizing potential under the<br />
conditions of this test (RIFM, 1981b).<br />
4.6. Absorption, distribution <strong>and</strong> metabolism<br />
No data available on this material.<br />
4.7. Repeated dose toxicity<br />
No data available on this material.<br />
4.8. Reproductive <strong>and</strong> developmental toxicity<br />
No data available on this material.<br />
4.9. Genotoxicity<br />
No data available on this material.<br />
4.10. Carcinogenicity<br />
No data available on this material.<br />
This individual <strong>Fragrance</strong> Material Review is not intended as a<br />
st<strong>and</strong>-alone document. Please refer to A Safety Assessment of<br />
Branched Chain Saturated Alcohols When Used as <strong>Fragrance</strong> Ingredients<br />
(Belsito et al., 2010) <strong>for</strong> an overall assessment of this<br />
material.<br />
Conflict of interest statement<br />
This research was supported by the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong><br />
Materials, an independent research institute that is funded<br />
by the manufacturers of fragrances <strong>and</strong> consumer products containing<br />
fragrances. The authors are all employees of the <strong>Research</strong><br />
<strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials.<br />
References<br />
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,<br />
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chain<br />
saturated alcohols when used as fragrance ingredients. <strong>Food</strong> Chem. Toxicol. 48<br />
(S4), S1–S46.<br />
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:<br />
providing estimates <strong>for</strong> safety evaluation. Regul. Toxicol. Pharm. 36, 246–252.<br />
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface<br />
Suite <strong>for</strong> Microsoft Ò Windows, v 4.00 or insert version used]. United States<br />
Environmental Protection Agency, Washington, DC, USA.<br />
Ford, R.A., Api, A.M., Letizia, C.S., 1992. Monographs on fragrance raw materials, 2,6-<br />
dimethyl-2-heptanol. <strong>Food</strong> Chem. Toxicol. 30 (Suppl.), 23.<br />
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria <strong>for</strong><br />
development of a database <strong>for</strong> safety evaluation of fragrance ingredients. Regul.<br />
Toxicol. Pharm. 31, 166–181.<br />
IFRA (International <strong>Fragrance</strong> Association), 2004. Use Level Survey, August 2004.<br />
IFRA (International <strong>Fragrance</strong> Association), 2007. Volume of Use Survey, February<br />
2007.<br />
Kligman, A.M., 1969. The identification of contact allergens by animal assay. The<br />
guinea pig maximization test. J. Invest. Dermatol. 52 (3), 268–276.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1969. Sensitization <strong>and</strong><br />
irritation studies of 2,6-dimethyl-2-heptanol. Unpublished report from<br />
Givaudan, 30 June. Report number 41345. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1971a. Eye irritation study<br />
with 2,6-dimethyl-2-heptanol in rabbits. Unpublished report from International<br />
Flavors <strong>and</strong> <strong>Fragrance</strong>s, Report number 53500. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1971b. Repeated insult patch<br />
test with 2,6-dimethyl-2-heptanol. Unpublished report from International<br />
Flavors <strong>and</strong> <strong>Fragrance</strong>s, Report number 53498. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1971c. Skin irritation study<br />
with 2,6-dimethyl-2-heptanol in rabbits. Unpublished report from International<br />
Flavors <strong>and</strong> <strong>Fragrance</strong>s, Report number 53501. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1972. Repeated insult patch<br />
test with 2,6-dimethyl-2-heptanol. Unpublished report from International<br />
Flavors <strong>and</strong> <strong>Fragrance</strong>s, Report number 53499. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1976a. Acute toxicity studies<br />
in rats, mice, rabbits <strong>and</strong> guinea pigs. RIFM report number 2019, October 08.<br />
RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1976b. Report on human<br />
maximization studies. RIFM report number 1797, November 04. RIFM,<br />
Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1979. Acute toxicity studies<br />
on 2,6-dimethyl-2-heptanol. Unpublished report from BASF, 08 February.<br />
Report number 4458. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1981a. Guinea pig assay of<br />
photosensitizing potential of 2,6-dimethyl-2-heptanol. Unpublished report<br />
from Givaudan, 09 July. Report number 41343. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1981b. Determination of<br />
phototoxicity of 2,6-dimethyl-2-heptanol in guinea pigs. Unpublished report<br />
from Givaudan, 07 April. Report number 41346. RIFM, Woodcliff Lake, NJ, USA.<br />
RIFM (<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc.), 1983. 2,6-Dimethyl-2-<br />
heptanol: Phototoxicity test on a fragrance raw material in humans.<br />
Unpublished report from Givaudan, 23 September. Report number 41344.<br />
RIFM, Woodcliff Lake, NJ, USA.<br />
Watanabe, S., Kinosaki, A., Kawasaki, M., Yoshida, T., Kaidbey, K., 1988. The contact<br />
sensitizing potential of (+)- <strong>and</strong> ( )-hydroxycitronellal. In flavors <strong>and</strong><br />
fragrances: a world perspective. Proceedings of 10th International Congress of<br />
Essential Oils, 11/86, pp. 1029–1038.
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S115–S129<br />
Contents lists available at ScienceDirect<br />
<strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong><br />
journal homepage: www.elsevier.com/locate/foodchemtox<br />
Review<br />
<strong>Fragrance</strong> material review on 2-ethyl-1-hexanol<br />
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api<br />
<strong>Research</strong> <strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA<br />
article<br />
Keywords:<br />
Review<br />
<strong>Fragrance</strong><br />
info<br />
abstract<br />
A summary of the safety data available <strong>for</strong> 2-ethyl-1-hexanol when used as a fragrance ingredient is presented.<br />
2-Ethyl-1-hexanol is a member of the fragrance structural group branched chain saturated alcohols<br />
in which the common characteristic structural element is one hydroxyl group per molecule, <strong>and</strong> a C 4<br />
to C 12 carbon chain with one or several methyl side chains. This review contains a detailed summary of all<br />
available toxicology <strong>and</strong> dermatology papers that are related to this individual fragrance ingredient <strong>and</strong> is<br />
not intended as a st<strong>and</strong>-alone document. A safety assessment of the entire branched chain saturated alcohol<br />
group will be published simultaneously with this document; please refer to Belsito et al. (2010) <strong>for</strong> an<br />
overall assessment of the safe use of this material <strong>and</strong> all other branched chain saturated alcohols in<br />
fragrances.<br />
Ó 2010 Published by Elsevier Ltd.<br />
Contents<br />
Introduction . . . .................................................................................................... S116<br />
1. Identification . . .................................................................................................... S116<br />
2. Physical properties . . . . . . . . . . . . . . . . . ................................................................................. S116<br />
3. Usage. . . . . . . . . .................................................................................................... S116<br />
4. <strong>Toxicology</strong> data .................................................................................................... S117<br />
4.1. Acute toxicity (see Table 2). .................................................................................... S117<br />
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S117<br />
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S117<br />
4.1.3. Intraperitoneal (ip) studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S117<br />
4.1.4. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S118<br />
4.2. Skin irritation. ............................................................................................... S118<br />
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S118<br />
4.2.2. Animal studies (see Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S118<br />
4.3. Mucous membrane (eye) irritation (see Table 4) ................................................................... S118<br />
4.4. Skin sensitization. ............................................................................................ S118<br />
4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S118<br />
4.4.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S119<br />
4.5. Phototoxicity <strong>and</strong> photoallergy. . ................................................................................ S119<br />
4.6. Absorption, distribution <strong>and</strong> metabolism ......................................................................... S119<br />
4.6.1. Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S119<br />
4.6.2. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S119<br />
4.6.3. Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S119<br />
4.7. Repeated dose toxicity (see Table 6) . . . .......................................................................... S120<br />
4.7.1. Two to 30-day studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S120<br />
4.7.2. Subchronic (31–90 days) studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S122<br />
4.7.3. Chronic (90+ days) studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S122<br />
4.8. Reproductive <strong>and</strong> developmental toxicity (see Table 7) .............................................................. S123<br />
4.9. Genotoxicity. ................................................................................................ S124<br />
4.9.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S124<br />
4.9.2. In vivo studies (see Table 10) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S125<br />
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.<br />
E-mail address: dmcginty@RIFM.org (D. McGinty).<br />
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.<br />
doi:10.1016/j.fct.2010.05.042
S116<br />
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S115–S129<br />
4.10. Carcinogenicity . . ............................................................................................ S125<br />
4.10.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S125<br />
4.10.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S125<br />
4.11. Miscellaneous studies (see Table 12). . . .......................................................................... S125<br />
Conflict of interest statement . . ....................................................................................... S127<br />
References . ....................................................................................................... S127<br />
Introduction<br />
This document provides a summary of the toxicologic review,<br />
including all human health endpoints, of 2-ethyl-1-hexanol when<br />
used as a fragrance ingredient. 2-Ethyl-1-hexanol (see Fig. 1; CAS<br />
Number 104-76-7) is a fragrance ingredient used in cosmetics, fine<br />
fragrances, shampoos, toilet soaps <strong>and</strong> other toiletries as well as in<br />
non-cosmetic products such as household cleaners <strong>and</strong> detergents.<br />
It is a colorless, oily liquid with mild, sweet <strong>and</strong> slightly floral-rosy<br />
odor of considerable tenacity (Arct<strong>and</strong>er, 1969). This material has<br />
been reported to occur in nature, with highest quantities observed<br />
in tea (VCF, 2009).<br />
In 2007, a complete literature search was conducted on 2-ethyl-<br />
1-hexanol. On-line toxicological databases were searched including<br />
those from the <strong>Chemical</strong> Abstract Services, [e.g. ToxCenter<br />
(which in itself contains 18 databases including <strong>Chemical</strong> Abstracts)],<br />
<strong>and</strong> the National Library of Medicine [e.g. Medline, Toxnet<br />
(which contains 14 databases)] as well as 26 additional sources<br />
(e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance<br />
companies were asked to submit all test data.<br />
The safety data on this material was last reviewed by Opdyke,<br />
1978. All relevant references are included in this document. More<br />
details have been provided <strong>for</strong> unpublished data. The number of<br />
animals, sex <strong>and</strong> strain are always provided unless they are not given<br />
in the original report or paper. Any papers in which the vehicles<br />
<strong>and</strong>/or the doses are not given have not been included in this<br />
review. In addition, diagnostic patch test data with fewer than 100<br />
consecutive patients have been omitted.<br />
1. Identification<br />
1.1. Synonyms: 2-Ethylhexanol; 1-hexanol, 2-ethyl-<br />
1.2. CAS registry number: 104-76-7.<br />
1.3. EINECS number: 203-234-3.<br />
1.4. Formula: C 8 H 18 O.<br />
1.5. Molecular weight: 130.23.<br />
1.6. JECFA (1998): The Joint FAO/WHO Expert Committee on<br />
<strong>Food</strong> Additives (JECFA No. 267) concluded that the substance<br />
does not present a safety concern at current levels of intake<br />
when used as a flavoring agent.<br />
1.7. FEMA (1970): Flavor <strong>and</strong> Extract Manufacturers’ Association<br />
states: Generally Recognized as Safe as a flavor ingredient –<br />
GRAS 4 (3151).<br />
HO<br />
Fig. 1. 2-Ethyl-1-hexanol.<br />
2. Physical properties<br />
1.1. Physical <strong>for</strong>m: Colorless, oily liquid with mild, sweet <strong>and</strong><br />
slightly floral-rosy odor.<br />
1.2. Boiling point (calculated; EPA, 2010): 188.52 °C.<br />
1.3. Flash point: 167°F;CC.<br />
1.4. Henry’s law (calculated; EPA, 2010): 0.000031 atm m 3 /mol<br />
25 °C.<br />
1.5. Log K ow (calculated): 2.73.<br />
1.6. Refractive index: no in<strong>for</strong>mation available.<br />
1.7. Specific gravity: 0.833.<br />
1.8. Vapor pressure (calculated; EPA, 2010): 0.06 mm Hg (20 °C);<br />
0.185 mm Hg (25 °C); 24.6 Pa (25 °C).<br />
1.9. Water solubility (calculated; EPA, 2010): 1379 mg/l (25 °C).<br />
1.10. UV spectra available at RIFM, peaks at 210–215 nm <strong>and</strong><br />
returns to baseline at 400 nm; minor absorption from 290–<br />
400 nm.<br />
3. Usage<br />
2-Ethyl-1-hexanol is a fragrance ingredient used in many fragrance<br />
compounds. It may be found in fragrances used in decorative<br />
cosmetics, fine fragrances, shampoos, toilet soaps <strong>and</strong> other<br />
toiletries as well as in non-cosmetic products such as household<br />
cleaners <strong>and</strong> detergents. Its use worldwide is in the region of<br />
0.1–1.0 metric tons per annum (IFRA, 2004). The reported volume<br />
of use is <strong>for</strong> 2-ethyl-1-hexanol as used in fragrance compounds<br />
(mixtures) in all finished consumer product categories. The volume<br />
of use is surveyed by IFRA approximately every four years through<br />
a comprehensive survey of IFRA <strong>and</strong> RIFM member companies. As<br />
such the volume of use data from this survey provides volume of<br />
use of fragrance ingredients <strong>for</strong> the majority of the fragrance<br />
industry.<br />
The dermal systemic exposure in cosmetic products (see Table 1)<br />
is calculated based on the concentrations of the same fragrance<br />
ingredient in ten types of the most frequently used personal care<br />
<strong>and</strong> cosmetic products (anti-perspirant, bath products, body lotion,<br />
eau de toilette, face cream, fragrance cream, hair spray, shampoo,<br />
shower gel, <strong>and</strong> toilet soap). The concentration of the fragrance<br />
ingredient in fine fragrances is obtained from examination of several<br />
thous<strong>and</strong> commercial <strong>for</strong>mulations. The upper 97.5 percentile<br />
concentration is calculated from the data obtained. This upper 97.5<br />
percentile concentration is then used <strong>for</strong> all 10 consumer products.<br />
These concentrations are multiplied by the amount of product applied,<br />
the number of applications per day <strong>for</strong> each product type,<br />
<strong>and</strong> a ‘‘retention factor” (ranging from 0.001 to 1.0) to account<br />
<strong>for</strong> the length of time a product may remain on the skin <strong>and</strong>/or<br />
likelihood of the fragrance ingredient being removed by washing.<br />
The resultant calculation represents the total consumer exposure<br />
(mg/kg/day) (Cadby et al., 2002; Ford et al., 2000).<br />
This is a conservative calculation of dermal systemic exposure<br />
because it makes the unlikely assumption that a consumer will<br />
use these 10 products containing; which are all perfumed with<br />
the upper 97.5 percentile level of the fragrance ingredient from a<br />
fine fragrance type of product (Cadby et al., 2002; Ford et al.,<br />
2000). The 97.5 percentile use level in <strong>for</strong>mulae <strong>for</strong> use in cosmet-
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S115–S129 S117<br />
Table 1<br />
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2-ethyl-1-hexanol.<br />
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient mg/kg/day b<br />
Anti-perspirant 0.5 1 1 0.01 0.02 0.000020<br />
Bath products 17 0.29 0.001 0.02 0.02 0.000001<br />
Body lotion 8 0.71 1 0.004 0.02 0.000080<br />
Eau de toilette 0.75 1 1 0.08 0.02 0.000200<br />
Face cream 0.8 2 1 0.003 0.02 0.000020<br />
<strong>Fragrance</strong> cream 5 0.29 1 0.04 0.02 0.000190<br />
Hair spray 5 2 0.01 0.005 0.02 0.000001<br />
Shampoo 8 1 0.01 0.005 0.02 0.000001<br />
Shower gel 5 1.07 0.01 0.012 0.02 0.000001<br />
Toilet soap 0.8 6 0.01 0.015 0.02 0.000001<br />
Total 0.0005<br />
a<br />
b<br />
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.<br />
Based on a 60-kg adult.<br />
ics <strong>for</strong> 2-ethyl-1-hexanol has been reported to be 0.02% (IFRA,<br />
2007), which would result in a maximum daily exposure on the<br />
skin of 0.0005 mg/kg <strong>for</strong> high end users (see Table 1).<br />
A maximum skin level is then determined <strong>for</strong> consideration of<br />
potential sensitization. The exposure is calculated as the percent<br />
concentration of the fragrance ingredient applied to the skin based<br />
on the use of 20% of the fragrance mixture in the fine fragrance<br />
consumer product (IFRA, 2007). The average maximum use level<br />
in <strong>for</strong>mulae that go into fine fragrances has been reported to be<br />
0.008% (IFRA, 2007), assuming use of the fragrance oil at levels<br />
up to 20% of the final product.<br />
4. <strong>Toxicology</strong> data<br />
4.1. Acute toxicity (see Table 2)<br />
4.1.1. Oral studies<br />
In a study with a total of 85 rats, it was determined that the<br />
lethal dose of 2-ethyl-1-hexanol by oral gavage was 3.2 g/kg<br />
(Hodge, 1943).<br />
In a structure–activity study of a large number of organic solvents,<br />
it was reported that the oral LD 50 of 2-ethyl-1-hexanol in<br />
rats was 2.049 g/kg (Nishimura et al., 1994).<br />
The acute oral LD 50 of 2-ethyl-1-hexanol in groups of five<br />
non-fasted, Carworth–Wistar male rats was reported to be 2.46<br />
(1.82–3.33) g/kg. No additional details were reported (Smyth<br />
et al., 1969).<br />
Table 2<br />
Summary of acute toxicity studies.<br />
Route Species No.<br />
animals/<br />
dose group<br />
LD 50<br />
(g/kg)<br />
References<br />
Oral Rat 5–15 3.2 Hodge (1943)<br />
Oral Rat N/A 2.049 Nishimura et al. (1994)<br />
Oral Rat 5 2.46 Smyth et al. (1969)<br />
Oral Rat N/A 7.1 Shaffer et al. (1945)<br />
Oral Rat N/A 3.2 Bar <strong>and</strong> Griepentrog<br />
(1967)<br />
Dave <strong>and</strong> Lidman (1978)<br />
Schmidt et al. (1973)<br />
Oral Rat 5 3.73 Scala <strong>and</strong> Burtis (1973)<br />
Dermal Rabbit 4 2.38 Smyth (1969)<br />
Dermal Rabbit 10 >5.0 RIFM (1977)<br />
Dermal Rabbit 4 >2.6 Scala <strong>and</strong> Burtis (1973)<br />
Intraperitoneal Rat 5–15 0.65 Hodge (1943)<br />
Intraperitoneal Rat 5 0.5– Dave <strong>and</strong> Lidman (1978)<br />
1.0<br />
Intraperitoneal Mice 5–15 0.78 Hodge (1943)<br />
In a study primarily addressing the toxicity of diethylhexyl<br />
phthalate, it was reported that the oral LD 50 of 2-ethyl-1-hexanol<br />
in 90–120 g male Wistar rats is 7.1 (5.5–9.1) g/kg. No additional<br />
details are reported (Shaffer et al., 1945).<br />
The oral LD 50 of 2-ethyl-1-hexanol in rats was reported to be<br />
3.2 g/kg. No additional details are reported (Bar <strong>and</strong> Griepentrog,<br />
1967; Dave <strong>and</strong> Lidman, 1978).<br />
The oral LD 50 of 2-ethyl-1-hexanol in rats was reported to be<br />
3.29 (2.87–3.79) g/kg (Schmidt et al., 1973).<br />
The oral LD 50 <strong>for</strong> 2-ethyl-1-hexanol in Sprague–Dawley rats (5/<br />
dose) was reported to be 3.73 g/kg. The principal clinical signs<br />
were central nervous system depression <strong>and</strong> labored respiration.<br />
The depression included inactivity, ataxia, limb sprawling, depressed<br />
righting <strong>and</strong> placement reflexes, prostration, <strong>and</strong> coma.<br />
The intensity of the signs was related to dose. The signs of effect<br />
had an early onset, <strong>and</strong> recovery was complete by the second or<br />
third day. Where deaths occurred, they were seen in the first<br />
24 h. Gross necropsy revealed some evidence of gastrointestinal<br />
irritation (Scala <strong>and</strong> Burtis, 1973).<br />
In a study to investigate the mechanism of action <strong>for</strong> induction<br />
of peroxisome proliferation by several compounds including 2-<br />
ethyl-1-hexanol, it was reported that a single dose of 100 mg/kg<br />
administered by oral gavage to Fischer 344 rats resulted in no difference<br />
from controls in hepatic acyl CoA oxidase or catalase activity<br />
5 h after dosing (Bojes <strong>and</strong> Thurman, 1994).<br />
4.1.2. Dermal studies<br />
The dermal LD 50 of 2-ethyl-1-hexanol in groups of four male albino<br />
New Zeal<strong>and</strong> rabbits was reported to be 2.38 (1.7–3.34) g/kg.<br />
No additional details are reported (Smyth et al., 1969).<br />
The dermal LD 50 of 2-ethyl-1-hexanol in 10 rabbits was reported<br />
to be >5.0 g/kg. One of 10 animals died on day 12, but the<br />
necropsy was reported to be normal in the animal that died. Skin<br />
irritation with moderate redness <strong>and</strong> edema was reported in all<br />
10 animals (RIFM, 1977).<br />
The dermal LD 50 <strong>for</strong> 2-ethyl-1-hexanol applied occlusively <strong>for</strong><br />
24 h to rabbits (4/dose) was reported to be >2.6 g/kg. There were<br />
no clinical signs indicative of systemic effects at the highest level<br />
tested. Dermal irritation was dose-dependent (Scala <strong>and</strong> Burtis,<br />
1973).<br />
4.1.3. Intraperitoneal (ip) studies<br />
In a study with 102 mice, it was determined that the lethal ip<br />
dose in mice was approximately 0.78 g/kg. 2-Ethyl-1-hexanol<br />
was also administered to 101 rats as ip injections to determine<br />
an LD 50 of 0.65 g/kg. Clinical signs included irregular gait, dragging<br />
of hind limbs, gasping without cyanosis, insensibility <strong>and</strong> sleepiness<br />
at high doses. The 2-ethyl-1-hexanol was rapidly anaesthetic<br />
in mice as well as rats (Hodge, 1943).
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Dave <strong>and</strong> Lidman (1978) reported a literature value from the<br />
H<strong>and</strong>book of <strong>Toxicology</strong> of 0.65 g/kg <strong>for</strong> the ip LD 50 of 2-ethyl-1-<br />
hexanol in rats. In a separate study, Sprague–Dawley rats (5/sex/<br />
dose) were given undiluted 2-ethyl-1-hexanol at doses of 0.05,<br />
0.1, 0.5, 1.0, or 5.0 g/kg. Observations were made continuously over<br />
14-days. The ip LD 50 was reported to be between 0.5 <strong>and</strong> 1.0 g/kg.<br />
At doses of 1.0 <strong>and</strong> 5.0 g/kg coma <strong>and</strong> death were observed in the<br />
rats within two hours. At 0.5 g/kg, the animals went into comas in<br />
5 min, but then recovered <strong>and</strong> survived throughout the experimental<br />
period. At the post-mortem examinations, no pathological<br />
changes were noted.<br />
4.1.4. Inhalation studies<br />
No deaths were reported when 10 rats, mice, <strong>and</strong> guinea pigs<br />
were exposed by whole body inhalation <strong>for</strong> 6 h to air bubbled<br />
through 2-ethyl-1-hexanol to yield a nominal chamber concentration<br />
of 227 ppm (ml/m 3 ). Clinical signs indicated moderate local<br />
irritation <strong>and</strong> slight to moderate systemic effects. Local irritation<br />
involved the mucous membranes of the eyes, nose, throat, <strong>and</strong><br />
respiratory passages <strong>and</strong> was manifest as blinking, lacrimation,<br />
preening, nasal discharge, salivation, gasping, <strong>and</strong> chewing movements.<br />
Responses were temporary <strong>and</strong> all animals had recovered<br />
within 1 h after termination of exposure. Gross necropsy findings<br />
were confined to areas of slight hemorrhage in the lungs. All other<br />
tissues <strong>and</strong> organs were normal in appearance (Scala <strong>and</strong> Burtis,<br />
1973).<br />
4.2. Skin irritation<br />
4.2.1. Human studies<br />
In a maximization test pre-screen, 2-ethyl-1-hexanol at 4% was<br />
applied to the backs of 29 healthy male volunteers <strong>for</strong> 48 h under<br />
occlusion. No subject had any irritation (RIFM 1976).<br />
4.2.2. Animal studies (see Table 3)<br />
Uncovered application of undiluted 2-ethyl-1-hexanol to the<br />
clipped skin on the underbelly of five rabbits <strong>for</strong> 24 h produced<br />
irritation Grade 3 (moderate) on a 10-Grade scale with Grade 2<br />
representing the least visible capillary injection from undiluted<br />
material, Grade 6 representing necrosis from undiluted material,<br />
<strong>and</strong> Grade 10 representing necrosis from a 0.01% solution with propylene<br />
glycol or water (Smyth et al., 1969).<br />
In an acute dermal toxicity test in which 0.10, 0.316. 1.00, <strong>and</strong><br />
3.16 mg/kg of undiluted 2-ethyl-1-hexanol was applied occlusively<br />
<strong>for</strong> 24 h to the clipped intact abdominal skin of rabbits, 2-ethyl-1-<br />
hexanol was reported to cause moderate dermal irritation (Scala<br />
<strong>and</strong> Burtis, 1973).<br />
In an acute dermal toxicity test in which 5 g/kg was applied to the<br />
skin of rabbits, moderate redness <strong>and</strong> edema was observed in all 10<br />
treated animals. No additional details are reported (RIFM, 1977).<br />
4.3. Mucous membrane (eye) irritation (see Table 4)<br />
2-Ethyl-1-hexanol was reported to be a severe eye irritant when<br />
applied undiluted in a 0.1 ml dose to the left eye of each of six<br />
Table 3<br />
Summary of animal irritation studies.<br />
Method Dose (%) Species Reactions References<br />
Patch test 100 Rabbits Moderate Smyth et al. (1969)<br />
irritation<br />
Patch test 100 Rabbits Moderate Scala <strong>and</strong> Burtis (1973)<br />
irritation<br />
Patch test 100 Rabbits Moderate<br />
erythema <strong>and</strong><br />
edema<br />
RIFM (1977)<br />
rabbits. Observations were made at 1, 4, <strong>and</strong> 24 h <strong>and</strong> 2, 3, 4, <strong>and</strong><br />
7 days. Median irritation scores according to the Draize system<br />
were 19, 20, <strong>and</strong> 0 at 24 h, 72 h, <strong>and</strong> 7 days, respectively. Corneal<br />
dullness, opacity (widespread corneal opacity), vascularization,<br />
irritates, conjunctival erythema, chemosis, <strong>and</strong> discharge were all<br />
observed (Scala <strong>and</strong> Burtis, 1973).<br />
Application of 2-ethyl-1-hexanol to the eyes of rabbits produced<br />
irritation Grade 5 on a 10-Grade scale with Grade 5 representing<br />
‘‘severe burn” from 0.005 ml of undiluted material <strong>and</strong><br />
Grade 10 representing severe burn from 0.5 ml of a 1% solution<br />
with propylene glycol or water (Smyth et al., 1969; Carpenter et<br />
al., 1946).<br />
In a TSCA 8(e) submission, it was reported that 2-ethyl-1-hexanol<br />
produced persistent corneal effects in rabbits (EPA, 1991,<br />
1992).<br />
Draize rabbit eye irritation scores of 9, 30, 39, 35, <strong>and</strong> 51 were<br />
reported <strong>for</strong> 1%, 3%, 10%, 30%, <strong>and</strong> 100% 2-ethyl-1-hexanol, respectively,<br />
in a study designed to evaluate the predictive value of<br />
changes in corneal thickness <strong>for</strong> quantitating eye irritation<br />
(Kennah et al., 1989).<br />
Schmidt et al. (1973) conducted an eye irritation study in rabbits<br />
with a single application of 2-ethyl-1-hexanol, undiluted or<br />
in solution with oil at 50%, 25%, or 12.5%. Reactions were graded<br />
after 18–24 h. There were no effects on the cornea <strong>for</strong> all concentrations,<br />
<strong>and</strong> at 12.5%. Conjunctival redness, swelling, lacrimation,<br />
<strong>and</strong> discharge were observed at remaining concentrations. These<br />
effects did not reverse within 96 h with the undiluted concentration<br />
(Schmidt et al., 1973).<br />
4.4. Skin sensitization<br />
4.4.1. Human studies<br />
4.4.1.1. Induction studies.<br />
4.4.1.1.1. Human repeated insult patch test (HRIPT). No in<strong>for</strong>mation<br />
available.<br />
4.4.1.1.2. Maximization studies. In a human maximization study<br />
involving 29 subjects, 2-ethyl-1-hexanol was applied in petrolatum<br />
at 4% under occlusion to the <strong>for</strong>earms <strong>for</strong> a total of five alternate<br />
days, 48 h periods. Each application was preceded by a 24 h<br />
occlusive treatment of the patch sites with 5% aqueous sodium lauryl<br />
sulfate. Following a 10–14 day rest period, challenge patches<br />
were applied to fresh sites on the scapular back under occlusion<br />
<strong>for</strong> 48 h. The challenge sites were pretreated <strong>for</strong> 30 min with a<br />
5% aqueous sodium lauryl sulfate solution. Challenge sites were<br />
evaluated at 48 <strong>and</strong> 72 h, there were no positive reactions to 2-<br />
ethyl-1-hexanol (RIFM, 1976).<br />
Table 4<br />
Summary of eye irritation studies.<br />
Dose (%) Vehicle Reactions References<br />
100 – Severe eye irritant Scala <strong>and</strong> Burtis<br />
(1973)<br />
100 – Severe burn Smyth et al.<br />
(1969)<br />
Carpenter <strong>and</strong><br />
Smyth (1946)<br />
N/A N/A Persistent corneal effects EPA (1992)<br />
100, 30, 10,<br />
3, or 1<br />
PEG a Eye irritation observed at all<br />
concentrations<br />
Kennah et al.<br />
(1989)<br />
100, 50, 25,<br />
12.5<br />
N/A No effects to the cornea<br />
Conjunctival redness, swelling,<br />
lacrimation, <strong>and</strong> discharge<br />
100%: not reversed at 96h<br />
12.5%: no effects observed<br />
Schmidt et al.<br />
(1973)<br />
a<br />
PEG, polyethylene glycol.
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4.4.1.1.3. Cross-sensitization. No in<strong>for</strong>mation available.<br />
4.4.1.1.4. Diagnostic studies. No in<strong>for</strong>mation available.<br />
4.4.2. Animal studies<br />
No in<strong>for</strong>mation available.<br />
4.5. Phototoxicity <strong>and</strong> photoallergy<br />
No in<strong>for</strong>mation available.<br />
4.6. Absorption, distribution <strong>and</strong> metabolism<br />
4.6.1. Absorption<br />
In a comparison of in vitro percutaneous absorption in rat <strong>and</strong><br />
human skin (n = 12 <strong>for</strong> rat <strong>and</strong> human skin), it was reported that<br />
the absorption rates were 0.22 ± 0.09 <strong>and</strong> 0.038 ± 0.014 mg/cm 2 /h<br />
in rat <strong>and</strong> human skin. The permeability constants were 2.59 ±<br />
1.10 10 4 cm/h <strong>for</strong> rats <strong>and</strong> 4.54 ± 1.66 10 5 cm/h <strong>for</strong> humans.<br />
The ratio of the permeability constants (rat/human) of 5.78 indicates<br />
that 2-ethyl-1-hexanol penetrated full thickness rat skin<br />
more rapidly than it penetrated human stratum corneum (Barber<br />
et al., 1992).<br />
Dermal absorption in the rat was determined to be 5.2% of a<br />
dose of 1000 mg 2-ethyl-1-hexanol/kg body weight applied <strong>for</strong><br />
6 h. An absorption rate of 0.57 mg/cm 2 /h <strong>and</strong> a terminal half-life<br />
of 77 h were calculated (Deisinger et al., 1994).<br />
4.6.2. Distribution<br />
No in<strong>for</strong>mation available.<br />
4.6.3. Metabolism<br />
4.6.3.1. In vivo studies in animals. Single oral gavage administration<br />
of 14 C labeled 2-ethyl-1-hexanol was given to Fischer 344 rats (4/<br />
group) at 50 mg/kg so that absorption, distribution, metabolism,<br />
<strong>and</strong> elimination (ADME) could be studied. A repeated oral dose<br />
of 50 mg/kg (unlabeled 2-ethyl-1-hexanol) was also given to rats<br />
<strong>for</strong> 14 consecutive days. On the final (15th day) the rats were given<br />
a 50 mg/kg dose of 14 C labeled 2-ethyl-1-hexanol. All applications<br />
were neat. The oral doses were eliminated rapidly, predominantly<br />
in urine <strong>and</strong> feces. Urinary excretion accounted <strong>for</strong> 56–60% of the<br />
administered dose, with all but about 2% of administered dose excreted<br />
in the first 24 h. Urinary metabolites eliminated were predominately<br />
glucuronides of oxidized metabolites, including<br />
glucuronides of 2-ethyladipic acid, 2-ethylhexanoic acid, 5-hydroxy-2-ethylhexanoic<br />
acid, <strong>and</strong> 6-hydroxy-2-ethylhexanoic acid. Fecal<br />
excretion accounted <strong>for</strong> 13–15% of the dose, primarily between<br />
8 <strong>and</strong> 24 h after dosing. Sodium hydroxide breath traps accounted<br />
<strong>for</strong> 8–14% of the dose, primarily in the first 24 h. Silica gel breath<br />
traps accounted 0.25–0.28% following oral dosing. There was some<br />
evidence of metabolic saturation at the high dose, <strong>and</strong> no evidence<br />
of metabolic induction following pretreatment with unlabeled<br />
compound <strong>for</strong> 14 days. The total recovery <strong>for</strong> the low, high, <strong>and</strong> repeated<br />
doses ranged was 94–97% (Deisinger et al., 1994, 1993).<br />
Single oral gavage administration of 14 C labeled 2-ethyl-1-hexanol<br />
was given to Fischer 344 rats (4/group) at 500 mg/kg so that<br />
absorption, distribution, metabolism, <strong>and</strong> elimination (ADME)<br />
could be studied. After oral administration to rats, 69–75% of a<br />
dose of 500 mg 14 C-labeled 2-ethyl-1-hexanol/kg body weight<br />
was excreted in the urine within 96 h. About 13–15% of the dose<br />
was excreted in the feces <strong>and</strong> about the same amount was exhaled.<br />
More than 50% of the dose was excreted within 24 h (Deisinger<br />
et al., 1993, 1994).<br />
2-Ethyl-1-hexanol was efficiently absorbed following oral<br />
administration of a 14 C labeled dose <strong>and</strong> was rapidly excreted in<br />
respiratory CO 2 (6–7%), feces (8–9%), <strong>and</strong> urine (80–82%) with<br />
essentially complete elimination in 28 h. The amount of radiolabel<br />
recovered in CO 2 matched the amount of unlabeled 2-heptanone<br />
plus 4-heptanone recovered from urine in study in which both labeled<br />
<strong>and</strong> unlabeled compound were administered, suggesting<br />
that both types of metabolite may have been derived from the major<br />
urinary metabolite, 2-ethylhexanoic acid, by decarboxylation,<br />
following partial beta-oxidation. The radio-labeled CO 2 appeared<br />
not to be derived from acetate (urinary acetic acid <strong>and</strong> liver <strong>and</strong><br />
brain cholesterol were not labeled) or by reductive decarboxylation<br />
(heptane was not present). Other identified metabolites were<br />
2-ethyl-5-hydroxyhexanoic acid, 2-ethyl-5-ketohexanoic acid, <strong>and</strong><br />
2-ethyl-1,6-hexadecanoic acid. Only about 3% of the dose was excreted<br />
unchanged. In vitro incubation with mammalian alcohol<br />
dehydrogenase resulted in a V max of 0.30 lmol/min/mg protein<br />
<strong>and</strong> a K m value of 0.74 mM (Albro, 1975).<br />
In a study of DNA binding of diethylhexylphthalates <strong>and</strong> related<br />
compounds, it was reported that radio-labeled 2-ethyl-1-hexanol<br />
was not bound to hepatic DNA of Fischer 344 rats 24 h following<br />
oral gavage administration (Albro et al., 1982).<br />
It was reported that oral administration of 2.55 g of 2-ethyl-1-<br />
hexanol to a rabbit resulted in urinary excretion (24 h) of the glucuronide<br />
of alpha-ethylhexanoic acid (Kamil et al., 1953).<br />
It was reported that urinary glucuronide ester accounted <strong>for</strong><br />
86.9% of a 25 mMol dose of 2-ethyl-1-hexanol administered by gavage<br />
to a rabbit weighing approximately 3 kg (Kamil et al., 1953).<br />
In the same ADME study, two groups of Fischer 344 rats (4/<br />
group) received a 6 h dermal application (1 g/kg) of 14 C labeled<br />
2-ethyl-1-hexanol. Pyrex glass containment cells (exposure area<br />
of 2.27 cm 2 ) were covered <strong>and</strong> adhered to the clipped back of eight<br />
rats. Blood pharmacokinetics were studied on four of the eight rats.<br />
Dermal dosing resulted in only about 5% absorption of the applied<br />
dose. Dermal dosing led to a recovery of 1.41% of the dose in silica<br />
gel breath traps compared to 0.25–0.28% following oral dosing. The<br />
small portion of the dose that was absorbed dermally was eliminated<br />
primarily in the urine, with smaller amounts eliminated in<br />
the feces, <strong>and</strong> as 14 CO 2 in the breath. Urinary metabolites eliminated<br />
were predominately glucuronides of oxidized metabolites,<br />
including glucuronides of 2-ethyladipic acid, 2-ethylhexanoic acid,<br />
5-hydroxy-2-ethylhexanoic acid, <strong>and</strong> 6-hydroxy-2-ethylhexanoic<br />
acid (Deisinger et al., 1994, 1993).<br />
An i.v. injection of 2-ethyl-1-hexanol (1 mg/kg in saline) was given<br />
to two groups of Fischer 344 rats (4/group). Blood pharmacokinetics<br />
was studied on four of the eight rats; on the other four rats<br />
ADME was evaluated. Urinary excretion was rapid with 53% of the<br />
dose recovered within 8 h of dosing. The next largest portions<br />
recovered were from the sodium hydroxide breath traps at 22.9%<br />
<strong>and</strong> fecal excretion at 3.8%. The terminal half-life was estimated<br />
to be 60 h (Deisinger et al., 1993, 1994).<br />
Asano <strong>and</strong> Yamakawa (1950) reported that following a subcutaneous<br />
injection to rabbits with 11 g of 2-ethyl-1-hexanol over<br />
10 days, a volatile urinary metabolite (believed to be 2-ethylcaproic<br />
acid) <strong>and</strong> a non-volatile metabolite (believed to be the bis-pphenylphenacyl<br />
ester of 2-ethyl adipic acid) was <strong>for</strong>med. Their<br />
assessment was based on comparison of the melting points of<br />
the isolated metabolites <strong>and</strong> synthesized compounds.<br />
4.6.3.2. In vitro studies in animals (see Table 5). Primary rat hepatocyte<br />
cultures were used to compare the effects of some alkyl phthalate<br />
esters on peroxisomal enzyme activities. Linear diesters <strong>and</strong><br />
their constituent monoesters <strong>and</strong> alcohols were compared with<br />
branched chain 2-eythylhexyl derivatives. There was no significant<br />
difference between 2-ethyl-1-hexanol treated <strong>and</strong> control cells in<br />
activities of cyanide-insensitive palmitoyl-CoA oxidation, a specific<br />
peroxisomal marker. Yet, there was a six fold increase with 1 mM 2-<br />
ethyl-1-hexanol on carnitine acyl transferase activity (P < 0.01). The<br />
authors concluded that the measurement of carnitine acyl transfer-
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Table 5<br />
Summary of in vitro animal studies.<br />
Test system in vitro Species Concentration Results References<br />
Hepatocyte cultures Rat 0.2 or 1 mM (DMSO) No significant differences in peroxisomal enzyme activities Gray et al. (1983)<br />
Liver, lung, <strong>and</strong> kidney<br />
homogenates<br />
Rat 40 mg (DEHP) <strong>and</strong> 20 mg Tween<br />
80<br />
Hydrolyses DEHP to mono-(2-ethylhexyl)phthalate <strong>and</strong> 2-<br />
ethylhexanol<br />
Carter et al.<br />
(1974)<br />
ase alone was not an adequate criterion <strong>for</strong> assessing peroxisomal<br />
effects in cultured hepatocytes (Gray et al., 1983).<br />
It was reported that 2-ethyl-1-hexanol is one of the metabolites<br />
produced from diethylhexyl phthalate by rat liver, lung, <strong>and</strong> kidney<br />
homogenates (Carter et al., 1974).<br />
4.7. Repeated dose toxicity (see Table 6)<br />
4.7.1. Two to 30-day studies<br />
4.7.1.1. Dermal studies. 2-Ethyl-1-hexanol was administered by occluded<br />
patch doses to Fischer 344 rats <strong>for</strong> five days, followed by<br />
2 days untreated, followed by 4 days treated at 0, 500, or<br />
1000 mg/kg/day. Treatment-related clinical signs of toxicity were<br />
restricted to the skin at the treatment site <strong>and</strong> included exfoliation<br />
(minimal severity) at both doses <strong>and</strong> transient erythema (days<br />
4–7) (graded as barely perceptible) at the high dose. There were<br />
no differences from control in food consumption, water consumption,<br />
body weight, or weight gain. There was a statistically significant<br />
decrease in lymphocytes compared to control <strong>for</strong> females at<br />
the high dose <strong>and</strong> statistically significant increases in triglycerides<br />
<strong>for</strong> both males <strong>and</strong> females at both doses. There was a statistically<br />
significant reduction in absolute spleen weight at 1000 mg/kg/day<br />
<strong>and</strong> in females only at 500 mg/kg/day. Spleen weight relative to<br />
both body weight <strong>and</strong> brain weight were also reduced in females<br />
at both 500 <strong>and</strong> 1000 mg/kg/day. There were no other effects on<br />
absolute or relative organ weights in males. There is no discussion<br />
of gross necropsy or histopathological findings. (EPA, 1992b;<br />
Weaver et al., 1989).<br />
For 12 days, 2-ethyl-1-hexanol was applied to the shaved backs<br />
of 10 rats at 2 ml/kg body weight/day (1600 mg/kg body weight/<br />
day). Observations included a decrease in absolute <strong>and</strong> relative<br />
thymus weights, liver granulomas, bronchiectasis in the lung, renal<br />
tubular epithelial necroses, edematous heart <strong>and</strong> testes, as well as<br />
decreased spermatogenesis (Schmidt et al., 1973).<br />
4.7.1.2. Oral studies. 2-Ethyl-1-hexanol was included in a study to<br />
further investigate the relationship between peroxisome proliferation<br />
<strong>and</strong> induction of cytosolic epoxide hydrolase in mouse liver.<br />
Male C57BI/6 mice were given 10,000 ppm (1500 mg/kg body<br />
weight/day) of 2-ethyl-1-hexanol in their diet <strong>for</strong> 4 days. At this<br />
dose microsomal epoxide hydrolases were unaffected, but activity<br />
of the cytosolic epoxide hydrolases increased (Lundgren et al., 1988).<br />
In a study of the hepatic effects of DEHP <strong>and</strong> its metabolites,<br />
2-ethyl-1-hexanol was administered by oral gavage to male Wistar<br />
rats <strong>for</strong> 7 days at 850, 1335, <strong>and</strong> 1425 mg/kg/day. Livers were excised<br />
<strong>for</strong> biochemical <strong>and</strong> histological evaluations. 2-Ethyl-1-hexanol,<br />
like DEHP, resulted in decreased glucose-6-phosphatase<br />
activity. An increase in relative liver weight, biphenyl-4-hydroxylase<br />
activity, <strong>and</strong> cytochrome P-450 content per mg microsomal<br />
protein, was observed when compared to controls. Additionally,<br />
there was a similar increase in histochemical alcohol dehydrogenase<br />
activity in the centrilobular area of the liver lobule, <strong>and</strong> electronmicroscopy<br />
studies showed an increase in microbodies <strong>and</strong><br />
dilation of the endoplasmic reticulum. In contrast to DEHP,<br />
succinate dehydrogenase activity was not decreased <strong>and</strong> aniline-<br />
4-hydroxylase activity was not increased by 2-ethyl-1-hexanol<br />
treatment compared to controls (Lake, 1974, 1975).<br />
In contrast to treatment with DEHP <strong>and</strong> MEHP, treatment with<br />
2-ethyl-1-hexanol at dietary levels of 50–2500 ppm (5–250 mg/kg<br />
body weight/day) <strong>for</strong> 7 days did not prevent orotic acid induced<br />
hepatic triglyceride accumulation. Also, the hepatic enzymes involved<br />
in lipid transport <strong>and</strong> metabolism did not increase (Morton<br />
<strong>and</strong> Rubin, 1979).<br />
Fischer 344 rats (10/sex/dose) were treated by oral gavage with<br />
undiluted 2-ethyl-1-hexanol <strong>for</strong> 5 days, followed by 2 days untreated,<br />
followed by 4 days treated at 0, 100, 330, 1000, or<br />
1500 mg/kg/day. The NOEL was 100 mg/kg/d. At 100 mg/kg/day,<br />
no treatment related effects were observed <strong>for</strong> any in-life, clinical<br />
pathology, gross necropsy, or histopathology parameters. Treatment-related<br />
dose-dependent effects seen at 330 mg/kg/day <strong>and</strong><br />
higher included hypoactivity, ataxia, prostration, delayed righting<br />
reflex, muscle twitch, lacrimation, <strong>and</strong> urine stained fur. <strong>Food</strong> consumption<br />
<strong>and</strong> body weights were decreased. Total leukocytes <strong>and</strong><br />
lymphocytes <strong>and</strong> spleen weight <strong>and</strong> size were decreased. Lymphoid<br />
necrosis in the spleen <strong>and</strong> thymic atrophy <strong>and</strong> lymphoid cell degeneration<br />
in the thymus were also observed. Liver weight was increased.<br />
Stomach weight was increased <strong>and</strong> histopathological<br />
findings of the stomach included hyperkeratosis, mucosal hyperplasia,<br />
edema, exocytosis, <strong>and</strong> gastritis. Absolute <strong>and</strong> relative testes<br />
weights were decreased at the highest dose. Absolute <strong>and</strong> relative<br />
kidney weights were increased at 1000 mg/kg/day, <strong>and</strong> relative kidney<br />
weight was increased at 1500 mg/kg/day. However, there were<br />
no histopathological findings in testes or kidneys (EPA, 1992b).<br />
2-Ethyl-1-hexanol was administered to Fischer 344 rats via the<br />
drinking water continuously <strong>for</strong> 9 days at 0, 308 ppm (half-saturated)<br />
<strong>and</strong> 636 ppm (saturated). Mean intake was estimated to<br />
be 61.1 <strong>and</strong> 151.1 mg/kg/day <strong>for</strong> males <strong>and</strong> 73.4 <strong>and</strong> 173.5 mg/<br />
kg/day <strong>for</strong> females at the low <strong>and</strong> high doses, respectively. There<br />
were no clinical signs of toxicity <strong>and</strong> no differences from control<br />
in food consumption, body weight, or weight gain. There were statistically<br />
significant increases in water consumption <strong>for</strong> both dose<br />
levels. There were no alterations in hematology or clinical chemistry<br />
parameters. There were no effects on absolute or relative organ<br />
weights. Exposure of Fischer 344 rats to 2-ethyl-1-hexanol in<br />
drinking water <strong>for</strong> 9 days at the maximum possible concentration<br />
did not result in any significant toxicological changes (EPA, 1992b;<br />
Weaver et al., 1989).<br />
The administration of 2-ethyl-1-hexanol to male Swiss–Webster<br />
mice (6/group) in the diet at a concentration of 2%<br />
(2857 mg/kg body weight/day) <strong>for</strong> 10 days resulted in a significant<br />
increase in absolute liver weight, significantly raised activities of<br />
cytoplasmic <strong>and</strong> microsomal epoxide hydrolases <strong>and</strong> glutathione-<br />
S-transferase <strong>and</strong> a significant increase in the cytoplasmic <strong>and</strong><br />
microsomal protein content of the liver (Hammock <strong>and</strong> Ota, 1983).<br />
2-Ethyl-1-hexanol was microencapsulated in the diet at doses<br />
of 0.46%, 0.92%, 1.38% or 2.75% (a mean daily substance intake of<br />
500, 980, 1430, or 2590 mg/kg body weight/day in 10 males <strong>and</strong><br />
540, 1060, 1580, or 2820 mg/kg body weight/day in 10 females)<br />
<strong>for</strong> 11 days. All groups exhibited reductions in feed consumption,<br />
cholesterol, triglycerides <strong>and</strong> alanine-aminotransferases. Increased<br />
relative stomach <strong>and</strong> liver weights were also observed. Overall the<br />
authors felt the NOEL under these study conditions was less than<br />
0.46% (500, or 540 mg/kg/day) microcapsules in the feed of male<br />
<strong>and</strong> female rats (EPA, 1992c).
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Table 6<br />
Summary of repeated dose studies.<br />
Method Dose Species Results References<br />
9 day Dermal<br />
(occluded)<br />
0, 500, or 1000 mg/kg/day Rat P500 mg/kg Body weight/day: exfoliation (minimal severity),<br />
spleen weight decreased; serum triglycerides increased (females);<br />
1000 mg/kg body weight: transient erythema (days 4–7) (graded<br />
as barely perceptible), decreased absolute spleen weight,<br />
lymphocytes decreased<br />
12 day Dermal 2 ml/kg Body weight/day<br />
(1600 mg/kg body weight/<br />
day)<br />
4 day Oral (In food) 10,000 ppm (1500 mg/kg<br />
body weight/day)<br />
7 day Oral (gavage) 800, 1335, or 1425 mg/kg/<br />
day<br />
EPA (1992b)<br />
Weaver et al. (1989)<br />
Rat<br />
Absolute <strong>and</strong> relative thymus weights decreased, liver<br />
granulomas, bronchiectasis in the lung, renal tubular epithelial<br />
necroses, edematous heart <strong>and</strong> testes <strong>and</strong> decreased<br />
spermatogenesis<br />
Schmidt et al. (1973)<br />
Mice Activity of the cytosolic epoxide hydrolases increased. Lundgren et al. (1988)<br />
Rat<br />
Decreased: glucose-6-phosphatase activity<br />
Increased: liver weight, biphenyl-4-hydroxylase activity, <strong>and</strong><br />
cytochrome P-450<br />
Lake (1974, 1975)<br />
7 day Oral (In food) 5–250 mg/kg/day Rat No effects Morton <strong>and</strong> Rubin<br />
(1979)<br />
9 day Oral (gavage) 0, 100, 330, 1000, 1500 mg/ Rat NOEL 100 mg/kg/day EPA (1992b)<br />
kg/day<br />
9 day Oral (drinking<br />
water)<br />
61.1 or 151.1 mg/kg/day<br />
(males)<br />
73.4 or 173.5 mg/kg/day<br />
(females)<br />
Rat Significant increase in water consumption EPA (1992b), Weaver<br />
et al. (1989)<br />
10 days Oral (in food) 2857 mg/kg body weight/<br />
day<br />
11 day Oral (in food) 500, 980, 1430, or 2590 mg/<br />
kg/day (males)<br />
540, 1060, 1580, or<br />
2820 mg/kg/day (females)<br />
11 day Oral (gavage) Nine doses in propylene<br />
glycol of 100, 330, 1000, or<br />
1500 mg/kg/day<br />
11 day Oral (gavage) 0, 100, 330, 1000 or<br />
1500 mg/kg/day<br />
11 day Oral (gavage) Nine doses: 0, 100, 330,<br />
1000, or 1500 mg/kg body<br />
weight/day, in an aqueous<br />
emulsion in Cremophor EL<br />
Mice<br />
Rat<br />
Mice<br />
Rats <strong>and</strong> Mice<br />
B6C3F1 mice<br />
(10/sex)<br />
2857 mg/kg body weight/day: absolute liver weight, activities of<br />
cytoplasmic <strong>and</strong> microsomal epoxide hydrolase <strong>and</strong> glutathione-<br />
S-transferase <strong>and</strong> the cytoplasmic <strong>and</strong> microsomal protein<br />
content of the liver increased<br />
NOAEL < 500 (m) or 540 (f) mg/kg bodyweight/day P 500 (m) or<br />
540 (f) mg /kg/d: relative stomach weights increased females (f);<br />
triglycerides <strong>and</strong> alanine aminotransferase decreased, males (m);<br />
feed consumption significantly decreased (m)<br />
NOEL between 100 <strong>and</strong> 330 mg/kg body weight/day<br />
Toxic effects in the 330 – 1500 mg/kg dosage groups<br />
Decreased (rat) body weights at 1500 mg/kg<br />
Increased relative liver/stomach weights, <strong>and</strong> gross lesions (rats)<br />
at 1000 <strong>and</strong> 1500 mg/kg/day. Kidney weights were increased in<br />
females at 330 mg/kg/day.<br />
Systemic NOAEL 100 mg/kg body weight/day<br />
300 mg/kg body weight/day: acanthosis with hyperkeratosis in<br />
the <strong>for</strong>estomach; P 1000 mg/kg body weight/day: relative liver<br />
(males) <strong>and</strong> stomach weights (female) increased, hypertrophy of<br />
hepatocytes; 1/20 deaths.<br />
1500 mg/kg body weight/day: ataxia, lethargy, piloerection,<br />
abdominal or lateral position <strong>and</strong> loss of consciousness; clinical<br />
chemistry <strong>and</strong> hematology, no substance-related changes; 5/20<br />
deaths.<br />
Hammock <strong>and</strong> Ota<br />
(1983)<br />
EPA (1992c)<br />
EPA (1992d)<br />
Astill et al. (1996a)<br />
EPA (1992e)<br />
14 day Oral (gavage) 0–1750 mg/kg/day Rats <strong>and</strong> mice Marked toxicity at the highest dose Kieth et al. (1992)<br />
14 day Oral (gavage) 130 mg/kg/day Rat No hepatomegaly, peroxisome proliferation, hypolipidemia, or Rhodes et al. (1984)<br />
testicular atrophy<br />
21 day Oral (In food) 20 mg/kg/day Rat Decreased serum cholesterol <strong>and</strong> triglyceride levels Moody <strong>and</strong> Reddy<br />
(1982)<br />
21 day Oral 833 mg/kg/day Rat Increased liver weights Yamada (1974)<br />
21 day Oral (gavage) 950 mg/kg/day Rat Increased absolute <strong>and</strong> relative liver weights. Slightly increased Hodgson (1987)<br />
hepatic peroxisome levels <strong>and</strong> pCoA activity<br />
21 day Oral (gavage 1000, 1500 mg/kg body<br />
weight/day<br />
Rat<br />
1000 mg/kg body weight/day: 30% increase in liver-to-bodyweight<br />
ratio; peroxisome cell fraction <strong>and</strong> peroxisome density in<br />
Barber <strong>and</strong> Topping<br />
(1995)<br />
the liver increase 500 mg/kg body weight/day: mortality<br />
22 day Oral (gavage) 0, 330, 660, 930 mg/kg body Rat 930 mg/kg: body weight on day 17 decreased, mortality: 1/10 Schmidt et al. (1973)<br />
weight in sunflower oil,<br />
controls 10 ml oil/kg body<br />
weight<br />
90 day (inhaled) 15, 40, 120 ppm Rat No substance-related effects were observed NOAEL: 120 ppm Klimisch et al. (1998)<br />
91 day Oral (gavage) 0, 25, 250 or 500 mg/kg<br />
(five consecutive days a<br />
week)<br />
18 months Oral<br />
(gavage)<br />
24 months Oral<br />
(gavage)<br />
50, 200, or 750 (five<br />
consecutive days a week)<br />
50, 150, or 500 (five<br />
consecutive days a week)<br />
Rats <strong>and</strong> Mice<br />
Mice<br />
Rats<br />
NOEL: 125 mg/kg/day<br />
Decreased body weight gain, gross lesions, serum ALT activities,<br />
total protein, albumin concentration, <strong>and</strong> serum cholesterol<br />
Increased pCoA activity (rats) at 500 mg/kg<br />
Lethargy, unkemptness, reductions in body weight gain, <strong>and</strong><br />
increased mortality compared to controls<br />
Astill et al. (1996a)<br />
Astill et al. (1996b)<br />
Astill et al. (1996b)<br />
At doses of 100, 330, 1000, or 1500 mg/kg body weight/day 2-<br />
ethyl-1-hexanol (in propylene glycol) was administered nine times<br />
by gavage to 10 male <strong>and</strong> 10 female B6C3F1 mice over a period of<br />
11 days. Toxic effects, such as gross lesions in the <strong>for</strong>estomach, increased<br />
relative <strong>and</strong> absolute stomach <strong>and</strong> liver weights, or clinical<br />
signs (ataxia, lethargy, piloerection, hypothermy, <strong>and</strong> loss of
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consciousness) were observed in the 330–1500 mg/kg body<br />
weight/day dosage groups. The authors felt the NOEL was between<br />
100 <strong>and</strong> 330 mg/kg bodyweight/day (EPA, 1992d).<br />
In a preliminary study 2-ethyl-1-hexanol was administered as<br />
an aqueous emulsion by oral gavage <strong>for</strong> 11 days to 10 male <strong>and</strong> female<br />
Fischer 344 rats <strong>and</strong> B6C3F1 mice at 0, 100, 330, 1000, or<br />
1500 mg/kg/day. Clinical signs in treated animals were ataxia,<br />
lethargy, <strong>and</strong> lateral/abdominal posturing in rats (at 1000 <strong>and</strong><br />
1500 mg/kg/day) <strong>and</strong> mice (1500 mg/kg/day). One female mouse<br />
from the 1000 mg/kg/day dose group died, <strong>and</strong> 5/10 died at<br />
1500 mg/kg/day. There were no mortalities in rats. Significant decreases<br />
in mean rat body weights were observed at 1500 mg/kg on<br />
day 10. Significant increases were observed in relative liver <strong>and</strong><br />
stomach weights of both male <strong>and</strong> female rats at 1000 <strong>and</strong><br />
1500 mg/kg/day. Kidney weights were significantly increased in<br />
females at 330 mg/kg/day. Gross lesions in the rats were observed<br />
in 2/10 males at 1000 mg/kg/day <strong>and</strong> 4/10 males <strong>and</strong> 7/10 females<br />
at 1500 mg/kg/day. The dose level of 500 mg/kg/day was selected<br />
as a tolerable upper dose based on this 11 day study (Astill,<br />
1996a).<br />
Oral toxicity of 2-ethyl-1-hexanol was studied in B6C3F1 mice<br />
after administration by gavage (aqueous emulsion) <strong>for</strong> 11 days.<br />
In total, nine applications of 0, 100, 330, 1000, or 1500 mg/kg were<br />
given to 10 male <strong>and</strong> 10 female mice per group. Some toxic effects<br />
were observed, such as increases in liver <strong>and</strong> stomach weights<br />
(absolute <strong>and</strong> relative), foci in the <strong>for</strong>estomach, hyperkeratosis<br />
<strong>and</strong> focal/multifocal acanthosis, or clinical signs (ataxia, lethargy,<br />
piloerection, abdominal/lateral position, <strong>and</strong> loss of consciousness)<br />
in the 330–1500 mg/kg dosage groups. The authors reported the<br />
NOEL was between 100 <strong>and</strong> 330 mg/kg of 2-ethyl-1-hexanol<br />
(EPA, 1992e).<br />
Kieth et al. (1992) studied the dose response <strong>for</strong> peroxisome<br />
proliferation due to 2-ethyl-1-hexanol in rats <strong>and</strong> mice. Rats <strong>and</strong><br />
mice, 5/sex/dose, were dosed by oral gavage <strong>for</strong> 14 days with up<br />
to 6.74 mmol/kg (2500 mg/kg/day) diethylhexyl adipate (DEHA)<br />
or 13.5 mmol/day (1750 mg/kg/day) of 2-ethyl-1-hexanol. 2-<br />
Ethyl-1-hexanol exhibited marked toxicity in male <strong>and</strong> female rats<br />
at doses of 8 mmol/kg/day (1160 mg/kg/day) <strong>and</strong> higher; the animals<br />
were killed in extremis. Such toxicity was not noted <strong>for</strong> DEHA.<br />
Both compounds resulted in dose-dependent increased liver<br />
weights <strong>and</strong> peroxisome proliferation in both rats <strong>and</strong> mice, with<br />
DEHA being about twice as potent, on a molar basis, as 2-ethyl-<br />
1-hexanol. Since DEHA is metabolized to 2 M equivalents of 2-<br />
ethyl-1-hexanol. These data suggest that 2-ethyl-1-hexanol is the<br />
proximate peroxisome proliferator of DEHA.<br />
Rhodes et al. (1984) reported that in contrast to results from<br />
previously reported high dose studies, treatment of male Wistarderived<br />
rats by oral gavage with 1 mmol/kg/day (130 mg/kg/day)<br />
2-ethyl-1-hexanol <strong>for</strong> 14 days resulted in no hepatomegaly, peroxisome<br />
proliferation, hypolipidemia, or testicular atrophy. In contrast,<br />
diethylhexylphthalte at 1 mmol/kg/day (390 mg/kg/day)<br />
produced hepatic effects.<br />
It was reported that serum cholesterol <strong>and</strong> triglyceride levels<br />
were significantly decreased in male F-344 rats fed ground rat<br />
chow diet containing 2% v/w (20 mg/kg body weight/day) 2-<br />
ethyl-1-hexanol <strong>for</strong> three weeks (Moody <strong>and</strong> Reddy, 1982).<br />
The subacute toxicity was tested in 2-ethyl-1-hexanol <strong>for</strong> three<br />
weeks by oral administration. Five rats were dosed at 1 ml/kg<br />
(833 mg/kg) <strong>and</strong> a statistical increase (p < 0.05) in liver weight<br />
was observed (no further details given) (Yamada, 1974).<br />
Fischer 344 rats were given doses of 2-ethyl-1-hexanol at 100,<br />
320, <strong>and</strong> 950 mg/kg/day in a 21-day gavage study. There was no<br />
apparent treatment affect on food intake, although there was a significant<br />
decrease in body weight gain in the 950 mg/kg/day group.<br />
A dose-related increase in cyanide-insensitive pamitoyl CoA oxidation<br />
was observed at 320 <strong>and</strong> 950 mg/kg/day (Hodgson, 1987).<br />
Male <strong>and</strong> female rats were given 1000 mg 2-ethyl-1-hexanol/kg<br />
body weight/day by gavage <strong>for</strong> 3 weeks. The test substance caused<br />
a 30% increase in liver-to-body-weight ratio, an increase in the peroxisome<br />
cell fraction <strong>and</strong> peroxisome density in the liver (Barber<br />
<strong>and</strong> Topping, 1995).<br />
Ten rats were given 0, 330, 660, 930 mg/kg body weight in sunflower<br />
oil by gavage 5 days per week <strong>for</strong> 22 days. At the highest<br />
dose, 930 mg/kg, one animal died <strong>and</strong> body weight was decreased<br />
on day 17 (Schmidt et al., 1973).<br />
4.7.2. Subchronic (31–90 days) studies<br />
A 90 day subchronic inhalation study was per<strong>for</strong>med on Wistar<br />
rats (10/sex/group) at concentrations of 15, 40, <strong>and</strong> 120 ppm. The<br />
rats were put into an inhalation chamber of glass/steel construction<br />
(manufactured by BASF AG, Ludwigshafen Germany). Pressure<br />
( 10.2 to 10.1 P) <strong>and</strong> temperature (23.1–23.8 °C) were measured<br />
continuously. Females of the 40 <strong>and</strong> 120 ppm exposure group<br />
had a decreased body weight gain, whereas the males of the<br />
15 ppm group showed an increase. No clinical signs or mortality<br />
were observed throughout the study. The authors stated that the<br />
differences in body weight/body weight gain are incidental, not<br />
dose-related <strong>and</strong> there<strong>for</strong>e of no toxicological significance. There<br />
were no macroscopic findings attributable to the material, or increase<br />
in the cyanice-insensitive palmitoyl Co A oxidation in any<br />
treatment group. Based on the results of this test the NOAEL of inhaled<br />
2-ethyl-1-hexanol was 120 ppm (corresponding to<br />
638.4 mg/m 3 ) (Klimisch, 1998).<br />
4.7.3. Chronic (90+ days) studies<br />
Male <strong>and</strong> female F344 rats <strong>and</strong> B63F1 mice (10/sex/dose) were<br />
administered 2-ethyl-1-hexanol by oral gavage at doses of 0, 25,<br />
250, or 500 mg/kg/day <strong>for</strong> 13 weeks. One female mouse at<br />
250 mg/kg/day died during treatment, but there were no other<br />
mortalities in rats or mice. Decreased body weight gain, 7% in male<br />
<strong>and</strong> 6% in female rats, was observed at 500 mg/kg starting at week<br />
4 (males) <strong>and</strong> week 11 (females). Decreases in serum ALT activities,<br />
<strong>and</strong> serum cholesterol concentrations were observed. Males, at<br />
500 mg/kg, had a decrease in total protein <strong>and</strong> albumin concentration.<br />
Significant differences in the relative organ weights from the<br />
control rats were moderate <strong>and</strong> limited to the brain, kidney, liver,<br />
stomach, <strong>and</strong> testes at 250 <strong>and</strong> 500 mg/kg/day. Gross lesions in<br />
both rats <strong>and</strong> mice were seen at 500 mg/kg/day only. Dose-related<br />
microscopic findings were limited to the <strong>for</strong>estomach <strong>and</strong> liver at<br />
500 mg/kg/day in rats <strong>and</strong> mice. No increases in palmitoyl Coenzyme<br />
A activity were seen in the livers of any mice. Increased activity<br />
was observed in rats of the 500 mg/kg/day group. A NOEL of<br />
125 mg/kg/day was concluded (Astill, 1996a).<br />
2-Ethyl-1-hexanol was given by oral gavage to B6C3F1 mice <strong>and</strong><br />
Fischer 344 rats (50/sex) as an emulsion with Cremophor in double-distilled<br />
water. Mice received 50, 200, or 750 mg/kg/day <strong>for</strong><br />
18 months in a volume of 10 ml/kg body weight. Rats received<br />
50, 150, or 500 mg/kg/day <strong>for</strong> 24 months in a volume of 10 ml/kg<br />
body weight. Mortality in male rats (38%) was not dose related,<br />
however female mortality in the 500 mg/kg/day amounted to<br />
52% of the animals in the group. Mice showed a marked increase<br />
in male <strong>and</strong> female mortality at 750 mg/kg/day, so dosing stopped<br />
at week 78. Weight gains were significantly different from controls<br />
to treated rats at 50, 150, <strong>and</strong> 500 mg/kg/day (males), as well as<br />
150, <strong>and</strong> 500 mg/kg/day (females). Weight gains were significantly<br />
different from control to treated mice at 200, <strong>and</strong> 750 mg/kg/day<br />
(males), as well as 750 mg/kg/day (females). Male <strong>and</strong> female rats<br />
did not show any differences in food consumption, but mice had a<br />
significant decrease at 750 mg/kg/day. Clinical observations revealed<br />
poor general condition, lethargy, poor grooming, <strong>and</strong> labored<br />
breathing in rats. There were no instances of poor general<br />
condition or labored breathing in mice. Moderate increase in focal
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S115–S129 S123<br />
lesions <strong>and</strong> discolorations of the lung were observed in rats of the<br />
high dose. In the rat only the 50 mg/kg/day group was associated<br />
with small statistically significant increases in relative female<br />
stomach weight. The mice showed no changes, besides a slight increase<br />
in testes weight, in relative organ weights at 50 <strong>and</strong> 200 mg/<br />
kg/day (Astill, 1996b).<br />
4.8. Reproductive <strong>and</strong> developmental toxicity (see Table 7)<br />
In a study of potential teratogenic effects of DEHP <strong>and</strong> its<br />
metabolites, 2-ethyl-1-hexanol was administered to pregnant<br />
Wistar rats by oral gavage on gestation day 12, <strong>and</strong> fetuses were<br />
examined on day 20. A dose of 6.25 mmol/kg (1 ml/kg; 833 mg/<br />
kg) 2-ethyl-1-hexanol resulted in 2.0% fetuses with mal<strong>for</strong>mations,<br />
compared to 22.2% at 12.5 mmol/kg (2 ml/kg; 1666 mg/kg) <strong>and</strong> 0%<br />
<strong>for</strong> controls. At 1666 mg/kg, the percent survivors with hydronephrosis<br />
or mal<strong>for</strong>mations of the cardiovascular system, tail, limbs,<br />
or other were 7.8, 0, 4.9, 9.7, <strong>and</strong> 1.0, respectively (Ritter et al.,<br />
1987).<br />
In a preliminary developmental toxicity test of 60 chemicals in<br />
female CD-1 mice, it was reported that 2-ethyl-1-hexanol administered<br />
by oral gavage at 1525 mg/kg/day on gestation days 6–15 resulted<br />
in 17/49 maternal deaths, <strong>and</strong> values significantly lower<br />
than control values <strong>for</strong> maternal weight gain, viable litters, live<br />
births per litter, <strong>and</strong> fetal percent survival, birth weight <strong>and</strong> weight<br />
gain (Hardin et al., 1987).<br />
In a study of differential prenatal toxicity of a series of alcohols,<br />
2-ethyl-1-hexanol was administered by oral gavage to Wistar rats<br />
on gestation days 6 to 19 at doses of 0, 1, 5, <strong>and</strong> 10 mmol/kg/day,<br />
equivalent to 0, 130, 650, <strong>and</strong> 1300 mg/kg/day. Maternal toxicity<br />
was evident at 650 <strong>and</strong> 1300 mg/kg/day, with significant differences<br />
from control in maternal body weight on days 15 <strong>and</strong> 20.<br />
There was one death at 650 mg/kg/day attributed to gavage error.<br />
In the 1300 mg/kg/day group there were six deaths attributed to<br />
treatment, on days 9, 10, <strong>and</strong> 13. Fetuses were also affected at<br />
the maternally toxic doses, with significant differences from control<br />
in post-implantation loss, resorptions, fetal weight, number<br />
<strong>and</strong> percent fetuses <strong>and</strong> litters with mal<strong>for</strong>mations <strong>and</strong> variations,<br />
<strong>and</strong> number <strong>and</strong> percent fetuses with developmental retardations.<br />
The maternal <strong>and</strong> the fetal NOAEL in this study were 130 mg/kg/<br />
day (Hellwig <strong>and</strong> Jackh, 1997).<br />
In a study of the effects of DEHP <strong>and</strong> its major metabolites on<br />
Sertoli cells <strong>and</strong> gonocytes of 3-day old CD Sprague Dawley rats<br />
(4/group), it was reported that 2-ethyl-1-hexanol administered<br />
by oral gavage at 1.28 mmol/kg (167 mg/kg) had no effects, while<br />
DEHP <strong>and</strong> MEHP at equimolar doses resulted in large, multinucleated<br />
gonocytes <strong>and</strong> a decrease in the number of BrdU labeled Sertoli<br />
cells. (Li et al., 2000).<br />
In a study of the effects of DEHP <strong>and</strong> its metabolites on rat testis<br />
in vivo <strong>and</strong> in vitro, it was reported that oral gavage doses daily <strong>for</strong><br />
five days of 2.7 mmol/kg (350 mg/kg) of 2-ethyl-1-hexanol did<br />
not induce testicular damage in 35 day old male Sprague Dawley<br />
rats <strong>and</strong> in vitro administration of 2-ethyl-1-hexanol did not enhance<br />
germ-cell detachment from mixed primary cultures of Sertoli<br />
<strong>and</strong> germ cells from 35-day old male Sprague Dawley rats,<br />
while MEHP had effects on these parameters. 2-Ethyl-1-hexanol<br />
(200 lM <strong>for</strong> 24 or 48 h) did not result in an increase of germ-cell<br />
detachment in rat testicular-cell cultures (Gray, 1986; Gray <strong>and</strong><br />
Beam<strong>and</strong>, 1984; Sjöberg et al., 1986).<br />
Groups of 28 CD-1 Swiss mice were given >99% pure 2-ethyl-1-<br />
hexanol microencapsulated in their diet at concentrations of 0,<br />
0.009, 0.03, <strong>and</strong> 0.09% from days 0–17 of pregnancy. This corresponded<br />
to calculated doses of 0.13, 43, <strong>and</strong> 129 mg/kg body<br />
weight/day. No maternal toxicity was observed <strong>and</strong> the birth rate<br />
was 93–96% in all groups. All of the litters survived <strong>and</strong> all gestational<br />
parameters were normal. There were no external, visceral,<br />
or skeletal mal<strong>for</strong>mations <strong>and</strong> no increase in variations occurred.<br />
The authors concluded that 2-ethyl-1-hexanol plays essentially<br />
no role in the expression of DEHP-induced maternal <strong>and</strong> developmental<br />
toxicity (NTP, 1991; Price et al., 1991).<br />
2-Ethyl-1-hexanol was given to female Sprague Dawley rats (6/<br />
group) by gavage so that developmental toxicity could be evaluated.<br />
On gestation day (GD) 11.5 dosed administration of 0, 6.25,<br />
9.38, or 12.5 mmol in corn oil (0, 813, 1219, 1625 mg/kg body<br />
weight) was followed by an 8 h intubation with 32 lCi 65 Zn.<br />
Maternal food intake decreased, <strong>and</strong> the 65 Zn was retained in the<br />
liver. The percentage of resorptions was not affected. The authors<br />
concluded that 2-ethyl-1-hexanol did not elicit a profile of<br />
Table 7<br />
Summary of reproductive <strong>and</strong> developmental toxicity studies.<br />
Method Dose mg/kg body weight/day Species Results References<br />
Oral 833, <strong>and</strong> 1666 Rat 2% mal<strong>for</strong>mations (833 mg/kg)<br />
Ritter et al. (1987)<br />
22.2% mal<strong>for</strong>mations (1666 mg/kg)<br />
Oral 1525 Mouse 17/49 maternal deaths<br />
Hardin et al. (1987)<br />
Significantly lower maternal weight gain, viable litters, live births/<br />
litter, fetal survival, <strong>and</strong> fetal weight<br />
Oral 0, 130, 650, <strong>and</strong> 1300 Rat Maternal toxicity at 650 <strong>and</strong> 1300 mg/kg/day.<br />
Hellwig <strong>and</strong> Jackh (1997)<br />
Maternal <strong>and</strong> fetal NOAEL 130 mg/kg/day<br />
Oral 167 Rat No effects Li et al. (2000)<br />
Oral 350 Rat Did not induce testicular damage Sjöberg et al. (1986)<br />
Gray et al. (1984)<br />
Gray (1986)<br />
Oral 0.13, 43 <strong>and</strong> 129 CD-1 Swiss mice<br />
(28 f/group)<br />
NOAEL maternal <strong>and</strong> developmental toxicity: 129 mg/kg body weight/<br />
day but no toxic dose tested<br />
NTP (1991), Price et al.<br />
(1991)<br />
no maternal toxicity; all of the litters survived <strong>and</strong> all gestational<br />
parameters were normal.<br />
Oral 0, 813, 1219, 1625 Rat P1219 mg/kg body weight: maternal food intake decreased; 1625 mg/<br />
kg body weight: percentage of 65 Zn retained in maternal liver increase<br />
Bui et al. (1998),<br />
Taubeneck (1996)<br />
The percentage of resorptions was not affected; 1625 mg/kg body<br />
weight: percentage of 65 Zn retained in the embryos decreased<br />
Whole 850 mg/m 3 Rat No effects Nelson et al. (1989)<br />
body<br />
Dermal 0, 420, 840, 1680, 2520 Rat NOAEL was 2520 mg/kg/day Fisher et al. (1989)<br />
Tyl et al. (1992)<br />
In vitro 200 uM Rat No effect Moss et al. (1988)<br />
In vitro 200 uM Rat Did not induce dissociation of germinal cells from Sertoli Cells Gangolli (1982)
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maternal or developmental toxicity compared to that of its parent<br />
compound, DEHP (Bui et al., 1998; Taubeneck, 1996).<br />
When pregnant Sprague Dawley rats were exposed by whole<br />
body exposure 7 h per day on gestation days 1–19 to 850 mg/m 3<br />
2-ethyl-1-hexanol, the maximum vapor concentration that could<br />
be achieved without increasing exposure chamber temperature<br />
above 80° F, overall mean food consumption was decreased compared<br />
to control, but there were no significant differences in<br />
maternal weight, water intake, corpora lutea per ovary, resorptions<br />
per litter, numbers of females or males per litter, or fetal weight of<br />
females or males, <strong>and</strong> no external, visceral, or skeletal mal<strong>for</strong>mations<br />
were observed (Nelson et al., 1989).<br />
There were no developmental effects when 2-ethyl-1-hexanol<br />
was administered by occluded cutaneous application to Fischer<br />
344 rats 6 h per day on gestation days 6–15 at doses of 0, 0.5,<br />
1.0, 2.0, <strong>and</strong> 3.0 ml/kg/d (0, 420, 840, 1680, or 2520 mg/kg/day)<br />
in a range-finding study (8/group) or at 0, 0.3, 1.0, <strong>and</strong> 3.0 ml/kg/<br />
day (0, 252, 840, or 2520 mg/kg/day) in the main study (25/group).<br />
Maternal weight gain was reduced at 1680 mg/kg <strong>and</strong> 2520 mg/kg/<br />
day. Persistent exfoliation <strong>and</strong> crusting <strong>and</strong> erythema were seen in<br />
both studies at 840, 1680, <strong>and</strong> 2520 mg/kg/day. Maternal liver, kidney,<br />
thymus, spleen, adrenal, <strong>and</strong> uterine weights <strong>and</strong> gestational<br />
<strong>and</strong> fetal parameters were unaffected by treatment. There were<br />
no treatment related increases in incidence of individual or pooled<br />
external, visceral, or skeletal mal<strong>for</strong>mations or variations. The<br />
NOAELs <strong>for</strong> maternal toxicity were 252 mg/kg/day based on skin<br />
irritation <strong>and</strong> 840 mg/kg/day based on systemic toxicity. The<br />
developmental NOAEL was at least 2520 mg/kg/day, with no teratogenicity<br />
(Fisher et al., 1989; Tyl et al., 1992).<br />
It was reported that 2-ethyl-1-hexanol had no effect in vitro on<br />
lactate <strong>and</strong> pyruvate production by Sertoli cell enriched cultures<br />
derived from 28 day old Sprague Dawley rats, whereas phthalate<br />
monoesters known to cause testicular atrophy in vivo increased<br />
Sertoli cell lactate production <strong>and</strong> lactate/pyruvate ratio (Moss<br />
et al., 1988).<br />
It was reported that 200 lM 2-ethyl-1-hexanol in vitro did not<br />
induce dissociation of germinal cells from Sertoli cells in cultures<br />
of rat seminiferous tubules (Gangolli, 1982).<br />
4.9. Genotoxicity<br />
4.9.1. In vitro studies<br />
4.9.1.1. Bacterial test systems (see Table 8). In Salmonella typhimurium<br />
(strains TA98, TA100, TA1535, TA1537, <strong>and</strong> TA1538 <strong>and</strong><br />
Eschericia coli (strain WP2uvrA) 2-ethyl-1-hexanol was found to<br />
be non-mutagenic with <strong>and</strong> without addition of the S9 mix from<br />
the livers of male Sprague–Dawley rats (Shimizu et al., 1985).<br />
In a study of 34 phthalates <strong>and</strong> related chemicals, 2-ethyl-1-<br />
hexanol was found to be non-mutagenic in S. typhimurium strains<br />
TA98, TA100, TA1535, <strong>and</strong> TA1537 with <strong>and</strong> without addition of<br />
microsomes from Aroclor induced rats <strong>and</strong> Syrian hamsters (Zeiger<br />
et al., 1982).<br />
2-Ethyl-1-hexanol was found to be non-mutagenic in<br />
S. typhimurium strains TA98, TA100, TA1535, TA1537, TA 1538,<br />
<strong>and</strong> TA2637 with <strong>and</strong> without metabolic activation (Agarwal et<br />
al., 1985).<br />
Salmonella typhimurium (strains not specified), 2-ethyl-1-hexanol<br />
was found to be non-mutagenic with <strong>and</strong> without addition of<br />
rat liver microsomes (Barber et al., 1985).<br />
2-Ethyl-1-hexanol was not mutagenic in S. typhimurium (strains<br />
TA98, TA100, TA1535, TA1537, <strong>and</strong> TA1538) tested with <strong>and</strong> without<br />
addition of microsomes from Aroclor induced rats (Kirby et al.,<br />
1983).<br />
2-Ethyl-1-hexanol was found to be non-mutagenic in<br />
S. typhimurium strains TA98 <strong>and</strong> TA100 with <strong>and</strong> without addition<br />
of rat liver microsomes (Warren et al., 1982).<br />
At 500 ug/disk, 2-ethyl-1-hexanol was found to be non-mutagenic<br />
in the Rec-assay with Bacillus subtilis strains H17 <strong>and</strong> M45<br />
(Tomita et al., 1982).<br />
Urine from Sprague–Dawley rats dosed by oral gavage <strong>for</strong><br />
15 days with 1000 mg/kg 2-ethyl-1-hexanol was found to be<br />
non-mutagenic in S. typhimurium strains TA98, TA100, TA1535,<br />
TA1537, <strong>and</strong> TA1538 with <strong>and</strong> without addition of rat liver microsomes<br />
or beta-glucuronidase/arylsulfatase (DiVincenzo et al., 1983,<br />
1985).<br />
2-Ethyl-1-hexanol was found to be mutagenic S. typhimurium<br />
strain TA 100 in an 8-azaguanine resistance assay (Seed, 1982).<br />
In a study of the thermal decomposition products of phthalates<br />
<strong>and</strong> poly(vinyl) chloride, 2-ethyl-1-hexanol was reported to cause<br />
DNA damage in the Rec-assay with B. subtilis strains HA101(rec+)<br />
<strong>and</strong> Rec-4 (rec ) (Saido et al., 2003).<br />
4.9.1.2. Studies in mammalian cells (see Table 9). 2-Ethyl-1-hexanol<br />
was found to be non-mutagenic in the L5178Y TK ± mouse lymphoma<br />
cell mutagenicity assay. Doses of 0.01, 0.05, 0.25, 0.5, <strong>and</strong><br />
1.0 ul/plate representing nontoxic, toxic, <strong>and</strong>/or maximum tolerated<br />
doses were selected based on preliminary toxicity studies<br />
(Kirby et al., 1983).<br />
Table 9<br />
Summary of mammalian cell studies.<br />
Method Species Results References<br />
Mouse lymphoma cell<br />
mutagenicity assay<br />
Mouse Non-mutagenic Kirby et al.<br />
(1983)<br />
Cytogenetic assay Rat Did not induce<br />
unscheduled DNA<br />
synthesis<br />
Hodgson<br />
et al.<br />
(1982)<br />
Balb 3T3<br />
trans<strong>for</strong>mation<br />
assay<br />
Chromosomal<br />
aberration assay<br />
Rat<br />
Hamster<br />
Did not induce<br />
trans<strong>for</strong>mation<br />
Did not increase frequency<br />
of chromosomal<br />
aberrations<br />
EPA (1983)<br />
Phillips<br />
et al.<br />
(1982)<br />
Table 8<br />
Summary of bacterial studies.<br />
Method Bacterial strains Results References<br />
Ames test S. typhimurium TA 98, 100, 1535, 1537, 1538 <strong>and</strong> E. coli WP2uvrA Non-mutagenic Shimizu et al. (1985)<br />
Ames test S. typhimurium TA 98, 100, 1535, 1537 Non-mutagenic Zeiger et al. (1982)<br />
Ames test S. typhimurium TA 98, 100, 1535, 1537, 1538, 2637 Non-mutagenic Agarwal et al. (1985)<br />
Ames test S. typhimurium (unspecified) Non-mutagenic Barber et al. (1985)<br />
Ames test S. typhimurium TA 98, 100, 1535, 1537, 1538 Non-mutagenic Kirby et al. (1983)<br />
Ames test S. typhimurium TA 98, 100, Non-mutagenic Warren et al. (1982)<br />
Rec-assay B. subtilis H17 <strong>and</strong> M45 Non-mutagenic Tomita et al. (1982)<br />
Ames test S. typhimurium TA 98, 100, 1535, 1537, 1538 Non-mutagenic DiVincenzo et al. (1983), (1985)<br />
Resistance assay S. typhimurium TA 100 Mutagenic Seed (1982)<br />
Rec-assay B. subtilis HA101 (rec+) <strong>and</strong> Rec-4 (rec-) Mutagenic Saido et al. (2003)
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2-Ethyl-1-hexanol was evaluated <strong>for</strong> its ability to induce<br />
unscheduled DNA synthesis (UDS) in primary rat hepatocytes<br />
cultures prepared from Fischer 344 rats. Cells were treated simultaneously<br />
with test compound <strong>and</strong> tritiated thymidine <strong>for</strong> 1 h.<br />
2-ethyl-1-hexanol did not induce UDS in this assay (Hodgson<br />
et al., 1982, abstract).<br />
2-Ethyl-1-hexanol was tested <strong>and</strong> found to not induce trans<strong>for</strong>mation<br />
in an assay <strong>for</strong> in vitro trans<strong>for</strong>mation of Balb 3T3 cells with<br />
metabolic activation by primary rat hepatocytes obtained from<br />
Fischer 344 rats. The compound was tested over the concentration<br />
range of 96–180 nl/ml. This concentration range corresponded to<br />
approximately 31.7–72% survival in the concomitant cytotoxicity<br />
test. The positive control treatments of cyclophosphamide induced<br />
a total of 26 foci among 18 flasks; there<strong>for</strong>e, the sensitivity of the<br />
assay appeared normal (EPA, 1983).<br />
2-Ethyl-1-hexanol over a 1.5–2.8 mM concentration range did<br />
not cause a statistically significant increase in frequency of chromosomal<br />
aberrations compared to control in Chinese Hamster<br />
ovary cells (Phillips et al., 1982).<br />
4.9.2. In vivo studies (see Table 10)<br />
In the in vivo mouse micronucleus assay using the B6C3F1<br />
mouse <strong>and</strong> in the Balb 3T3 trans<strong>for</strong>mation assay, 2-ethyl-1-hexanol<br />
was found to be non-mutagenic in the presence <strong>and</strong> absence<br />
of a co-cultivated rat hepatocyte activation system (Barber et al.,<br />
1985; Astill et al., 1986).<br />
Male Fischer 344 rats were dosed by oral gavage <strong>for</strong> five consecutive<br />
days with 0.02, 0.07, <strong>and</strong> 0.21 ml/kg/day of 2-ethyl-1-hexanol.<br />
When compared to controls, there was no increase in<br />
chromatid <strong>and</strong> chromosome breaks. The mitotic index was also<br />
not affected in bone marrow cells (Putman et al., 1983).<br />
A dominant lethal study was conducted in ICR/SIM mice treated<br />
orally with 2-ethyl-1-hexanol. Dose levels of 250, 500, <strong>and</strong><br />
1000 mg/kg/day representing the MTD, were selected based on a<br />
preliminary acute toxicity study. The animals were treated by oral<br />
gavage daily <strong>for</strong> five consecutive days. After treatment, each male<br />
was housed with two virgin females per week <strong>for</strong> eight consecutive<br />
weeks to span the spermatogenic cycle. Females were sacrificed on<br />
day 14–17 of caging with males <strong>and</strong> scored <strong>for</strong> pregnancy, living<br />
fetuses, <strong>and</strong> early <strong>and</strong> late fetal deaths. Fertility indices <strong>and</strong> average<br />
numbers of dead <strong>and</strong> total implants per pregnancy were within<br />
the normal range. It was concluded that 2-ethyl-1-hexanol did not<br />
induce dominant lethal mutations after oral administration<br />
(Rushbrook et al., 1982).<br />
4.10. Carcinogenicity<br />
4.10.1. In vitro studies<br />
In a tumor initiation/promotion study of diethylhexyl phthalate<br />
<strong>and</strong> its hydrolysis products, 2-ethyl-1-hexanol was evaluated in an<br />
Table 10<br />
Summary of in vivo studies.<br />
Method Species Results References<br />
Mouse<br />
micronucleus<br />
assay<br />
Balb 3T3<br />
trans<strong>for</strong>mation<br />
assay<br />
B6C3F1<br />
mouse<br />
Rat<br />
Non-mutagenic<br />
Non-mutagenic<br />
Barber et al.<br />
(1985)<br />
Astill et al.<br />
(1986)<br />
Cytogenetic assay Rat No effects Putman et al.<br />
(1983)<br />
Dominant lethal<br />
study<br />
Mouse Did not induce dominant<br />
lethal mutations<br />
Rushbrook<br />
et al. (1982)<br />
in vitro promotion potential study with mouse epidermis-derived<br />
JB6 cells. 2-Ethyl-1-hexanol did not promote JB6 cells to anchorage<br />
independence (Ward et al., 1986).<br />
A cell trans<strong>for</strong>mation assay with BALB 3T3 cells did not induce a<br />
significant number of trans<strong>for</strong>med foci (Barber et al., 1985).<br />
4.10.2. In vivo studies<br />
2-Ethyl-1-hexanol was given to male <strong>and</strong> female rats <strong>and</strong> mice<br />
by gavage five times a week in 0.005% aqueous Cremophor EL (rats:<br />
0 (water), 0 (vehicle), 50, 150, 500 mg/kg body weight/day,<br />
24 months; mice: 0 (water), 0 (vehicle), 50, 200, 750 mg/kg body<br />
weight/day, 18 months). The incidences of carcinomas <strong>and</strong> basophilic<br />
foci in the liver increased in female mice with the dose<br />
<strong>and</strong> attained statistical significance in the highest dose group compared<br />
with the vehicle control group but not with the water control<br />
group. The time-adjusted incidence of hepatocellular<br />
carcinomas in female mice (13.1%) was outside the normal range<br />
(0–2%), but in male mice (18.8%) was within the historical control<br />
range at the testing facility (0–22%). No adenomas were observed.<br />
The number of basophilic liver foci was increased in male mice in<br />
the mid dose group only (Table 5). The authors considered the liver<br />
tumors in the mouse to be inconclusive because the incidence of<br />
hepatocarcinoma precursors did not significantly increase with<br />
the dose. Nevertheless, they concluded that 2-ethylhexanol is<br />
weakly or questionably carcinogenic <strong>for</strong> the female mouse. Under<br />
the conditions of this study 2-ethyl-1-hexanol was not oncogenic<br />
to rats. Doses of 150 <strong>and</strong> 500 mg/kg body weight/day led to reduced<br />
body weight gains <strong>and</strong> in some animals to lethargy <strong>and</strong> poor<br />
grooming which proves that the maximum tolerated dose was<br />
reached. At the end of the study the mortality was about 52% in<br />
the high dose group females <strong>and</strong> about 28% in the other groups<br />
(Table 11; Astill et al., 1996b).<br />
4.11. Miscellaneous studies (see Table 12)<br />
In studies in perfused livers from starved female Sprague–Dawley<br />
rats, 2-ethyl-1-hexanol (3 mM or 0.39 g) in the perfusion<br />
media (Krebs–Henseleit buffer pH 7.4, 37 °C saturated with 95%<br />
O 2 :5%CO 2 ) inhibited oxygen uptake in periportal, but not centrilobular<br />
regions, <strong>and</strong> caused damage primarily in the periportal regions,<br />
as reflected by trypan blue staining. 2-Ethyl-1-hexanol<br />
perfusion also resulted in lactate dehydrogenase release into the<br />
perfusion effluent. In isolated mitochondria from the treated livers,<br />
oxygen uptake was inhibited in the presence of succinate with ADP<br />
<strong>and</strong> stimulated in the presence of succinate without ADP, indicating<br />
an uncoupling of oxidative phosphorylation. It was proposed<br />
that peroxisome proliferators accumulate in the liver due to their<br />
lipophilicity where they inhibit actively respiring mitochondria<br />
in periportal regions of the liver lobule <strong>and</strong> cause local toxicity<br />
(Keller et al., 1990, 1992).<br />
In an investigation of the effect of 2-ethyl-1-hexanol on fatty<br />
acid metabolism, it was reported that rates of ketone body production<br />
by perfused livers from starved female Sprague–Dawley<br />
rats were decreased about 60% by 200 uM (0.026 g) 2-ethyl-1-<br />
hexanol in the perfusion media (Krebs–Henseleit buffer pH 7.4,<br />
37 °C saturated with 95% O 2 :5%CO 2 ). Studies were conducted<br />
to determine the site of inhibition of fatty acid oxidation. Rates<br />
of ketone body production in the presence of oleate, which requires<br />
transport of the corresponding CoA compound into the<br />
mitochondria, were reduced by 2-ethyl-1-hexanol. In contrast, ketone<br />
body production from hexanoate, which is activated in the<br />
mitochondria, was not affected by 2-ethyl-1-hexanol. Basal <strong>and</strong><br />
oleate-stimulated H 2 O 2 productions were not affected by 2-<br />
ethyl-1-hexanol, indicating that beta-oxidation was not altered<br />
by the compound. Based on these data, it was concluded that<br />
2-ethyl-1-hexanol inhibits beta-oxidation of fatty acids in
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Table 11<br />
Study of the carcinogenicity of 2-ethyl-1-hexanol administered to B6C3F1 mice by oral gavage <strong>for</strong> 18 months (Astill et al., 1996b) – liver findings.<br />
Dose (mg/kg body weight/day) Water control Vehicle control 50 mg/kg 200 mg/kg 750 mg/kg<br />
Congestion m 1/50 0/50 0/50 0/50 7/50 2<br />
f 1/50 0/50 0/50 3/50 2/50<br />
Peripheral fatty infiltration m 0/50 0/50 0/50 1/50 31/50 3<br />
f 0/50 1/50 0/50 3/50 22/50 3<br />
Basophilic foci m 4/50 4/50 5/50 12/50 1 6/50<br />
f 2/50 1/50 2/50 4/50 6/50 1<br />
Focal hyperplasia m 2/50 7/50 4/50 9/50 10/50<br />
f 1/50 0/50 3/50 4/50 1 1/50<br />
Adenomas m 0/50 0/50 0/50 0/50 1/50<br />
Carcinomas m 4/50 6/50 6/50 7/50 9/50<br />
f 1/50 0/50 1/50 3/50 5/50 1<br />
Compared with the vehicle control (Fisher’s exact test).<br />
1 p < 0.05,<br />
2 p < 0.01,<br />
3 p < 0.001, f, female; m, male.<br />
Table 12<br />
studies on the mechanism of hepatotoxicity of 2-ethyl-1-hexanol.<br />
Test system Concentration Results References<br />
Isolation of mitochondria from<br />
perfused rat livers<br />
Perfused livers<br />
Isolated cylinders of periportal <strong>and</strong><br />
pericentral regions of the liver<br />
lobule<br />
70 lM, 3 mM in the<br />
perfusion medium<br />
200 lM in the<br />
perfusion medium<br />
0.1–3 mM:<br />
incubation of plugs<br />
2-Ethyl-1-hexanol in the perfusion media: inhibition of the oxygen uptake in<br />
periportal, but not centrilobular regions; damage primarily in the periportal regions,<br />
as reflected by trypan blue staining; lactate dehydrogenase release into the perfusion<br />
effluent.<br />
Isolated mitochondria from the perfused livers: inhibition of the oxygen uptake in the<br />
presence of succinate with ADP <strong>and</strong> stimulation in the presence of succinate without<br />
ADP, indicating an uncoupling of oxidative phosphorylation.<br />
It was proposed that peroxisome proliferators accumulate in the liver due to their<br />
lipophilicity where they inhibit actively respiring mitochondria in periportal regions<br />
of the liver lobule <strong>and</strong> cause local toxicity.<br />
2-Ethyl-1-hexanol in the perfusion media: rates of ketone body production were<br />
decreased about 60%; rates of ketone body production in the presence of oleate, which<br />
requires transport of the corresponding CoA compound into the mitochondria, were<br />
reduced by 2-ethyl-1-hexanol; in contrast, ketone body production from hexanoate,<br />
which is activated in the mitochondria, was not affected by 2-ethyl-1-hexanol; basal<br />
<strong>and</strong> oleate-stimulated H 2 O 2 productions were not affected by 2-ethyl-1-hexanol,<br />
indicating that beta-oxidation was not altered by the compound;Based on these data,<br />
it was concluded that 2-ethyl-1-hexanol inhibits beta-oxidation of fatty acids in<br />
mitochondria but not in peroxisomes.<br />
Incubation of plugs with 0.1 to 3 mM 2-ethyl-1-hexanol: extensive cell damage<br />
assessed from LDH leakage in incubations at 800 lMO 2 but significantly less injury at<br />
200 lMO 2 ; Concomitantly, inhibition of urea synthesis by over 80% at 800 lMO 2 , but<br />
less than 50% at 200 lMO 2 ; Plugs isolated from both regions of the liver were affected<br />
similarly by 2-ethyl-1-hexanol <strong>and</strong> O 2 .<br />
The authors concluded that these data indicate that 2-ethyl-1-hexanol toxicity is<br />
dependent on oxygen tension in isolated sublobular regions of the liver lobule, <strong>and</strong><br />
there<strong>for</strong>e it is unlikely that drug delivery can explain the selective injury to periportal<br />
regions in studies with perfused liver.<br />
GST from rats <strong>and</strong> mice Up to 15 mM Cytosolic GST activity (substrates: 1,2-dichloro-4-nitrobenzene- or 1,2-epoxy-3-(pnitrophenoxy)-propane)<br />
was only weakly inhibited in rats (IC 50 70 mM or no<br />
inhibition up to 10 mM) <strong>and</strong> mice (IC 50 23 mM or 15 mM), in contrast to the effects of<br />
other peroxisome proliferators (e.g. DEHP, MEHP)<br />
Rat liver homogenates 2.5 to 15 mM Concentration-dependent reduction in the activities of aniline hydroxylase <strong>and</strong><br />
aminopyrine-N-demethylase<br />
Keller et al.<br />
(1990, 1991,<br />
1992)<br />
Badr et al.<br />
(1990)<br />
Liang et al.<br />
(1991)<br />
Law <strong>and</strong> Moody<br />
(1989, 1991)<br />
Agarwal et al.<br />
(1982) Seth<br />
(1982)<br />
Kupffer cells in culture Up to 0.9 mM No effect on the Kupffer cell superoxide production Rose et al.<br />
(1999)<br />
Kupffer cells in culture Up to 3 mM No effect on the cytosolic free calcium concentrations in Kupffer cells up to 2 mM<br />
(Wy-16,643 had an effect at 1,25 mM), only at 3 mM increase of the free calcium<br />
Hijioka et al.<br />
(1991)<br />
concentration<br />
Mitochondrial fraction from rat liver 1% Little inhibitory effect on mitochondrial respiration at a concentration of 1% Takahashi<br />
(1977)<br />
Cultured hepatocytes 10, 100, 500 lM Inhibition of GJIC was observed, no cytotoxicity in the tested concentration range, a<br />
NOEL <strong>for</strong> GJIC was observed, n.f.i.<br />
Lington et al.<br />
(1994)<br />
ADP, adenosine diphosphate; CoA, Coenzyme A; DEHP, di(2-ethylhexyl) phthalate; GJIC, gap junctional intercellular communication; GST, glutathione-S-transferase; MEHP,<br />
mono-(2-ethylhexyl) phthalate; n.f.i., no further in<strong>for</strong>mation; LDH, lactate dehydrogenase.
D. McGinty et al. / <strong>Food</strong> <strong>and</strong> <strong>Chemical</strong> <strong>Toxicology</strong> 48 (2010) S115–S129 S127<br />
mitochondria but not in peroxisomes. Treatment of rats ip with<br />
0.32 g/kg 2-ethyl-1-hexanol deceased plasma ketone bodies, increased<br />
hepatic triglycerides, <strong>and</strong> increased lipid predominantly<br />
in periportal regions of the liver lobule. It was concluded, data<br />
indicates that alterations in hepatic fatty acid metabolism in periportal<br />
regions of the liver lobule may be early events in peroxisome<br />
proliferation (Badr et al., 1990).<br />
To determine whether the selective toxicity of 2-ethyl-1-hexanol<br />
<strong>for</strong> the periportal region in the perfused rat liver (fasted female<br />
Sprague–Dawley rats, pretreated with phenobarbital 1 mg/l <strong>for</strong> at<br />
least 7 days) was due to local oxygen tension or drug delivery,<br />
isolated cylinders of periportal <strong>and</strong> pericentral regions of the liver<br />
lobule were collected with a micropunch following brief perfusion<br />
of the organ. Incubation of liver punch biopsy samples with<br />
0.1–3 mM (0.01–0.39 g) 2-ethyl-1-hexanol caused extensive cell<br />
damage assessed from lactose dehydrogenase (LDH) leakage in<br />
incubations at 800 uM O 2 but significantly less injury at 200 uM<br />
O 2 . Concomitantly, urea synthesis was inhibited by over 80% at<br />
800 uM O 2 , but less than 50% at 200 uM O 2 . Liver punch biopsy<br />
samples isolated from both regions of the liver were affected similarly<br />
by 2-ethyl-1-hexanol <strong>and</strong> O 2 . The authors concluded that<br />
these data indicate that 2-ethyl-1-hexanol toxicity is dependent<br />
on oxygen tension in isolated sublobular regions of the liver lobule,<br />
<strong>and</strong> there<strong>for</strong>e it is unlikely that drug delivery can explain the selective<br />
injury to periportal regions in studies with perfuse liver (Liang<br />
et al., 1991).<br />
A study was conducted to determine how peroxisome proliferators<br />
<strong>and</strong> 2-ethyl-1-hexanol, up to 15 mM, would affect mouse <strong>and</strong><br />
rat liver glutathione S-transferases (GST) in vitro. Cytosolic GST<br />
activity was only weakly inhibited in rats <strong>and</strong> mice when compared<br />
to the effects of other peroxisome proliferators (Law <strong>and</strong><br />
Moody, 1989, 1991).<br />
The in vitro effects of 2-ethyl-a-hexanol on the activity of aminopyrine<br />
N-demethylase <strong>and</strong> aniline hydroxylase were studied.<br />
Aliquots of 2.5–15 mM were used the enzyme assay. A concentration<br />
dependent reduction in the activities of aniline hydroxylase<br />
<strong>and</strong> aminopyrine-N-demthylase was observed (Agarwal et al.,<br />
1982; Seth, 1982).<br />
Kupffer cells <strong>and</strong> hepatocytes were isolated to study cell proliferation.<br />
Incubation of 2-ethyl-1-hexanol with Kupffer cells in culture<br />
up to 0.9 mM had no effect of the superoxide production<br />
(Rose et al., 1999). Furthermore, there were no effects on the cytosolic<br />
free calcium concentrations in Kupffer cells up to 2 mM. At<br />
3 mM an increase of free calcium concentration was observed,<br />
whereas, Wy-16,643 had an effect at 1.25 mM (Hijioka et al., 1991).<br />
The effects of 2-ethyl-1-hexanol at 1% on mitochondrial respiration<br />
of Wistar rat livers were investigated. Little inhibitory effects<br />
were observed (Takahashi, 1977).<br />
Inhibition of gap junctional intercellular communication (GJIC)<br />
was observed <strong>for</strong> 2-ethyl-1-hexanol in cultured hepatocytes from<br />
B 6 C 3 F 1 female mice <strong>and</strong> F344 female rats. Reversible effects were<br />
observed following the removal of the compound, <strong>and</strong> 2-ethyl-1-<br />
hexanol was not considered the most potent metabolite <strong>for</strong> inhibition<br />
to the GJIC (Lington et al., 1994).<br />
This individual <strong>Fragrance</strong> Material Review is not intended as<br />
a st<strong>and</strong>-alone document. Please refer to a safety assessment<br />
of branched chain saturated alcohols when used as fragrance<br />
ingredients (Belsito et al., 2010) <strong>for</strong> an overall assessment of this<br />
material.<br />
Conflict of interest statement<br />
This research was supported by the <strong>Research</strong> <strong>Institute</strong> <strong>for</strong><br />
<strong>Fragrance</strong> Materials, an independent research institute that is<br />
funded by the manufacturers of fragrances <strong>and</strong> consumer products<br />
containing fragrances. The authors are all employees of the <strong>Research</strong><br />
<strong>Institute</strong> <strong>for</strong> <strong>Fragrance</strong> Materials.<br />
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(Contents continued from outside back cover)<br />
D. McGinty, J. Scognamiglio,<br />
C. S. Letizia <strong>and</strong> A. M. Api<br />
D. McGinty, J. Scognamiglio,<br />
C. S. Letizia <strong>and</strong> A. M. Api<br />
D. McGinty, A. Lapczynski,<br />
J. Scognamiglio, C. S. Letizia <strong>and</strong><br />
A. M. Api<br />
D. McGinty, J. Scognamiglio,<br />
C. S. Letizia <strong>and</strong> A. M. Api<br />
D. McGinty, J. Scognamiglio,<br />
C. S. Letizia <strong>and</strong> A. M. Api<br />
S93–S96<br />
S97–S101<br />
S102–S109<br />
S110–S114<br />
S115–S129<br />
<strong>Fragrance</strong> material review on 3-methyl-1-pentanol<br />
<strong>Fragrance</strong> material review on 2-methylbutanol<br />
<strong>Fragrance</strong> materials review on isoamyl alcohol<br />
<strong>Fragrance</strong> material review on 2,6-dimethyl-2-heptanol<br />
<strong>Fragrance</strong> material review on 2-ethyl-1-hexanol
FOOD AND CHEMICAL TOXICOLOGY<br />
VOLUME 48 (2010) SUPPLEMENT 4<br />
CONTENTS<br />
A Safety Assessment of Saturated Branched Chain Alcohols when used as<br />
<strong>Fragrance</strong> Ingredients<br />
D. Belsito, D. Bickers, M. Bruze,<br />
P. Calow, H. Greim, J. M. Hanifin,<br />
A. E. Rogers, J. H. Saurat, I. G. Sipes,<br />
H. Tagami, <strong>and</strong> The RIFM Expert<br />
Panel<br />
D. McGinty, J. Scognamiglio,<br />
C. S. Letizia <strong>and</strong> A. M. Api<br />
D. McGinty, J. Scognamiglio,<br />
C. S. Letizia <strong>and</strong> A. M. Api<br />
D. McGinty, J. Scognamiglio,<br />
C. S. Letizia <strong>and</strong> A. M. Api<br />
D. McGinty, J. Scognamiglio,<br />
C. S. Letizia <strong>and</strong> A. M. Api<br />
D. McGinty, J. Scognamiglio,<br />
C. S. Letizia <strong>and</strong> A. M. Api<br />
D. McGinty, J. Scognamiglio,<br />
C. S. Letizia <strong>and</strong> A. M. Api<br />
D. McGinty, J. Scognamiglio,<br />
C. S. Letizia <strong>and</strong> A. M. Api<br />
D. McGinty, S. P. Bhatia,<br />
J. Scognamiglio, C. S. Letizia <strong>and</strong><br />
A. M. Api<br />
D. McGinty, J. Scognamiglio,<br />
C. S. Letizia <strong>and</strong> A. M. Api<br />
D. McGinty, J. Scognamiglio,<br />
C. S. Letizia <strong>and</strong> A. M. Api<br />
D. McGinty, C. S. Letizia <strong>and</strong><br />
A. M. Api<br />
D. McGinty, J. Scognamiglio,<br />
C. S. Letizia <strong>and</strong> A. M. Api<br />
S1–S46<br />
S47–S50<br />
S51–S54<br />
S55–S59<br />
S60–S62<br />
S63–S66<br />
S67–S69<br />
S70–S72<br />
S73–S78<br />
S79–S81<br />
S82–S84<br />
S85–S88<br />
S89–S92<br />
A safety assessment of branched chain saturated alcohols when used as<br />
fragrance ingredients<br />
<strong>Fragrance</strong> material review on 3,5,5-trimethyl-1-hexanol<br />
<strong>Fragrance</strong> material review on 3,7-dimethyl-7-methoxyoctan-2-ol<br />
<strong>Fragrance</strong> material review on 4-methyl-2-pentanol<br />
<strong>Fragrance</strong> material review on 2-methylundecanol<br />
<strong>Fragrance</strong> material review on 3,4,5,6,6-pentamethylheptan-2-ol<br />
<strong>Fragrance</strong> material review on isodecyl alcohol<br />
<strong>Fragrance</strong> material review on isooctan-1-ol<br />
<strong>Fragrance</strong> material review on isotridecan-1-ol (isomeric mixture)<br />
<strong>Fragrance</strong> material review on isononyl alcohol<br />
<strong>Fragrance</strong> material review on 6,8-dimethylnonan-2-ol<br />
<strong>Fragrance</strong> material review on 2-ethyl-1-butanol<br />
<strong>Fragrance</strong> material review on 2,6-dimethyl-4-heptanol<br />
(Contents continued on inside back cover)<br />
Available online at www.sciencedirect.com<br />
Fd Chem. Toxic. is indexed/abstracted in Analyt. Abstr., Aqua. Abstr.,<br />
Biosis Data., CAB Inter., CABS (Current Awareness in Biological Sciences),<br />
Cam. Sci. Abstr., Chem. Abstr. Serv., Chem. Haz. in Indus.,<br />
Curr. Cont. ISI/BIOMED Database, Curr. Cont. Sci. Cit. Ind.,<br />
Curr. Cont. SCISEARCH Data., Excerp. Med., Health & Saf. Sci. Abstr.,<br />
Ind. Med., Int. Pack., MEDLINE, Res. Alert, Tox. Abstr.<br />
http://www.elsevier.com/locate/foodchemtox<br />
ISSN 0278-6915<br />
48(S4) S1–S130 (2010)<br />
Printed by Polestar Wheatons Ltd, Exeter, UK 237