Food and Chemical Toxicology - Research Institute for Fragrance ...

Volume 48, Supplement 4, July 2010 ISSN 0278-6915
Food and
Chemical
Toxicology
Editors
J F Borzelleca
A R Boobis
A Safety Assessment of Saturated Branched Chain
Alcohols when used as Fragrance Ingredients

FOOD AND CHEMICAL TOXICOLOGY
Founding Editor
The late Leon Golberg
Editors
JOSEPH
F. BORZELLECA
Department of Pharmacology and
Toxicology, Medical College of Virginia,
Richmond, VA 23298-0613, USA
ALAN
R. BOOBIS
Section of Experimental Medicine and Toxicology,
Division of Medicine, Imperial College, Hammersmith Campus,
Ducane Road, London W12 0NN, UK
JOHN
CHRISTIAN
LARSEN
National Food Institute, Technical University of Denmark,
19 Mørkhøj Bygade, DK-2860 Søborg, Denmark
BRYAN
DELANEY
Senior Research Scientist – Toxicology, Pioneer Hi-Bred International,
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GARY
WILLIAMS
Department of Pathology, New York Medical College, Basic Science
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SAMUEL
M. COHEN
Department of Pathology and Microbiology, University of Nebraska
Medical Center, 983135 Nebraska Medical Center,
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T. F. X. COLLINS, USA
Y. P. DRAGAN, USA
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S. J. S. FLORA, India
ERGUSON, New Zealand
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W. H. GLINSMANN
LINSMANN, USA
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ACEW, Canada
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ANG, People’s Republic of China
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A Safety Assessment of Saturated Branched Chain
Alcohols when used as Fragrance Ingredients

Food and Chemical Toxicology 48 (2010) S1–S46
Contents lists available at ScienceDirect
Food and Chemical Toxicology
journal homepage: www.elsevier.com/locate/foodchemtox
Review
A safety assessment of branched chain saturated alcohols when used
as fragrance ingredients q
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 ,
I.G. Sipes i , H. Tagami j , The RIFM Expert Panel
a University of Missouri (Kansas City), c/o American Dermatology Associates, LLC, 6333 Long Avenue, Third Floor, Shawnee, KS 66216, USA
b Columbia University Medical Center, Department of Dermatology, 161 Fort Washington Ave., New York, NY 10032, USA
c Malmo University Hospital, Department of Occupational and Environmental Dermatology, Sodra Forstadsgatan 101, Entrance 47, Malmo SE-20502, Sweden
d Roskilde University, Department of Environmental, Social and Spatial Change, Isafjordvej 66, Roskilde, Denmark
e Technical University of Munich, Institute for Toxicology and Environmental Hygiene, Hohenbachernstrasse 15-17, Freising-Weihenstephan D-85354, Germany
f Oregon Health Sciences University, Department of Dermatology L468, 3181 SW Sam Jackson Park Rd., Portland, OR 97201-3098, USA
g Boston University School of Medicine, Department of Pathology and Laboratory Medicine, 715 Albany Street, L-804, Boston, MA 02118-2526, USA
h Dermatotoxicology Swiss Centre for Applied Human Toxicology, University Medical Center, Rue Michel Servet, 1211 Genève 4, Switzerland
i Department of Pharmacology, University of Arizona, College of Medicine, 1501 North Campbell Avenue, P.O. Box 245050, Tucson, AZ 85724-5050, USA
j 3-27-1 Kaigamori, Aoba-ku, Sendai 981-0942, Japan
article
info
abstract
Keywords:
Review
Safety
Fragrance ingredients
Branched chain saturated alcohols
The Branched Chain Saturated Alcohol (BCSA) group of fragrance ingredients was evaluated for safety. In
humans, no evidence of skin irritation was found at concentrations of 2–10%. Undiluted, 11 materials
evaluated caused moderate to severe eye irritation. As current end product use levels are between
0.001% and 1.7%, eye irritation is not a concern. The materials have no or low sensitizing potential. For
individuals who are already sensitized, an elicitation reaction is possible. Due to lack of UVA/UVB
light-absorbing structures, and review of phototoxic/photoallergy data, the BCSA are not expected to elicit
phototoxicity or photoallergy. The 15 materials tested have a low order of acute toxicity. Following
repeated application, seven BCSA tested were of low systemic toxicity. Studies performed on eight BCSA
and three metabolites show no in vivo or in vitro genotoxicity. A valid carcinogenicity study showed that
2-ethyl-1-hexanol is a weak inducer of liver tumors in female mice, however, the relevance of this effect
and mode of action to humans is still a matter of debate. The Panel is of the opinion that there are no
safety concerns regarding BCSA under the present levels of use and exposure.
Ó 2010 Elsevier Ltd. All rights reserved.
Contents
1. Introduction .......................................................................................................... S2
2. Chemical identity, regulatory status, and exposure . ......................................................................... S2
2.1. Rationale for grouping branched chain saturated alcohols together . ..................................................... S2
2.2. Occurrence and use. . . . . ........................................................................................ S7
2.3. Estimated consumer exposure . . . . . . . . . . . . ........................................................................ S7
3. Metabolism .......................................................................................................... S8
3.1. Primary alcohols . . . . . . . ........................................................................................ S8
3.2. Secondary alcohols . . . ............................................................................................ S8
3.3. Tertiary alcohols ................................................................................................. S8
4. Pharmacokinetics. . .................................................................................................... S8
4.1. Dermal route of exposure ........................................................................................ S8
4.2. Oral route of exposure . . ........................................................................................ S8
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:
amapi@rifm.org.
0278-6915/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.fct.2010.05.046

S2
D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
4.3. Respiratory route of exposure . ..................................................................................... S9
4.4. Parenteral route of exposure ...................................................................................... S9
5. Toxicological studies .................................................................................................. S9
5.1. Acute toxicity .................................................................................................. S9
5.2. Repeated dose toxicity ........................................................................................... S9
5.2.1. Dermal studies ........................................................................................... S9
5.2.2. Oral studies . . . . . . . . . . . ................................................................................. S10
5.2.3. Inhalation studies . . . . . . ................................................................................. S11
5.3. Mutagenicity and genotoxicity . . . . . . . . . .......................................................................... S13
5.3.1. In vitro mutagenicity studies. . . . . . . . . . . . . . ................................................................. S13
5.3.2. In vivo studies . . . . . . . . . ................................................................................. S18
5.4. Carcinogenicity . . ............................................................................................. S18
5.4.1. Cell transformation assays . . . . . . . . . . . . . . . ................................................................. S18
5.4.2. Carcinogenicity studies . . ................................................................................. S18
5.5. Reproductive and developmental toxicity .......................................................................... S20
5.5.1. Fertility . . . . . . . . . . . . . . . ................................................................................. S20
5.5.2. Developmental toxicity . . ................................................................................. S20
5.6. Skin irritation . . . ............................................................................................. S32
5.6.1. Human studies . . . . . . . . . ................................................................................. S32
5.6.2. Animal studies . . . . . . . . . ................................................................................. S32
5.7. Mucous membrane irritation . . . . . . . . . . .......................................................................... S32
5.7.1. Sensory irritation . . . . . . . ................................................................................. S32
5.7.2. Eye irritation . . . . . . . . . . ................................................................................. S33
5.8. Skin sensitization ............................................................................................. S33
5.8.1. Human studies . . . . . . . . . ................................................................................. S33
5.8.2. Animal studies . . . . . . . . . ................................................................................. S33
5.9. Phototoxicity and photoallergenicity . . . . .......................................................................... S33
5.10. Miscellaneous studies .......................................................................................... S36
6. Conclusion . . ........................................................................................................ S36
Conflict of interest statement. . . ........................................................................................ S41
References . . ........................................................................................................ S42
1. Introduction
In 2006 complete literature searches were conducted on the
branched chain saturated alcohol group of fragrance ingredients.
This document provides a risk assessment of these materials as fragrance
ingredients and is a critical evaluation of the pertinent data.
The scientific evaluation focuses on dermal exposure, which is considered
to be the primary route for fragrance materials. Where relevant,
toxicity, metabolism and biological fate data from other
exposures have been considered.
The current format includes a group summary evaluation paper
and individual Fragrance Material Reviews on discrete chemicals.
The group summary is an evaluation of relevant data
selected from the large bibliography of studies and reports on
the individual chemicals. The selected data were deemed to be
relevant based on the currency of protocols, quality of the data,
statistical significance and appropriate exposure. These are identified
in tabular form in the group summary. Details that are
provided in the tables are not always discussed in the text of
the group summary. The Fragrance Material Reviews contain a
comprehensive summary of all published reports including complete
bibliographies (McGinty et al., 2010a,b,c,d,e,f,g,h,i,j,k,l,m,n,
o,p,q).
2. Chemical identity, regulatory status, and exposure
2.1. Rationale for grouping branched chain saturated alcohols together
The group consists of 12 primary, 5 secondary and 3 tertiary
alcohols. Of these materials, three have been previously reviewed
in RIFM’s Safety Assessment on Terpene Alcohols (Belsito et al.,
2008). The names and structures of the materials reviewed are
shown in Table 1. 1 In addition, several noncyclic branched chain
alcohols used as examples here have been reviewed in other recent
RIFM publications. Information on previously reviewed substances
of this group is not presented again unless it is new or required to
evaluate remaining fragrance ingredients. The common characteristic
structural elements of the alcohols with saturated branched chain
are one hydroxyl group per molecule, a C 4 –C 12 carbon chain with
one or several methyl side chains. Two members of the group, 2-
ethyl-1-butanol and 2-ethyl-1-hexanol, contain an ethyl side chain.
One member contains a methoxy group. Metabolism studies are
lacking for this compound, however, a methoxy group is enzymatically
not readily cleaved and if it were so, another primary alcohol
group would be formed.
As the database for the alcohols under review is limited, additional
data for some metabolites of these alcohols have been used.
It was demonstrated that 4-methyl-2-pentanol, a group member, is
metabolized to 4-methyl-2-pentanone and 4-hydroxy-4-methyl-2-
pentanone is a metabolite of both substances (Gingell et al.,
2003). It can also be expected that 2,6-dimethyl-4-heptanol is
metabolized to 2,6-dimethylheptan-4-one. Therefore, studies on
pharmacokinetics, metabolism, genotoxicity and systemic toxicity
of 4-methyl-2-pentanone, 4-hydroxy-4-methyl-2-pentanone and 2,6-
dimethylheptan-4-one have been added to the database. These
materials are not used as fragrance ingredients. Due to their structural
similarity, these alcohols also share common metabolic pathways
(see below). As metabolism is crucial for pharmacokinetics
and toxicity, these alcohols or their metabolites are expected to
have the same primary target organs (liver, kidney, and blood) as
was shown for 2-ethyl-1-hexanol, isoamyl alcohol, isotridecan-1-
1 Isooctan-1-ol, isononyl alcohol, isodecyl alcohol and Isotridecan-1-ol (isomeric
mixture) are generic names for mixtures of isomers of primary branched alcohols
with an average C-number of 8, 9, 10, or 13, respectively.

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46 S3
Table 1
Material identification, summary of volume of use, and dermal exposure.
Material Synonyms Structure Worldwide metric Dermal systemic exposure
tons (annual) a in cosmetic products (mg/
kg/day)
Maximum skin
level (%) b
Subgroup: primary
3,7-Dimethyl-1-octanol c
C10H22O
CAS# 106-21-8 Dihydrocitronellol 100–1000 0.0005 d 0.02
Henry’s Law: 0.0000547 atm m 3 /mol 25 °C 1-Octanol, 3,7-dimethyl-
LogK ow : 3.9 at 35 °C Pelargol
Molecular weight: 158.29 Tetrahydrogeraniol
Vapor pressure: 0.06 mm Hg 20 °C
Water solubility: 175.4 mg/l at 25 °C
2-Ethyl-1-butanol
C 6 H 14 O
CAS# 97-95-0 1-Butanol,2-ethyl-

S4
D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
Table 1 (continued)
Material Synonyms Structure Worldwide metric Dermal systemic exposure
tons (annual) a in cosmetic products (mg/
kg/day)
Maximum skin
level (%) b
Isooctan-1-ol
C 8 H 18 O
CAS# 26952-21-6 Isooctanol

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46 S5
Subgroup: secondary
2,6-Dimethyl-4-heptanol
C9H20O
CAS# 108-82-7 Diisobutylcarbinol 10–100 0.0005 d 0.02
Henry’s Law: 0.0000412 atm m 3 /mol 25 °C 4-Heptanol,2,6-dimethyl-
LogK ow 3.08 calc 2,6-Dimethylheptan-4-ol
Molecular weight: 144.26
Vapor pressure: 0.0624 mm Hg 25 °C
Water solubility: 613.8 mg/l at 25 °C
3,7-Dimethyl-7-methoxyoctan-2-ol
C 11 H 24 O 2
CAS# 41890-92-0 7-Methoxy-3,7-dimethyloctan-2-ol 1–10 0.09 1.3
Henry’s Law: 0.000000404 atm m 3 /mol 25 °C 2-Octanol,7-methoxy-3,7-dimethyl-
LogK ow : 2.76 calc Osirol
Molecular weight: 188.31 Osyrol
Vapor pressure: 0.0119 mm Hg 25 °C
Water solubility: 707.1 mg/l at 25 °C
6,8-Dimethylnonan-2-ol
C 11 H 24 O
CAS# 70214-77-6 2-Nonanol,6,8-dimethyl- 1–10 0.001 0.009
LogKow: 4.06 calc Nonadyl
Molecular weight: 172.12
Vapor pressure: 0.000115 mm Hg 25 °C
4-Methyl-2-pentanol
C 6 H 14 O
CAS# 108-11-2 Isobutyl methyl carbinol 0.01–0.1 0.0005 d 0.02
Henry’s Law: 0.0000176 atm m 3 /mol 25 °C Methyl isobutyl carbinol
LogKow: 1.68 calc MIC
Molecular weight: 102.18 2-Pentanol,4-methyl-
Vapor pressure: 3.7 mm Hg 20 °C 4-Methylpentan-2-ol
Water solubility: 13,800 mg/l at 25 °C
3,4,5,6,6-Pentamethylheptan-2-ol
C 12 H 26 O
CAS# 87118-95-4 2-Heptanol,3,4,5,6,6-pentamethyl- 10–100 0.14 1.7
LogKow: 4.36 calc Koavol DH
Molecular weight: 186.39
Vapor pressure: 0.0000000461 mm Hg 25 °C
Subgroup: tertiary
2,6-Dimethyl-2-heptanol
C 9 H 20 O
CAS# 13254-34-7 Dimetol 10–100 0.0614 1.4
Henry’s Law: 0.0000412 atm m 3 /mol 25 °C Freesiol
LogK ow 3.0 at 45 °C 2-Heptanol,2-6-dimethyl-
Molecular weight: 144.26 Lolitol
Vapor pressure: 0.2 mm Hg 20 °C 2,6-Dimethylheptan-2-ol
Water solubility: 572 mg/l at 25 °C
(continued on next page)

S6
D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
Table 1 (continued)
Material Synonyms Structure Worldwide metric Dermal systemic exposure
tons (annual) a in cosmetic products (mg/
kg/day)
Maximum skin
level (%) b
3,6-Dimethyl-3-octanol
C 10 H 22 O
CAS# 151-19-9 3-Octanol,3,6-dimethyl- 0.1–1 0.0005 d 0.02
Henry’s Law: 0.0000547 atm m 3 /mol 25 °C 3,6-Dimethyloctan-3-ol
LogK ow : 3.6 calc
Molecular weight: 158.29
Vapor pressure: 0.0651 mm Hg 25 °C
Water solubility: 188.9 mg/l at 25 °C
Tetrahydrolinalool c
C 10 H 22 O
CAS# 78-69-3 2,6-Dimethyl-6-octanol >1000 0.0005 d 0.02
Henry’s Law: 0.0000547 atm m 3 /mol 25 C 3,7-Dimethyloctan-3-ol
LogKow: 3.6 at 45 °C 3-Octanol, 3,7-dimethyl-
Molecular weight: 158.29
Vapor pressure: 0.0713 mm Hg 25 °C
Water solubility: 188.9 mg/l at 25 °C
Tetrahydromyrcenol c
C10H22O
CAS# 18479-57-7 2,6-Dimethyloctan-2-ol 100–1000 0.06 0.7
Henry’s Law: 0.0000547 atm m 3 /mol 25 C 2,6-Dimethyl-2-octanol
LogK ow : 3.6 calc 2-Octanol, 2,6-dimethyl
Molecular weight: 158.29
Vapor pressure: 0.05 mm Hg 20 °C
Water solubility: 188.9 mg/l at 25 °C
a 2007 Volume of use survey.
b Skin levels were based on the assumption that the fragrance mixture is used at 20% in a consumer product.
c
d
Materials have been previously reviewed by in RIFM’s Safety Assessment of Terpene Alcohols.
A default value of 0.02% was used to calculate dermal systemic exposure.

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46 S7
ol (isomeric mixture), 3,5,5-trimethyl-1-hexanol, 2,6-dimethylheptan-4-one,
4-hydroxy-4-methyl-2-pentanone, 4-methyl-2-pentanol,
and 4-methyl-2-pentanone.
Data for 2-ethyl-1-hexanol, 2-ethylbutanol, 4-methyl-2-pentanol,
isoamyl alcohol, 2-methylbutanol and 4-methyl-2-pentanone
show that the alcohols share common metabolic pathways. The
major pathways of metabolism and fate are:
– conjugation of the alcohol group with glucuronic acid;
– oxidation of the alcohol group;
– side-chain oxidation yielding polar metabolites, which may be
conjugated and excreted – or further oxidized to an aldehyde,
a carboxylic acid, and to CO 2 ;
– excretion of the unchanged parent compound.
In most cases, metabolism yields innocuous metabolites. Intermediary
reactive products of oxidation of primary alcohols are
aldehydes, which are toxic and possibly genotoxic, although no relevant
genotoxicity was shown with the primary alcohols tested.
The alcohols under review are summarized in Table 1. CAS No.
and synonyms for the alcohols considered in this review are shown
in Table 1. The structural formulas are provided in Table 1.
2.2. Occurrence and use
The alcohols under review are used as fragrance ingredients.
They may be found in fragrances used in decorative cosmetics, fine
fragrances, shampoos, toilet soaps, and other toiletries as well as in
non-cosmetic products such as household cleaners and detergents.
This report summarizes and synthesizes animal and human data,
including studies by various routes of exposure, and emphasizes
the risk assessment for use as fragrance ingredients. The scientific
evaluation focuses on dermal exposure, which is considered the
primary exposure route for fragrance materials. Where relevant
the metabolism, toxicity, and biological fate data of other routes
of exposure have also been considered.
The selected data from published and unpublished reports were
deemed relevant based on the nature of the protocols, quality of
the data, and appropriate exposure. These data are presented in
tabular form.
Some of the alcohols assessed in this report have been evaluated
and approved for use as flavor ingredients in foodstuffs. In the United
States, 2-ethyl-1-hexanol, isoamyl alcohol, and 3-methyl-1-
pentanol have been approved for use as food additives or in food
contact materials by the Food and Drug Administration (FDA). In
addition, 2,6-dimethyl-4-heptanol, 2-methylbutanol, and 3,5,5-trimethyl-1-hexanol
are listed as food additives (FDA, 2007).
The International Joint FAO/WHO Expert Committee on Food
Additives (JECFA) has evaluated alicyclic ketones, secondary alcohols
and related esters including 2,6-dimethyl-4-heptanol from
the group under review and its metabolite 2,6-dimethylheptan-4-
one (JECFA, 1999). JECFA also evaluated aliphatic, branched chain
saturated and unsaturated alcohols, aldehydes, acids, and related
esters including 2-methylbutanol (JECFA, 2004). These materials
were judged by this Committee not to present a safety concern
at the current estimated intake levels.
The annual worldwide use of the individual alcohols reviewed
herein varies greatly and ranges from 10 metric tons are 2,6-dimethyl-2-heptanol,
2,6-dimethyl-4-heptanol, isotricedan-1-ol,
and 3,4,5,6,6-pentamethylheptan-2-ol (IFRA, 2007; Table 1).
2.3. Estimated consumer exposure
Exposure data have been provided by the fragrance industry.
Potential consumer exposure to fragrance materials occurs
through the dermal and inhalation routes of exposure. Worst-case
scenario calculations indicate that depositions on the surface of the
skin following use of cosmetics represents the major route of exposure
to fragrance ingredients when conservative estimates for
evaporation, rinsing and other forms of product removal are employed
(Cadby et al., 2002). Therefore, the dermal route was the
major route in assessing the safety of these compounds.
The fragrance industry has developed three types of approaches
to estimate potential exposure for consumers to fragrance materials.
All three types of exposure are summarized in Table 1. The first is volume
of use. The total worldwide volume of use for fragrance materials
in the branched chain saturated alcohols ranges from 1000 metric tons per year (IFRA, 2004). The reported volume is
for the fragrance ingredient as used in fragrance compounds (mixtures)
in all finished consumer product categories. The volume of
use is determined by IFRA approximately every 4 years through a
comprehensive survey of IFRA and RIFM member companies. As such
the volume of use data from this survey provides volume of use of
fragrance ingredients for the majority of the fragrance industry.
The second method estimates the potential percutaneous (total
skin exposure) absorption from the entire body based on the use of
multiple consumer personal care products containing the same fragrance
ingredient. The dermal systemic exposure in cosmetic products
is calculated based on the concentrations in 10 types of the
most frequently used personal care and cosmetic products (antiperspirant,
bath products, body lotion, eau de toilette, face cream,
fragrance cream, hair spray, shampoo, shower gel, and toilet soap).
The concentration of the fragrance ingredient in fine fragrances is
obtained from examination of several thousand commercial formulations.
The upper 97.5 percentile concentration is calculated
from the data obtained. This upper 97.5 percentile concentration
is then used for all 10 consumer products. These concentrations
are multiplied by the amount of product applied, the number of
applications per day for each product type, and a ‘‘retention factor”
(ranging from 0.001 to 1.0) to account for the length of time a
product may remain on the skin and/or likelihood of the fragrance
ingredient being removed by washing. The resultant calculation
represents the total consumer exposure (mg/kg/day) (Cadby
et al., 2002; Ford et al., 2000). In view of all of the above assumptions,
the total calculated consumer exposure is conservative; it is
unlikely that a consumer will consistently use a number of different
consumer products which are all perfumed with the upper 97.5
percentile level of the fragrance ingredient from a fine fragrance
type of product (Cadby et al., 2002; Ford et al., 2000). The total consumer
exposures to fragrance ingredients range from 0.0002 to
0.11 mg/kg/body weight (bw)/day for the branched chain saturated
alcohols fragrance ingredients in high-end users of cosmetic
products containing these materials (see Table 1) (IFRA, 2004).
The third method provides maximum skin levels. For consideration
of potential sensitization, the exposure is calculated as the
percent concentration of the fragrance ingredient applied to the
skin based on the use of 20% of the fragrance mixture in the fine
fragrance consumer product (IFRA, 2007). The maximum skin
exposure levels of the branched chain saturated alcohol compounds
that form part of the formulae of fine fragrances vary
widely and have been report to range from 0.008% to 1.7%. The
maximum skin exposure for branched chain saturated alcohols in
fine fragrance products are listed in Table 1 (IFRA, 2007).
In assessing safety, the calculated dermal systemic exposure in
cosmetic products can then be compared to the indices of systemic
toxicity such as NOAEL and LOAEL that are obtained from the repeat
dose subchronic, chronic and reproductive toxicity studies
to derive a margin of exposure (MOE). Systemic exposures (i.e.,
the dose absorbed through the skin and available to the systemic
circulation) were estimated based on dermal absorption rates.
Where such data were lacking, as a conservative measure, dermal

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D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
absorption was considered to be 100% (i.e., the maximum skin
exposure value was considered as the estimate of systemic
exposure).
All exposure data were provided by the fragrance industry. Further
explanation of how the data were obtained and of how exposures
were determined has been previously reported by Cadby
et al. (2002) and Ford et al. (2000).
3. Metabolism
3.1. Primary alcohols
When 25 mmoles (2.55 g) of 2-ethyl-1-butanol were administered
by gavage to rabbits, 40% of the dose was excreted in the urine
as the glucuronide conjugate. The excretion of glucuronide was
completed within 24 h (Kamil et al., 1953a). A rabbit was given
3.1 ml (2.55 g) 2-ethyl-1-butanol and the 24-h urine was collected.
2-Ethyl-1-butanol was excreted mainly as diethylacetylglucuronide
and a minor amount of methyl n-propyl ketone was also
found (Kamil et al., 1953b).
Main metabolites of 2-ethyl-1-hexanol identified in the urine of
rats after oral or dermal application were 2-ethylhexanoic acid, 5-
hydroxy-2-ethylhexanoic acid, 5-keto-2-ethylhexanoic acid, 2-
ethyl-1,6-hexanedioic acid and 6-hydroxy-2-ethylhexanoic acid,
mainly as their glucuronides, and expired carbon dioxide. Potential
metabolites not detected in each study were 2-ethylhexanoic acid,
4- and 2-heptanone. One to three percent 2-ethyl-1-hexanol was
excreted unchanged or as glucuronide. Metabolic saturation was
seen with 500 mg/kg body weight applied (Kamil et al., 1953a,b).
This metabolite pattern demonstrates the well-known metabolic
pathways of primary alcohols: oxidation of the alcohol group and
oxidation of the side chain at various positions, glucuronidation
of the oxidation products, and decarboxylation (Fig. 1; Albro,
1975; Deisinger et al., 1993, 1994). Induction of metabolism was
not seen with repeated oral dosing (Deisinger et al., 1994). In rabbits
the glucuronide of 2-ethylhexanoic acid was identified as the
main metabolite (87%) after oral application of 2-ethyl-1-hexanol
(Kamil et al., 1953a,b). In vitro incubation with mammalian alcohol
dehydrogenase resulted in a V max of 0.30 lmol/min/mg protein and
a K m value of 0.74 mM (Albro, 1975).
Only about 9% of the administered dose was found in the form
of the glucuronide when isoamyl alcohol (3-methylbutanol) or 2-
methylbutanol was given to rabbits. Other metabolites were not
identified (Kamil et al., 1953a). Age-dependent glucuronidation
activity was demonstrated in vitro in the olfactory mucosa of rats
with isoamyl alcohol (Leclerc et al., 2002). The glucuronidation of
isoamyl alcohol and other short-chained aliphatic alcohols was
investigated in vitro with human liver microsomes. The V max value
was 3.3 nmol/min/mg protein and the K m was determined as
13.3 mM. The glucuronidation increased with chain length (C2–
C5) of the alcohols studied (Jurowich et al., 2004).
Oxidation to the aldehyde and glucuronidation was demonstrated
for isoamyl alcohol and 2-methylbutanol with microsomes
from rats pretreated with ethanol (Iwersen and Schmoldt, 1995).
The rate of oxidative metabolism of isoamyl alcohol was about
0.1 mmol/g liver in rat liver homogenate and about 0.05 mM/g perfused
rat liver (Hedlund and Kiessling, 1969). The rate of oxidation
of isoamyl alcohol by human skin alcohol dehydrogenase was
183.3 nM/mg protein per minute (Wilkin and Stewart, 1987). The
K m -values of isoamyl alcohol with alcohol dehydrogenase from human
and horse liver were 0.07 and 0.08 mM, respectively (Pietruszko
et al., 1973). After intraperitoneal application of 1000 mg
isoamyl alcohol or 2-methylbutanol/kg body weight, the corresponding
aldehydes could not be detected in expired air of rats
(Haggard et al., 1945).
3.2. Secondary alcohols
After application of 4-methyl-2-pentanol (methyl isobutyl carbinol
in Fig. 2) to rabbits 33.7% of the dose was excreted as the glucuronide
(Kamil et al., 1953a). In mammals, the metabolism of
secondary alcohols proceeds primarily through their respective ketones.
4-Methyl-2-pentanol is metabolized to 4-methyl-2-pentanone
(methyl isobutyl ketone in Fig. 2) and further to 4-hydroxy-4-
methyl-2-pentanone in rats (Fig. 2; OECD/SIDS, 2007).
Plasma levels of 4-methyl-2-pentanol, 4-methyl-2-pentanone,
and 4-hydroxy-4-methyl-2-pentanone were determined up to 12 h
after oral gavage administration of 5 mmol/kg of 4-methyl-2-pentanol
or 4-methyl-2-pentanone to male rats. After dosing rats by gavage
with 4-methyl-2-pentanol or 4-methyl-2-pentanone, the
major material in the plasma for both compounds was 4-hydroxy-4-methyl-2-pentanone.
No other metabolites were detected in
the plasma. The extent of metabolism of 4-methyl-2-pentanol to
4-methyl-2-pentanone was at least 73%. The reduction of 4-
methyl-2-pentanone to 4-methyl-2-pentanol was insignificant
(Gingell et al., 2003; Hirota, 1991a).
Similar results were obtained with intraperitoneal application
of 4-methyl-2-pentanol and 4-methyl-2-pentanone in mice. After
intraperitoneal administration of 4-hydroxy-4-methyl-2-pentanone,
neither 4-methyl-2-pentanol nor 4-methyl-2-pentanone could be
detected in the blood and in the brain (Fig. 2; Granvil et al.,
1994). This result shows that in rats and mice 4-methyl-2-pentanol
is predominantly oxidized to 4-methyl-2-pentanone and both compounds
share the same principal metabolite, namely 4-hydroxy-4-
methyl-2-pentanone.
In workers exposed to mixed solvents including 4-methyl-2-
pentanone and 4-methyl-2-pentanol was identified by GC–MS in
the urine. In a subject exposed to 42.3 ml pure 4-methyl-2-pentanone/m
3 for 6 h, 0.42 mg 4-methyl-2-pentanol/g creatinine was excreted
(Hirota, 1991b). This result confirms, that in humans as well,
the reduction of 4-methyl-2-pentanone is insignificant (6 h 42 ml/
m 3 4-methyl-2-pentanone corresponds to about 320 mg at 66%
retention in the lung and a minute volume of 8 l).
3.3. Tertiary alcohols
Data on the tertiary alcohols under review are not available. A
tertiary alcohol group cannot be oxidized. Tertiary alcohols are expected
to be excreted either via conjugation or unchanged or undergo
hydroxylation of the carbon chain, which in turn may give
rise to a metabolite which can be easily excreted.
4. Pharmacokinetics
4.1. Dermal route of exposure
In vitro absorption rates for 2-ethyl-1-hexanol were 0.22 ± 0.09
and 0.038 ± 0.014 mg/cm 2 /h for rat and human skin, respectively,
giving a rat/human ratio of 5.78. The permeability constants were
2.59 ± 1.10 10 4 cm/h for rats and 4.54 ± 1.66 10 5 cm/h for
humans (Barber et al., 1992).
The dermal absorption in the rat was determined to be 5.2% of a
dose of 1000 mg 2-ethyl-1-hexanol/kg body weight applied for 6 h;
the absorption rate was calculated to be 0.57 mg/cm 2 /h. The terminal
half-life was calculated to be 77 h (Deisinger et al., 1994).
4.2. Oral route of exposure
In rats, oral administration of 2000 mg isoamyl alcohol/kg body
weight led to a peak concentration of 170 mg/l blood 1 h later. The

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46 S9
authors calculated an oxidation rate of 5 mg/kg body weight/h
(Gaillard and Derache, 1965).
After oral administration to rats, 69–75% of a dose of 500 mg
14 C-labeled 2-ethyl-1-hexanol/kg body weight was excreted in
the urine within 96 h. About 13–15% of the dose was excreted in
the feces and about the same amount was exhaled. More than
50% of the dose was excreted within 24 h (Deisinger et al., 1993,
1994).
Plasma levels of 4-methyl-2-pentanol, 4-methyl-2-pentanone,
and 4-hydroxy-4-methyl-2-pentanone were determined up to 12 h
after oral gavage administration of 5 mmol/kg of 4-methyl-2-pentanol
or 4-methyl-2-pentanone to male rats. The major material in
the plasma for both compounds was 4-hydroxy-4-methyl-2-pentanone,
with similar areas under the curve (AUCs) and C max at 9 h
after dosing for both 4-methyl-2-pentanol and 4-methyl-2-pentanone.
4-Methyl-2-pentanone plasma levels and AUC were also similar
after 4-methyl-2-pentanone or 4-methyl-2-pentanol
administration. 4-Methyl-2-pentanol AUC was only about 6% of
the total material in the blood following 4-methyl-2-pentanol
administration, and insignificant after 4-methyl-2-pentanone
administration (Gingell et al., 2003).
4.3. Respiratory route of exposure
Respiratory uptake of isoamyl alcohol was investigated in four
healthy volunteers. Air concentration was 25–200 ppm and exposure
duration was 10 min. The mean uptake for the last 5 min of
exposure was 63% and the mean respiratory rate was 15.3 min 1
(Kumagai et al., 1998).
4.4. Parenteral route of exposure
After intravenous administration to rats, about 74% of a dose of
1mg 14 C-labeled 2-ethyl-1-hexanol/kg body weight was excreted
in the urine within 96 h. About 4% of the dose was excreted in
the feces and 23% was exhaled. More than 50% of the dose was excreted
within 8 h. The terminal half-life was estimated to be 60 h
(Deisinger et al., 1993, 1994).
The concentration of isoamyl alcohol in blood declined within
5 h to non-detectable levels after intraperitoneal administration
of 1000 mg isoamyl alcohol/kg body weight. Similar values were
found for 2-methylbutanol administered at the same dose. An
elimination half-life was not calculated. For isoamyl alcohol and
2-methylbutanol, 1.2% and 7.6%, respectively, were excreted via urine
and expired air. Compared to other amyl alcohols tested by the
authors, primary alcohols were eliminated from the blood more
quickly than secondary and tertiary alcohols (Haggard et al., 1945).
5. Toxicological studies
5.1. Acute toxicity
Fig. 1. Metabolism of 2-ethyl-1-hexanol in the rat (from Albro, 1975). Metabolites
marked with asterisks were detected.
Acute dermal toxicity studies have been performed with six primary,
three secondary, and three tertiary alcohols, all but one in
rabbits. The dermal LD 50 values in rabbits and the one in rats are
in the range of 1000–>5000 mg/kg body weight. In summary all
the compounds are of low acute toxicity by the dermal route (Table
2-1).
Eight primary alcohols, four secondary, and three tertiary alcohols
have been tested for oral acute toxicity. The oral LD 50 values in
rats, mice, and rabbits are in the range of 1000–>5000 mg/kg body
weight, and therefore, all the compounds exhibit a low toxicity
when administered via the oral route (Table 2-2).
Lethargy was the most often reported clinical sign after oral or
dermal administration, diarrhea and ataxia after oral administration,
and irritation of the skin after dermal administration. Signs
of gastrointestinal irritation were noted at necropsy in acute oral
toxicity tests.
In inhalation tests with five primary and two secondary alcohols,
no mortality was observed in rats exposed to air saturated
with alcohol vapor at room temperature for as long as 8 h. LC 50 values
were not determined. Local ocular and upper respiratory tract
irritation was seen with 2-ethyl-1-hexanol. However, 4-methyl-2-
pentanol exposure at 2000 ml/m 3 for 8 h resulted in death at
14 days of 5/6 rats, and exposure to saturated air at 20 °C resulted
in anesthesia at 4 h and death of 6/10 mice after 10 h.
Acute toxicity data obtained from studies with other than oral
or dermal exposure are summarized in Table 2-3.
5.2. Repeated dose toxicity
The evaluation of repeated dose systemic toxicity is based on
several oral studies with mainly primary alcohols and only one secondary
alcohol. The metabolic pathways with all the materials in
this group yield innocuous metabolites. The database could be
strengthened by an evaluation of the systemic toxicity of a secondary
and tertiary alcohol. Other studies can be found in Section 5.10.
5.2.1. Dermal studies
Dermal studies with branched chain saturated alcohols are
summarized in Table 3-1.
5.2.1.1. Primary alcohols. Over a period of 12 days, rats were treated
with undiluted 2-ethyl-1-hexanol (2 ml/kg body weight/day, about
1600 mg/kg body weight/day) on their shaved backs. At necropsy,
the treated animals had decreased absolute and relative thymus
weights, liver granulomas, bronchiectasis in the lung, renal tubular
epithelial necrosis in the kidneys, edema in heart and testes, decreased
spermatogenesis, and an increase in lipids in adrenals were
found on day 17. These effects were reversed on day 30 (Schmidt
et al., 1973).
2-Ethyl-1-hexanol was applied topically under occlusion to
Fischer 344 rats for 5 days, followed by 2 days untreated, 4 days

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D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
Fig. 2. Metabolism of 4-methyl-2-pentanol in the rat and mouse (OECD/SIDS,
2007).
treated with 0, 500, or 1000 mg/kg body weight/day. Treatmentrelated
clinical signs of toxicity were restricted to the skin at the
treatment site and included exfoliation (minimal severity) at both
doses and transient erythema at the high dose. Serum triglycerides
were increased in females at both doses. In high-dose females,
peripheral blood lymphocytes and absolute spleen weight were reduced
(RIFM, 1988; Weaver et al., 1989).
Albino rabbits (2/sex/dose) were treated by dermal occluded
application with 0, 400, or 2000 mg/kg body weight/day of isooctanol
(alcohols C7–9, branched CAS No. 68526-83-0) for 12 days
with 10 applications, lasting 18–24 h each. Control animals received
isopropyl alcohol. No relevant changes in appearance,
behavior, body weight, hematology, and urinalysis were noted in
treated animals. Necropsy and microscopic evaluation demonstrated
no treatment-related findings. Moderate to severe skin irritation
at the application site was noted in treated animals with
necrosis in high-dose animals. The systemic NOAEL was
2000 mg/kg body weight/day (Esso, 1961a, as cited in ExxonMobil
Chemical Company, 2001a).
5.2.1.2. Secondary alcohols. New Zealand White rabbits (5/sex/dose)
were treated topically by occlusive application of 0 or 1000 mg/kg
body weight/day of 3,4,5,6,6-pentamethylheptan-2-ol for 28 consecutive
days at the same site according to OECD test guideline
(TG) 410. Severe skin irritation was induced in rabbits receiving
1000 mg/kg body weight/day of 3,4,5,6,6-pentamethylheptan-2-
ol. However, no alterations in general health, hematology, biochemistry,
major organ weights, or histopathology were observed.
For systemic effects the NOAEL was 1000 mg/kg body weight/day
(RIFM, 1985c).
5.2.1.3. Tertiary alcohols. No studies are available for the members
of this subgroup.
5.2.2. Oral studies
Oral toxicity studies with branched chain saturated alcohols are
summarized in Table 3-2.
5.2.2.1. Primary alcohols. Three repeated dose oral toxicity studies
were done with isoamyl alcohol. In a 90-day study according to
OECD TG 408, isoamyl alcohol was administered in the drinking
water in concentrations of 0, 1000 ppm (about 80 mg/kg/d),
4000 ppm (about 340 mg/kg/d), and 16,000 ppm (about 1250 mg/
kg/d). The NOAEL of isoamyl alcohol was concluded to be
4000 ppm in males (340 mg/kg/d) by the authors because the increase
of erythrocyte counts at this dose fell within the historical
control range. The NOAEL for females was 16,000 ppm (1250 mg/
kg/d) because the increase in prothrombin time was only seen in females
and fell within the historical control range (Schilling et al.,
1997). Isoamyl alcohol was tested in a 17-week toxicity study with
Ash/CSE rats. The test substance was administered by gavage to 15
male and 15 female rats per group at dose levels of 0 (vehicle), 150,
500, or 1000 mg/kg body weight/day in corn oil. Observations
included mortality, behavior, body weight, food and water consumption,
hematology, serum analysis, urinalysis, renal concentration,
organ weights, and gross pathology; microscopic pathology
of 25 organs or tissues on control and top dose only. The only observed
effect was a statistically significant reduced body weight
in males at the highest dose level; food intake was reduced, but
not statistically. The NOAEL was 500 mg/kg body weight/day for
males and 1000 mg/kg body weight/day for females (Carpanini
and Gaunt, 1973). Finally, isoamyl alcohol was administered to
male and female Wistar rats as a 2% solution in drinking water
(about 2000 mg/kg body weight/day) for 56 weeks. No treatmentrelated
effects on body weight, liver weight, ADH, GOT, GPT
activity, and protein content of the liver were found. Histological
examinations of the livers, hearts, spleens, kidneys, and lungs did
not show any significant abnormalities (Johannsen and Purchase,
1969).
Several studies in mice (gavage, RIFM, 1992a,b) and rats (gavage,
RIFM, 1988; Weaver et al., 1989), given 2-ethyl-1-hexanol
by gavage or drinking water (RIFM, 1988; Weaver et al., 1989),
or feed (RIFM, 1992c) for periods of 9–11 days yielded NOAELs in
the range of 100–150 mg/kg body weight/day. Doses of 330 mg/
kg body weight/day and higher resulted in CNS depression, lacrimation,
decreased food consumption, and body weights. 2-Ethyl-
1-hexanol was administered by gavage to F344 rats and B6C3F1
mice of both sexes as an aqueous solution (0, 25, 125, 250, or
500 mg/kg body weight/day) for 13 weeks. Histopathology was
undertaken on tissues recommended in US EPA guidelines. The
NOAEL was 125 mg/kg body weight/day for rats and mice (Astill
et al., 1996a). In a carcinogenicity study (see Section 5.4) 2-ethyl-
1-hexanol was given to male and female rats and mice by gavage
5 times a week in 0.005% aqueous Cremophor EL (rats: 0 (water),
0 (vehicle), 50, 150, or 500 mg/kg body weight/day, 2 months;
mice: 0 (water), 0 (vehicle), 50, 200, or 750 mg/kg body weight/
day, 18 months). The NOAEL for systemic toxicity for mice was
200 mg/kg body weight/day. In rats, the NOAEL for systemic toxicity
was 50 mg/kg body weight/day (Astill et al., 1996b).
An oral study according to OECD TG 422 (combined repeated
dose and reproductive/developmental toxicity screening test) was
conducted with 3,5,5-trimethyl-1-hexanol. Twelve SD (Crj:CD) rats
per sex and dose group were gavaged with 0 (vehicle: olive oil), 12,
60, or 300 mg/kg body weight/day. Exposure duration in males was
46 days and in females from day 14 before mating to day 3 of lactation.
Males of all dose groups showed alpha-2u-globulin nephropathy.
In males and females dosed with 60 or 300 mg/kg body weight/
day, systemic effects were seen, including reduced body weight and
food consumption. On the basis of these findings, the NOAEL for repeated
dose toxicity was 12 mg/kg body weight/day for male and
female rats (MHW, Japan, 1997b as cited in OECD/SIDS, 2003).
In a 90-day study according to OECD TG 408 isotridecanol(iso
alcohols C11–14, C13 rich, CAS No. 68526-86-3) was administered
orogastrically (gavage) to Sprague–Dawley rats in doses of 0, 100,
500, or 1000 mg/kg body weight/day. No effects were observed
only at the lowest dose. The NOAEL for systemic toxicity was

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46 S11
100 mg/kg body weight/day (Exxon Biomedical Sciences Inc., 1986
as cited in ExxonMobil Chemical Company, 2001b).
5.2.2.2. Secondary alcohols. A combined repeated dose and reproductive/developmental
screening study according to OECD TG
422 is available with 4-hydroxy-4-methyl-2-pentanone,a metabolite
of 4-methyl-2-pentanol. Ten rats per sex and group were dosed by
gavage with 0, 30, 100, 300, or 1000 mg 4-hydroxy-4-methyl-2-
pentanone/kg body weight/day in distilled water. Males were
dosed for 44 days and females from day 14 before mating to day
3 of lactation (approximately for 45 days). No effects were noted
at 30 mg/kg body weight/day. Males treated with at least
100 mg/kg body weight/day showed male rat-specific alpha-2unephropathy.
At both 300 and 1000 mg/kg body weight/day, deleterious
effects were observed, including dilatation of the distal tubules
and fatty degeneration of the proximal tubular epithelium in
kidneys in females (300 mg/kg body weight/day) (MHW, Japan
1997, as cited in OECD/SIDS, 2007). The NOAEL was 100 mg/kg
body weight/day due to kidney effects in females at 300 mg/kg
body weight/day. The kidney effects in males at 100 mg/kg body
weight are not relevant for humans.
2,6-Dimethyl-4-heptanol was tested in a 13-week toxicity
study in rats. Male and female animals were fed a diet containing
the test substance mixed with five parts of microcrystalline cellulose
(16/sex/group). The daily intake of the test material was
11 mg/kg body weight/day for males and females. Female rats
showed a statistically significantly lower ( 12.1%) body weight
gain and reduced food efficiency. The authors concluded that the
reduction in body weight gain was most probably of no toxicological
significance since the reduction was not associated with other
toxicologically significant differences between test and control animals
(Posternak and Vodoz, 1975). Because only the range of body
weights at the start of the study is given, it is unclear whether the
animals were adequately randomized to control and test groups
based on body weight. Only one dose was tested, therefore, it cannot
be judged whether the body weight gain reduction is a substance-induced
effect. A NOAEL for this study for the females
cannot be deduced because of the reduction in body weight gain.
For males the NOAEL is 11 mg/kg body weight/day.
5.2.2.3. Tertiary alcohols. No data available.
5.2.3. Inhalation studies
Inhalation studies with branched chain saturated alcohols are
summarized in Table 3-3.
5.2.3.1. Primary alcohols. Male and female Wistar rats (10/group/
sex) were exposed 6 h daily on 5 days per week for 90 days to 2-
ethyl-1-hexanol (purity 99.9%) in concentrations of 15, 40, or
120 ml/m 3 (highest vapor concentration at room temperature).
Neither local nor systemic effects were found. The NOAEL is
120 ml/m 3 (Klimisch et al., 1998).
Three female Alderly-Park rats exposed in whole body exposure
chambers for 13 six-hour exposure periods to saturated vapor of a
mixture of branched chain alcohols designated isooctan-1-ol
(180 ml/m 3 ) showed no adverse effects (Gage, 1970).
5.2.3.2. Secondary alcohols. A 9-day study in rats (10/sex/group, 5 h/
day, 5 days/week) exposed to 98, 300, or 905 ml/m 3 2,6-dimethylheptan-4-one
demonstrated increased liver weights from 300 ml/
m 3 as well as alpha-2u-globulin accumulation in the kidneys of
males (Dodd et al., 1987). Considering the increased liver weights
as a sign of enzyme induction, the NOAEL is 98 ml/m 3 .
In a 6-week inhalation study with 2,6-dimethylheptan-4-one,
groups of 30 rats (15/sex) were exposed to 0, 125, 252, 534, 925,
or 1654 ml/m 3 of 2,6-dimethylheptan-4-one, 7 h/day, 5 days/week
for 6 weeks. Liver and kidney weights were increased at 252 ml/
m 3 in females. At 925 ml/m 3 ‘‘increased incidence of minor pathological
change” was reported. At 1654 ml/m 3 all females died during
the first exposure whereas 12/15 males survived all exposures
at this concentration. Among surviving males at 1654 ml/m 3 there
were no major histopathological changes; ‘‘cloudy swelling” in the
liver and the convoluted tubules in the kidneys and lung congestion
were observed in some surviving males (Carpenter et al.,
Table 2-1
Acute dermal toxicity studies.
Material Species No./dose LD 50 mg/kg body weight b References
Subgroup: primary
2-Ethyl-1-butanol Rabbit 4 1260 (95% C.I. 850–1870) Smyth et al. (1954)
Rabbit n.f.i. 2000 Draize et al. (1944)
2-Ethyl-1-hexanol Rabbit 10 >5000 RIFM (1977a)
Rabbit 4 (males) 2380 (95% C.I. 1700–3340) Smyth et al. (1969)
Rabbit 4 >2600 Scala and Burtis (1973)
Isoamyl alcohol Rabbit 10 >5000 RIFM (1976a)
Rabbit 6 4000 RIFM (1979c)
Rabbit 4 (males) 3970 (95% C.I. 2930–5370) Smyth et al. (1969)
Isotridecan-1-ol (isomeric mixture) Rabbit 4 (males) 7070 Smyth et al. (1962)
Rabbit 4 >2600 Scala and Burtis (1973)
2-Methylbutanol Rabbit 4 (males) 3540 Smyth et al. (1962)
Rabbit n.f.i. 3540 RIFM (1979b)
3,5,5-Trimethyl-1-hexanol Rabbit 10 >5000 RIFM (1977a)
Subgroup: secondary
2,6-Dimethyl-4-heptanol Rabbit 20 (males) 4591 (95% C.I. 2036–10,383) Smyth et al. (1949)
4-Methyl-2-pentanol Rabbit 5 3560 (2720–4760) Smyth et al. (1951)
3,4,5,6,6-Pentamethylheptan-2-ol Rat 10 (5/sex) >2000 RIFM (1985a)
Subgroup: tertiary
2,6-Dimethyl-2-heptanol Rabbit 10 >5000 RIFM (1976a)
3,6-Dimethyl-3-octanol a Rabbit 8 >5000 RIFM (1973a)
3-Methyloctan-3-ol a Rabbit 10 >5000 RIFM (1978c)
n.f.i.: no further information.
a No relevant use was reported.
b Units have been converted to make easier comparisons; original units are in the Fragrance Material Reviews.

S12
D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
1953). Considering the increased liver weights as a sign of enzyme
induction at 250 ml/m 3 , the NOAEL is 125 ml/m 3 .
Wistar rats were whole body exposed to 0, 211, 825, or 3700 mg
4-methyl-2 pentanol/m 3 (0, 50.5, 198, or 886 ml/m 3 ) (purity > 98%)
6 h per day and 5 days per week for 6 weeks, 12 animals per sex
and group. In females of all concentration groups and in males
treated with 198 ml/m 3 or more, increased levels of ketone bodies
in urine were noted. At the highest concentration, absolute kidney
weights increased in males and proteinuria was detected; an increase
in serum alkaline phosphatase in females was observed.
There were no exposure-related histopathological effects in the
kidneys or other organs. The increases in ketone bodies, kidney
weight, and alkaline phosphatase were not considered adverse toxicological
effects. Therefore, the NOAEL was assessed to be
3700 mg/m 3 (886 ml/m 3 ) by OECD/SIDs (Blair, 1982 as cited in
OECD/SIDS, 2007). However, since the increase in alkaline phosphatase
in high-concentration females was significantly elevated
the NOAEL is judged to be 198 ml/m 3 .
A 14-week inhalation study (equivalent to OECD TG 413) was
performed with the metabolite of 4-methyl-2-pentanol and
Table 2-2
Acute oral toxicity studies.
Material Species No./dose LD 50 mg/kg body weight b References
Subgroup: primary
2-Ethyl-1-butanol Rat 5 1850 (95% C.I. 1520–2240) Smyth et al. (1954)
Rat n.f.i. 1850 Nishimura et al. (1994) and Bar and
Griepentrog (1967)
Rabbit n.f.i. 1200 Draize et al. (1944)
2-Ethyl-1-hexanol Rat n.f.i. 2049 Nishimura et al. (1994)
Rat 5 2460 (1820–3330) Smyth et al. (1969)
Rat 5-15 3200 Hodge (1943)
Rat males, n.f.i. 7100 (95% C.I. 5500–9199) Shaffer et al. (1945)
Rat 36 total 3290 (95% C.I. 2870–3790) Schmidt et al. (1973)
Rat n.f.i. 3290 (95% C.I. 2870–3790) Bar and Griepentrog (1967) and Dave and
Lidman (1978)
Rat 5 3730 Scala and Burtis (1973)
Isoamyl alcohol Mouse 4 (2/sex) >2000 (pre-screen for micronucleus RIFM (2008)
test)
Rat 5 males 7100 (4820–10400) Smyth et al. (1969)
Rat 4/sex males: 1300 (95% C.I. 670–2410) Purchase (1969)
females: 4000 (95% C.I. 2450–6170)
Rat n.f.i. 4360 Golovinskaia (1976)
Rat n.f.i. 1300 Nishimura et al. (1994)
Rat n.f.i. >5000 RIFM (1979c)
Rabbit 10–35 3438 Munch (1972)
Isodecyl alcohol Rat n.f.i. 6500 Nishimura et al. (1994)
Isotridecan-1-ol (isomeric mixture) Rat 5 males 17,200 Smyth et al. (1962); Nishimura et al. (1994)
Rat 5 4750 (ca) Scala and Burtis (1973)
Rat 3 2000 RIFM (2002a)
Rat n.f.i. >2000 (50% branched, 50% linear ECB (1995) as cited in Greim (2000)
form)
Mouse n.f.i. 6500 RIFM (1963a)
Mouse n.f.i. 7257 (mixture of branched saturated
primary isomers, purity > 99.7%)
ECB (1995) and Hoechst (1961a) as cited in
Greim (2000)
2-Methylbutanol Rat 5 males 4920 (95% C.I. 3750–6460) Smyth et al. (1962)
Rat n.f.i. 1000 Nishimura et al. (1994)
Rat n.f.i. 4010 Rowe and McCollister (1982)
Rat 10 (5/sex) 4170 RIFM (1979b)
Rat 10 (5/sex) >5000 RIFM (1985e)
3-Methyl-1-pentanol Mouse 10 >2000 RIFM (1982a)
3,5,5-Trimethyl-1-hexanol Rat 10 2300 (95% C.I. 1700–3100) RIFM (1977a)
Rat n.f.i. >2000 MHW, Japan (1997a) as cited in OECD/SIDS
(2003)
Subgroup: secondary
2,6-Dimethyl-4-heptanol Rat 20 males (5/dose) 3560 (95% C.I. 1430–8860) Smyth et al. (1949)
Rat 32 total (16/sex) 4350 Posternak and Vodoz (1975)
Rat 5–11 6500 McOmie and Anderson (1949)
Mouse 6–14 5000 (95% C.I. 2500–7500) McOmie and Anderson (1949)
3,7-Dimethyl-7-methoxyoctan-2-ol Rat 5/sex 5000 RIFM (1976a)
4-Methyl-2-pentanol Rat n.f.i. 2950 Bar and Griepentrog (1967)
Rat n.f.i. 2590 Nishimura et al. (1994)
Rat 5 2590 (2260–2970) Smyth et al. (1951)
3,4,5,6,6-Pentamethylheptan-2-ol Rat 10 (5/sex) 5845 (95% C.I. 5360–6375) RIFM (1984a)
Subgroup: tertiary
2,6-Dimethyl-2-heptanol Rat 10 >5000 RIFM (1976a)
Rat n.f.i. 6800 RIFM (1979a)
3,6-Dimethyl-3-octanol a Rat 10 >5000 RIFM (1973a)
3-Methyloctan-3-ol a Rat 10 3400 (95% C.I: 2500–4700) RIFM (1978c)
n.f.i.: no further information.
a No relevant use was reported.
b Units have been converted to make easier comparisons; original units are in the Fragrance Material Reviews.

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46 S13
4-methyl-2-pentanone. Male and female rats and mice (14 per species/sex/group)
were exposed to 0, 50, 250, or 1000 ml 4-methyl-2-
pentanone/m 3 (0, 204, 1020, or 4090 mg/m 3 ) 6 h per day and 5 days
per week. Slight, but statistically significant, increases in absolute
and relative liver weight were observed in males of both species at
the highest concentration. As there were no histopathological
changes in the livers observed, the changes were considered to be
of no toxicological relevance. Male rats demonstrated alpha-2uglobulin
ephropathy. The NOAEL was considered to be 1000 ml/m 3
(4090 mg/m 3 ) for both species (Phillips et al., 1987).
In a two-generation study with rats with 4-methyl-2-pentanone clinical
signs in the form of CNS depression were noted during exposures of
adults to 1000 and 2000 ml/m 3 . The systemic NOAEL was 500 ml/m 3 in
this study. Signs of irritation were not reported (Nemec et al., 2004).
5.2.3.3. Tertiary alcohols. No data available.
5.3. Mutagenicity and genotoxicity
5.3.1. In vitro mutagenicity studies
The available studies are summarized in Table 4-1.
5.3.1.1. Indicator studies. In a study of the cytotoxic and genotoxic
effects of a number of alcohols and ketones, 2-methylbutanol
Table 2-3
Acute inhalation and miscellaneous toxicity studies in animals.
Material Dose route Species No./dose LD 50 and/or clinical signs References
Subgroup: primary
2-Ethyl-1-butanol
Inhalation, exposure to
Rat 6 Maximum time for no death: 8 h Smyth et al. (1954)
concentrated vapors
2-Ethyl-1-hexanol
Inhalation, exposure to
Rat 6 Maximum time for no death: 8 h Smyth et al. (1969)
concentrated vapors
Whole body exposure for 6 h to Rat, mouse, 10/species
No mortality, irritation of eyes, Scala and Burtis (1973)
air bubbled through 2-ethyl-1-
hexanol to yield a nominal
chamber concentration of
227 ml/m 3 guinea pig
nose, throat, and respiratory
passages, blinking, lacrimation,
preening, nasal discharge,
salivation, gasping, and chewing
movements
Intraperitoneal Rat 5–15 LD 50 650 mg/kg body weight Hodge (1943)
Intraperitoneal Rat 5/sex LD 50 500–1000 mg/kg body Dave and Lidman (1978)
weight
Intraperitoneal Mouse 5–15 LD 50 780 mg/kg body weight Hodge (1943)
Isoamyl alcohol i.v. Mouse Not reported LD 50 2.64 mmol/kg body weight
(233 mg/kg body weight)
Chvapil et al. (1962)
Isotridecan-1-ol
(isomeric mixture)
Inhalation, exposure to air
saturated with alcohol vapor at
room temperature for 8 h
Inhalation to 12 ml/m 3
(saturation concentration at
30 °C) for 6 h
Rat 6 rats/14 days No effects RIFM (1963c) and Smyth
et al. (1962)
Rat, mouse,
guinea pig
10/species No effects Scala and Burtis (1973)
Intraperitoneal Mouse n.f.i. LD 50 600 mg/kg body weight RIFM (1963b)
2-Methylbutanol Intraperitoneal Rat n.f.i. 1000 mg/kg body weight: Haggard et al. (1945)
sedation, irritation of the
peritoneum and injury of the
lungs; 2000 mg/kg body weight:
respiratory arrest and death
Intraperitoneal Mouse 10 (5/sex) LD 50 between 200 and
RIFM (1979b)
700 mg/kg body weight
Inhalation, saturated
Rat n.f.i. No mortality, escape behavior, RIFM (1979b)
atmosphere at 20 °C (calculated:
10,050 mg/m 3 bzw. 2744 ml/m 3 )
for 7 h
intermittent respiration
Inhalation, saturated vapor for
8h
Rat 6 No mortality Rowe and McCollister
(1982)
3-Methyl-1-pentanol Intraperitoneal Mouse 10 LD 50 > 250 mg/kg body weight;
P2000 mg/kg body weight:
10/10 animals died within
30 min (respiratory depression)
RIFM (1982a)
Subgroup: secondary
2,6-Dimethyl-4-heptanol
Inhalation, exposure to
substantially saturated vapor or
cooled mist (400 ml/m 3 ) for 8 h
Inhalation, exposure to a
saturated vapor–air mixture for
12 h
Rat 12 No mortality Smyth et al. (1949)
Mouse 10 2.0 mg/l: no mortality McOmie and Anderson
(1949)
4-Methyl-2-pentanol Inhalation for 8 h at 2000 ppm Rat 6 5/6 animals died within 14 days Carpenter et al. (1949) and
Smyth et al. (1951)
Inhalation exposure to a
saturated vapor–air at 20 °C for
4–15 h
Mouse 10 Somnolence and anesthesia
Mortality at 10 h (6/10) and 15 h
(8/10)
McOmie and Anderson
(1949)
3,4,5,6,6-
Pentamethylheptan-2-ol
n.f.i.: no further information.
Intraperitoneal injection at doses
of 50, 166, 500, 750, 1000, 1250,
1666, and 3000 mg/kg body
weight
Mouse 2 One death at 1250 mg/kg
Clinical signs observed for all
mice above 1000 mg/kg
RIFM (1985d)

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D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
Table 3-1
Repeated dose toxicity studies – dermal.
Material Method Dose Species (No./dose) Results References
Subgroup: primary
2-Ethyl-1-hexanol Single application/day on
the shaved back for 12 days
Isooctanol (alcohols C7–C9
branched CAS No.
68526-83-0)
5 days occlusive treatment,
2 days untreated, 4 days
treated
Occlusive, 18–24 h for
12 days (10 treatments)
2 ml/kg body weight/
day (1600 mg/kg body
weight/day)
0, 500, or 1000 mg/kg
body weight/day
0 (isopropyl alcohol),
400, 2000 mg/kg body
weight/day
Rat (10) Absolute and relative thymus weights decreased, liver
granulomas, bronchiectasis in the lung, renal tubular
epithelial necroses, edematous heart and testes and
decreased spermatogenesis
Fischer 344 rat (10/sex) P500 mg/kg body weight/day: exfoliation (minimal
severity), spleen weight decreased; serum triglycerides
increased (females);
1000 mg/kg body weight: transient erythema (days 4–7)
(graded as barely perceptible), decreased absolute
spleen weight, lymphocytes decreased
Rabbit (Albino) (2/sex) Systemic NOAEL: 2000 mg/kg body weight/day 400 mg/
kg body weight/day: moderate to severe irritation,
fissure, coriaceous skin
2000 mg/kg body weight/day:necrosis of the skin
Schmidt et al. (1973)
RIFM (1988); Weaver et al. (1989)
Esso Research and Engineering Company
(1961) as cited in ExxonMobil Chemical
Company (2001a)
Subgroup: secondary
3,4,5,6,6-
Pentamethylheptan-2-ol
Dermal (occlusive), 6 h/day
for 28 days (OECD TG 410)
Dermal (occlusive), 6 h/day
for 28 days
0 (water), 1000 mg/kg
body weight/day
30, 100, 300, and
1000 mg/kg/day
Rabbit (New Zealand
White) (5/sex)
Rabbit (New Zealand
White) (10/sex)
Systemic NOAEL: 1000 mg/kg body weight/day
1000 mg/kg body weight/day: (f), severe dermal
reactions: well defined severe erythema and edema,
histopathology of the skin: acanthotic and focal
ulcerative changes of epidermis, associated
inflammation, hyperkeratosis, scab formation
Systemic NOAEL: 1000 mg/kg body weight/day Slight to
moderate dermal irritation; severe irritation at high (300
and 1000 mg/kg/day) doses; reversible after 8 days
RIFM (1985c)
RIFM (1986b)
Abbreviations see Table 3-3.

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46 S15
Table 3-2
Repeated dose toxicity studies – oral.
Material Method Dose Species (No./dose) Results References
Subgroup: primary
2-Ethyl-1-hexanol Gavage, 5 days/week,
22 days
Gavage, 9 treatments in
11 days
0, 330, 660, 930 mg/kg body
weight in sunflower oil,
controls 10 ml oil/kg body
weight
0, 100, 330, 1000, 1500 mg/
kg body weight/day, test
substance undiluted
Drinking water, 9 days 0, 308 ppm (half-saturated)
and 636 ppm (saturated):
61.1 and 151.1 mg/kg body
weight/day for males and
73.4 and 173.5 mg/kg body
weight/day for females.
Gavage, 9 doses in 11 d 0, 100, 330, 1000, or
1500 mg/kg body weight/
day, in propylene glycol
Gavage, 9 doses in 11 d 0, 100, 330, 1000, or
1500 mg/kg body weight/
day, in an aqueous emulsion
in Cremophor EL
Diet, 11 days 500, 980, 1430, or 2590 mg/
kg/day (males) 540, 1060,
1580, or 2820 mg/kg/day
(females)
Rat (10) 930 mg/kg: body weight on day 17 decreased, mortality:
1/10
Fischer 344 rat
(10/sex)
Fischer 344 rat
(10/sex)
B6C3F1 mice
(10/sex)
B6C3F1 mice
(10/sex)
Systemic NOAEL 100 mg/kg body weight/day
330 mg/kg body weight/day: hypoactivity, ataxia,
prostration, delayed righting reflex, muscle twitch,
lacrimation, and urine-stained fur. Food consumption and
body weights decreased (males), thymic atrophy and
lymphoid cell degeneration in the thymus;
1000 mg/kg body weight/day: food consumption and body
weights decreased (females), total peripheral blood
leukocytes and lymphocytes, spleen weight decreased
(females), absolute and relative liver weight increased
without histopathological findings, absolute and relative
stomach weight increased with hyperkeratosis, mucosal
hyperplasia, edema, exocytosis, and gastritis;
1500 mg/kg body weight/day: total peripheral blood
leukocytes and lymphocytes, spleen weight decreased
(males), absolute and relative testes weights decreased, no
histopathological findings in testes or kidneys at any dose
Schmidt et al. (1973)
RIFM (1988); Weaver et al.
(1989)
No adverse effects RIFM (1988); Weaver et al.
(1989)
Systemic NOAEL 100 mg/kg body weight/day
330 mg/kg body weight/day: relative liver and stomach
weights (male) increased;
1000 mg/kg body weight/day: relative liver and stomach
weights (female) increased; 2/20 deaths;
1500 mg/kg body weight/day: ataxia, lethargy, piloerection,
dyspnea, hypothermy, abdominal or lateral position and loss
of consciousness, reduction in food consumption (males),
relative testes weight decreased; clinical chemistry and
hematology no substance-related changes. No
histopathological examinations; 10/20 deaths
Systemic NOAEL 100 mg/kg body weight/day
300 mg/kg body weight/day: acanthosis with hyperkeratosis
in the forestomach;
P1000 mg/kg body weight/day: relative liver (males) and
stomach weights (female) increased, hypertrophy of
hepatocytes; 1/20 deaths;
1500 mg/kg body weight/day: ataxia, lethargy, piloerection,
abdominal or lateral position and loss of consciousness;
clinical chemistry and hematology, no substance-related
changes; 5/20 deaths.
F344 rat (10/sex) NOAEL < 500 (m) or 540 (f) mg/kg bodyweight/day
P500 (m) or 540 (f) mg /kg/d: relative stomach weights
increased females (f); triglycerides and alanine
aminotransferase decreased, males (m); feed consumption
significantly decreased (m)
RIFM (1992a)
RIFM (1992b)
RIFM (1992c)
(continued on next page)

S16
D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
Table 3-2 (continued)
Material Method Dose Species (No./dose) Results References
Gavage, 5 days/week,
13 weeks
Gavage, 24 months,
5 days/week
3 weeks, oral
administration
Gavage, 18 months,
5 days/week
Isoamyl alcohol Drinking water
3 months
Gavage, daily for
17 weeks
Drinking water,
56 weeks
Neurotoxicity: Whole
body exposures with a
30 min habituation and
4 h exposure
Neurotoxicity: Whole
body exposure with a
30 min habituation and
2 h exposure
0, 25, 125, 250 or 500 mg/kg
body weight/day
0 (water), 0 (vehicle), 50,
150, 500 mg/kg/body
weight/day in 0.005%
Cremophor EL
F344 rat, B6C3F1
mice (10/sex)
P980 (m) or 1060 (f) mg/kg/d: absolute and relative liver
weights increased (m,f); feed consumption decreased (m,f);
water consumption significantly decreased (f); triglyceride
and alanine aminotransferase decreased (m);
P1430 (m) or 1580 (f) mg/kg/d: food consumption reduced
(m,f), hypertrophy of hepatocytes; body weight significantly
reduced (m); water consumption significantly reduced (m,f);
triglyceride and alanine aminotransferase decreased (males);
2590 (m) or 2820 (f) mg/kg/d: absolute and relative liver
weights increased (m,f);body weight decreased (m,f); feed
consumption decreased (m,f), water consumption
significantly decreased (m,f); triglyceride and alanine
aminotransferase decreased (m,f)
NOAEL: 125 mg/kg body weight/day, rats and mice
P250 mg/kg body weight/day: relative liver, kidney (rats,
both sexes) and stomach weights (female rats) increase, fat
deposits in the liver cells (male rats) decrease, relative liver
and stomach weights (male mice) increased;
500 mg/kg body weight/day: acanthosis of the forestomach
(female mice); peroxisome proliferation (marker: cyanideinsensitive
palmitoyl CoA oxidase) (rats, both sexes) increase
F344 rats (50/sex) Systemic NOAEL: 50 mg/kg body weight/day
P150 mg/kg body weight/day: body weight gain decreased,
poor clinical state, labored breathing, piloerection or urinestained
genital region
Astill et al. (1996a)
Astill et al. (1996b)
833 mg/kg n.f.i. Rat (n = 5) Statistical increase (p < .05) in liver was observed Yamada (1974)
0 (water), 0 (vehicle), 50,
200, 750 mg/kg body
weight/day in 0.005%
Cremophor EL
0, 1000, 4000, 16,000 mg/l
drinking water
(purity > 98.6%); estimated
to be: 0, 80, 320, 1280 mg/
kg body weight/day
0 (vehicle), 150, 500,
1000 mg/kg body weight/
day, in corn oil
0, 2% (2000 mg/kg body
weight/day)
3–4 exposures to the
various solvent
concentrations (between
25% and 75%)
3–4 exposures to various
solvent concentrations
(between 25% and 75%)
B6C3F1 mice
(50/sex)
Systemic NOAEL: 200 mg/kg body weight/day
750 mg/kg body weight/day: increased mortality, body
weight gains decreased, food consumption decreased, fatty
liver, hyperplasia of the forestomach epithelium
Wistar rat (10/sex) NOAEL females = 1280 mg/kg body weight/day
NOAEL males = 320 mg/kg body weight/day
1280 mg/kg body weight (males): erythrocyte value
increased; mean corpuscular volume (MCV) decreased; mean
corpuscular hemoglobin (MCH) decreased
320 and 1280 mg/kg/day (females): increased prothrombin
time
Ash/CSE rat
(15/sex)
additional 5
animals examined
after 3 and
6 weeks,
respectively
NOAEL females = 1000 mg/kg body weight/day NOAEL
males = 500 mg/kg body weight/day
1000 mg/kg body weight/day: males: body weight gain
decrease
Astill et al. (1996b)
Schilling et al. (1997) RIFM
(1991b)
Carpanini and Gaunt (1973)
Wistar rat (20/sex) No significant effects Johannsen and Purchase
(1969)
Male albino SPF
rats 16 (4/group)
Female mice of the
H strain 32
(4/group)
The concentration that evoked a 30% depression in the
recorded activity was determined to be 1700 ppm
The concentration that evoked a 30% depression in the
recorded activity was determined to be 950 ppm
Frantik et al. (1994)
Frantik et al. (1994)

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46 S17
Isotridecanol (Alcohols,
C11–14 iso, C13
rich, CAS No. 68526-
86-3)
3,5,5-Trimethyl-1-
hexanol
Subgroup: secondary
2,6-Dimethyl-4-
heptanol
4-Hydroxy-4-methyl-2-
pentanone
Abbreviations see Table 3-3.
Gavage, 7 days/week,
for 14 weeks, OECD TG
408
0 (distilled water), 100, 500,
1000 mg/kg body weight/
day
Sprague–Dawley
rat (20/sex)
Gavage, males: 14 days 144 mg/kg body weight/day Alderly-Park
Wistar rat
Gavage, males:
46 days, females: from
14 days before mating
to day 3 of lactation,
OECD TG 422
0, 12, 60, 300 mg/kg body
weight/day in olive oil
SD (Crj:CD) rat
(12/sex)
NOAEL: 100 mg/kg body weight/day
P500 mg/kg body weight/day: food consumption decreased
(m), body weight decreased (m), mean platelet counts
increased (f), glucose decreased (f), liver weight increased (m,
f),
1000 mg/kg body weight/day: glucose decreased (m),
cholesterol decreased (f), rel. brain and testes weight
increased (m), rel. adrenal weight increased (f)
Increase in the relative liver weight
No difference from controls in body weight, clinical, or
histopathological signs. Peroxisome proliferation,
hypocholesterolemia, and hypoglyceridaemia were not
evident
NOAEL systemic toxicity males and females: 12 mg/kg body
weight/day
P12 mg/kg body weight/day: renal hyaline droplets,
eosinophilic bodies (m)
P60 mg/kg body weight/day: relative liver and kidney
weight increase (m,f), renal epithelial fatty change (f);
implantation index decreased (f)
300 mg/kg body weight/day: 1 f died, 3 f killed (weakness);
body weights increase (m), food consumption increased (m),
body weights decreased (f), food consumption decrease (f);
total litter loss in 2 dams
Diet, 13 weeks 0, 11 (f), 11 (m) mg/kg body
weight/day mixed with
microcrystalline cellulose
Gavage, males:
44 days, females: from
14 d before mating to
day 3 of lactation
(approx. 45 days),
OECD TG 422
0, 30, 100, 300, 1000 mg/kg
body weight/day in water
Rat (16/sex) No NOAEL (females) based on reductions of body weight gain
systemic NOAEL (males): 11 mg/kg body weight;
11.06 mg/kg body weight/day: (females) body weight gain
and food efficiency (weight gained (g)/food consumed
(g) 100, 10.8%) decrease (body weight gain 12.1%).
Hematological and histological examinations without any
Crj:CD(SD) rat
(10/sex)
significant differences between test and control rats
NOAEL: 100 mg/kg body weight/day
P100 mg/kg body weight/day: male alpha-2u-nephropathy
P300 mg/kg body weight/day: locomotor activity and
stimulation response decrease (m,f); dilatation of the distal
tubules and fatty degeneration of the proximal tubular
epithelium in kidneys (f)
P1000 mg/kg body weight/day: hepatocellular hypertrophy
(m,f), altered blood parameters (increase: platelet counts,
GOT, total protein, total cholesterol, total bilirubin, blood
urea nitrogen, creatinine, calcium (m); decrease: glucose)
(m), dilatation of distal tubules of kidneys (m), vacuolization
of the zona fasciculata of the adrenals (m); body weight gain
decrease (f), rel. liver weight increase (f)
Exxon Biomedical Sciences
Inc. (1986) as cited in
ExxonMobil Chemical
Company (2001b)
Rhodes et al. (1984)
MHW, Japan (1997b) as
cited in OECD/SIDS (2003)
Posternak and Vodoz (1975)
MHW, Japan (1997) as cited
in OECD/SIDS (2007)

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D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
and isoamyl alcohol were tested for their potency to induce DNA
damage in V79 Chinese hamster fibroblasts, human lung carcinoma
epithelial A549 cells and human peripheral blood cells with
the alkaline comet assay. In V79 and A549 cells 2-methylbutanol
and isoamyl alcohol showed DNA damage only at cytotoxic concentrations.
The COMET assay could not be performed in human
peripheral blood cells due to extreme cytotoxicity (cells with completely
fragmented DNA) (Kreja and Seidel, 2001, 2002).
2-Methylbutanol and isoamyl alcohol gave negative results in a
light absorption umu test and positive results in a luminescent
umu test (Nakajima et al., 2006). These tests are based on the ability
of DNA damaging agents to induce expression of the umu operon,
which is responsible for chemical and radiation mutagenesis, in
Escherichia coli. The positive result is not plausible in view of the
other negative tests for genotoxicity (see below) and the overall
negative results for branched chain saturated alcohols. 2-Ethyl-1-
hexanol gave a negative and a positive result in two rec-assays
(Saido et al., 2003; Tomita et al., 1982). The results of this test system
are not considered for the evaluation of the genotoxicity of the
alcohols under study because positive results were often assessed
with substances, which were negative in other genotoxicity test
systems. A test for induction of unscheduled DNA synthesis with
2-ethyl-1-hexanol was negative in primary rat hepatocytes (Hodgson
et al., 1982).
4-Methyl-2-pentanone was negative in a vitro UDS test (no further
information; IPCS, 1990 as cited in OECD/SIDS, 2004).
5.3.1.2. Mutation studies. The primary alcohols 3,5,5-trimethyl-1-
hexanol, 2-ethyl-1-hexanol, isotridecan-1-ol (isomeric mixture),
the secondary alcohols 4-methyl-2-pentanol, its metabolites 4-
methyl-2-pentanone and 4-hydroxy-4-methyl-2-pentanone, 2,6-dimethyl-4-heptanol
and its metabolite 2,6-dimethylheptan-4-one,
as well as a mixture of the secondary alcohol 3,4,5,6,6-pentamethylheptan-2-ol
(55–80%) and 3,4,5,6,6-pentamethylheptan-2-on
(20-45%) were inactive in Ames tests. Urine from Sprague–Dawley
rats dosed by oral gavage for 15 days with 1000 mg 2-ethyl-1-hexanol/kg
body weight/day was found to be non-mutagenic in Salmonella
typhimurium with and without addition of rat liver
microsomes or beta-glucuronidase/arylsulfatase (DiVincenzo
et al., 1983, 1985). 2-Ethyl-1-hexanol was mutagenic in S. typhimurium
TA100 using the mutation to resistance to 8-azaguanine (Seed,
1982). As this test was performed only in one S. typhimurium strain
and the other mutagenicity tests using reversion to histidine independence
were negative, this result seems to be of limited
relevance.
The primary alcohols 2-methylbutanol, isoamyl alcohol, and 2-
ethyl-1-hexanol were also inactive in mammalian cell systems
(TK +/ mouse lymphoma mutagenicity assay in L5178Y cells or
HPRT assay with Chinese hamster V79 fibroblast cells) (Kirby
et al., 1983; Kreja and Seidel, 2002). For 4-methyl-2-pentanone, a
mouse lymphoma test was considered equivocal (no further information;
IPCS, 1990 as cited in OECD/SIDS, 2004).
A Saccharomyces cerevisiae mitotic gene conversion assay was
negative for 2,6-dimethylheptan-4-one (OECD/SIDS, 2004).
The secondary alcohol 4-methyl-2-pentanol tested for gene
mutation in Saccharomyces cerevisiae gave negative results (Clare,
1983 as cited in OECD/SIDS, 2007).
5.3.1.3. Chromosome aberration studies. The primary alcohols 2-
ethyl-1-hexanol and 3,5,5-trimethyl-1-hexanol as well as the secondary
alcohol 4-methyl-2-pentanol and 2,6-dimethylheptan-4-
one, did not induce chromosome aberrations in vitro when incubated
with Chinese hamster ovary, Chinese hamster lung or rat liver
cells (Brooks et al., 1985 as cited in OECD/SIDS, 2004; Brooks
et al., 1988; Clare, 1983 as cited in OECD/SIDS, 2007; MHW, Japan,
1997d as cited in OECD/SIDS, 2003; Phillips et al., 1982). 4-Hydroxy-4-methyl-2-pentanone,
tested for chromosomal aberrations in
Chinese hamster lung cells, revealed significantly increased polyploidy
in the two highest doses (600 and 1200 lg/ml). Information
as to whether this was done with or without S9 was not available.
This test was considered negative because a trend test showed no
dose-dependency (MHW, Japan, 1997 as cited in OECD/SIDS, 2007).
5.3.1.4. Micronucleus studies. The primary alcohols 2-methylbutanol
and isoamyl alcohol did not induce micronuclei in V79 Chinese
hamster fibroblasts, with or without addition of hepatic S9 mix
from Aroclor induced rats (Kreja and Seidel, 2002).
5.3.2. In vivo studies
The available studies are summarized in Table 4-2. No indication
for a covalent binding of 2-ethyl-1-hexanol to liver DNA of rats
and mice was noted (Albro et al., 1982; Däniken et al., 1984). 2-
Ethyl-1-hexanol was not mutagenic in the dominant lethal test
(Rushbrook et al., 1982; only as abstract) and not clastogenic in a
bone marrow chromosome aberration test (Putman et al., 1983),
although this result is not reliable because the doses used failed
to induce toxicity. 2-Ethyl-1-hexanol (Astill et al., 1986; Barber
et al., 1985; only as abstract, no information on the method, and
validity cannot be assessed) and 3,4,5,6,6-pentamethylheptan-2-
ol were not clastogenic in the mouse bone marrow micronucleus
test (RIFM, 1985d). Isoamyl alcohol showed an increase in chromosomal
aberrations in bone marrow cells of rats (Barilyak and Kozachuk,
1988). The study is invalid as no information is available if a
positive control group was used, the definite dose was not mentioned
(1/5 of LD 50 ), only one dose was tested, the control animals
did not show any chromosomal aberrations, and the purity of the
substance was not given. The authors also found chromosomal
aberrations with propanol, which was not genotoxic in a variety
of tests (Greim, 1996). An in vivo mouse micronucleus assay was
conducted on isoamyl alcohol (RIFM, 2008) at doses of 500, 1000,
and 2000 mg/kg there was no increase in the frequency of detected
micronuclei. Isoamyl alcohol was determined to be non-mutagenic
in the micronucleus assay.
Additionally, 4-methyl-2-pentanone was negative in an in vivo
micronucleus test (no further information; IPCS, 1990 as cited in
OECD/SIDS, 2004).
5.4. Carcinogenicity
The available carcinogenicity studies are summarized in Tables
5-1.
5.4.1. Cell transformation assays
In a cell transformation study with mouse epidermis-derived
JB6 cells 2-ethyl-1-hexanol did not promote JB6 cells to anchorage
independence (Ward et al., 1986). A cell transformation assay with
BALB 3T3 cells did not induce a significant number of transformed
foci (Barber et al., 1985; RIFM, 1983b).
5.4.2. Carcinogenicity studies
2-Ethyl-1-hexanol was given to male and female rats and mice
by gavage 5 times a week in 0.005% aqueous Cremophor EL (rats: 0
(water), 0 (vehicle), 50, 150, 500 mg/kg body weight/day,
24 months; mice: 0 (water), 0 (vehicle), 50, 200, 750 mg/kg body
weight/day, 18 months). The incidences of carcinomas and basophilic
foci in the liver increased in female mice with the dose
and attained statistical significance in the highest dose group compared
with the vehicle control group but not with the water control
group. The time-adjusted incidence of hepatocellular
carcinomas in female mice (13.1%) was outside the normal range
(0–2%), but in male mice (18.8%) was within the historical control
range at the testing facility (0–22%). No adenomas were observed.

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46 S19
Table 3-3
Repeated dose toxicity studies – inhalation.
Material Method Concentration Species (No./dose) Results References
Subgroup: primary
2-Ethyl-1-hexanol OECD TG 413 90 days,
6 h/day, 5 days/week
0, 15, 40, or 120 ml/m 3
(highest vapour
concentration at room
temperature), purity: 99.9%
Isooctanol 13 days, 6 h/day 180 ml/m 3 (highest vapour
concentration at room
temperature)
Wistar rat (10/sex) Local and systemic NOAEL: 120 ml/m 3 Klimisch et al. (1998)
Alderly-Park rat (3 f) No mortality, clinical signs, autopsy findings and
histopathological changes
Gage (1970)
Subgroup: secondary
2,6-Dimethylheptan-4-one 2 weeks, 5 h/day,
5 days/week
6 weeks, 7 h/day,
5 days/week
4-Methyl-2-pentanone 14 weeks, 6 h/day,
5 days/w (OECD TG
413)
14 weeks, 6 h/day,
5 days/w (OECD TG
413)
0, 98, 300, 905 ml/m 3 Rats (10/sex) NOAEL: 98 ml/m 3
0, 125, 252, 534, 925,
Rat (15/sex) NOAEL: 125 ml/m 3
1654 ml/m 3
0, 50, 250, 1000 ml/m 3
(0, 204, 1020, 4090 mg/m 3 )
0, 50, 250, 1000 ml/m 3
(0, 204, 1020, 4090 mg/m 3 )
Fischer 344 rat (14/sex) NOAEL: 250 ml/m 3
P 300 ml/m 3 : liver weight increased, alpha-2uglobulin
accumulation in the kidneys (m)
125 ml/m 3 : No adverse effects 252 ml/m 3 : Liver and
kidney weights increased (f)
534 ml/m 3 : Liver and kidney weights increased
(m + f)
925 ml/m 3 : Liver and kidney weights increased
(m + f)
1654 ml/m 3 : Mortality in all females and 3/15
males. Surviving males: body weight gain
decreased and liver and kidney weights increased
P250 ml/m 3 : hyaline droplets in proximal tubular
cells (m)
1000 ml/m 3 : abs. and rel. liver weight (slight but
statistically significant) increase (m)
B6C3F1 mouse (14/sex) NOAEL: 50 ml/m 3 1000 ml/m 3 : abs. and rel. liver
weight (slight but statistically significant) increase
(m)
4-Methyl-2-pentanol 12 4-h-exposures 0, 20,000 mg/m 3 Mouse (9) Unclear description of effects, unclear extent of
histopathology
6 weeks, 6 h/day,
5 days/w (OECD TG
407)
0, 50.5, 198, 886 ml/m 3
(0, 211, 825, 3700 mg/m 3 )
Wistar rat (12/sex) NOAEL: 198 ml/m 3
P50.5 ml/m 3 : concentration of ketone bodies in
urine increased (f)
P198 ml/m 3 : concentration of ketone bodies in
urine increased (m)
886 ml/m 3 : abs. kidney weight increased (m),
serum alkaline phosphatase increased (f)
Dodd et al. (1987)
Carpenter et al. (1953)
Phillips et al. (1987)
Phillips et al. (1987)
McOmie and Anderson (1949)
Blair (1982) as cited in OECD/
SIDS (2007)
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),
f: female, m: male, n.f.i.: no further information, n.s.: not statistically significant, s.a.: see above, s.c.: subcutaneous.

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D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
The number of basophilic liver foci was increased in male mice in
the mid dose group only. The authors considered the liver tumors
in the mouse to be inconclusive because the incidence of hepatocarcinoma
precursors did not significantly increase with the dose.
Nevertheless, they concluded that 2-ethylhexanol is weakly or
questionably carcinogenic for the female mouse. Under the conditions
of this study 2-ethyl-1-hexanol was not oncogenic to rats.
Doses of 150 and 500 mg/kg body weight/day led to reduced body
weight gains and in some animals to lethargy and unkemptness
which proves that the maximum tolerated dose was reached. At
the end of the study the mortality was about 52% in the high-dose
group females and about 28% in the other groups (Table 5-1; Astill
et al., 1996b).
5.5. Reproductive and developmental toxicity
5.5.1. Fertility
5.5.1.1. In vitro. 2-Ethyl-1-hexanol (200 lM for 24 h) had no effect
on lactate and pyruvate production by Sertoli-cell-enriched cultures
derived from 28-day old Sprague–Dawley rats, whereas
phthalate monoesters known to cause testicular atrophy in vivo increased
Sertoli cell lactate production and lactate/pyruvate ratio
(Moss et al., 1988).
In an in vitro model of rat seminiferous tubules 200 lM 2-ethyl-
1-hexanol did not induce dissociation of germinal cells from Sertoli
cells (Gangolli, 1982).
Ethyl-1-hexanol (200 lM for 24 or 48 h) did not result in an increase
of germ-cell detachment in rat testicular-cell cultures (Gray,
1986; Gray and Beamand, 1984; Sjoberg et al., 1986).
5.5.1.2. In vivo. In vivo studies of reproductive and developmental
toxicity of the branched chain saturated alcohols are summarized
in Tables 6-1 (dermal), 6-2 (oral), and 6-3 (inhalation).
5.5.1.3. Dermal. Effects on the reproductive organs of rats treated
dermally with 1000 mg 3,4,5,6,6-pentamethylheptan-2-ol/kg body
weight/day for 28 days did not occur (see also Section 5.2.1; RIFM,
1985c).
5.5.1.4. Oral.
5.5.1.4.1. Primary alcohols. 2-Ethyl-1-hexanol administered by
gavage, 167 mg/kg body weight/day, had no effects on Sertoli cells
and gonocytes of 3-day old CD Sprague–Dawley rats (4/group) (Li
et al., 2000). Daily gavage doses of 2.7 mmol 2-ethyl-1-hexanol/
kg (350 mg/kg body weight) of for 5 days did not induce testicular
damage in 35-day old male Sprague–Dawley rats (Sjoberg et al.,
1986).
In a 90-day gavage systemic toxicity study no effects on reproductive
organs of rats and mice were noted up to doses of 500 mg
2-ethyl-1-hexanol/kg body weight/day (see Section 5.2.1.1, Astill
et al., 1996a).
In combined repeated dose and reproductive/developmental
toxicity screening test (OECD TG 422) with gavage application
of3,5,5-trimethyl-1-hexanol (see Section 5.2.1.1) no effects on fertility
were observed in males. In females a dose dependent decrease
in implantation index was noted in the 60 and 300 mg/kg
group (MHW, Japan, 1997b as cited in OECD/SIDS, 2003). Based
on these findings, the NOAELs for fertility were 12 mg/kg body
weight/day for females and 300 mg/kg body weight/day for males.
5.5.1.4.2. Secondary alcohols. In the combined repeated dose
and reproductive/developmental toxicity screening test (OECD TG
422) with gavage application of 4-hydroxy-4-methyl-2-pentanone
(see Section 5.2.1.1), a metabolite of 4-methyl-2-pentanol, no statistically
significant changes in any reproductive parameter at any
dose were noted. According to the authors there was a tendency for
lower reproductive indices (fertility and implantations, no further
information) at the highest dose of 1000 mg/kg body weight/day.
Therefore the NOAEL for fertility was 300 mg/kg body weight/day
(MHW, Japan, 1997 as cited in OECD/SIDS, 2007).
2,6-Dimethyl-4-heptanol showed no effects on the reproductive
organs of rats in a 13-week feeding study with the only tested dose
of 11 mg/kg body weight/day (Posternak and Vodoz, 1975). Its
metabolite 2,6-dimethylheptane-4-one given by gavage has been
assessed in a reproduction/developmental toxicity screen (OECD
TG 421) and did not lead to reproductive effects up to the highest
tested dose of 1000 mg/kg body weight/day (Shell HSE, 1996 as cited
in OECD/SIDS, 2004).
5.5.1.4.3. Tertiary alcohols. No studies were available.
5.5.1.5. Inhalation.
5.5.1.5.1. Primary alcohols. In a 90-day inhalation study in rats,
no effects on the reproductive organs were seen at concentrations
up to 120 ml/m 3 2-ethyl-1-hexanol (Klimisch et al., 1998).
5.5.1.5.2. Secondary alcohols. With 4-methyl-2-pentanone, the
metabolite of 4-methyl-2-pentanol, a two-generation study performed
in Sprague–Dawley rats (30/sex/group) exposed to 0, 500,
1000, or 2000 ml/m 3 (0, 2050, 4090, or 8180 mg/m 3 ), for 6 h per
day, 7 days per week. Treatment started 70 days prior to mating
for the F 0 and F 1 generations, continued to the end of the mating
period for males and to day 20 of gestation for females. Treatment
of females resumed at day 5 of lactation. Because of CNS depression
in F 1 pups upon initiation of exposures on post-natal day 22
and the death of one F 1 male pup from the 2000 ml/m 3 group,
treatment was interrupted and continued on day 28. In males of
all exposure groups alpha-2u-globulin nephropathy was observed.
F 0 and F 1 adults of the mid and high exposure groups showed a
sedative effect, which was reversible 1 h after exposure. Decreased
body weight gain and slightly decreased food consumption during
the first 2 weeks of exposure occurred only at the high concentration
in both generations. There were no effects on reproductive and
developmental parameters, or on estrous cycle and sperm parameters.
The NOAEL for systemic toxicity was established at 1000 ml/
m 3 (4090 mg/m 3 ) due to slightly reduced body weight and feed
consumption at 2000 ml/m 3 . The NOAEL for reproductive toxicity
was 2000 ml/m 3 (8180 mg/m 3 ) (Nemec et al., 2004). In view of
the clinical signs of CNS depression of adults during the exposures
at 1000 and 2000 ml/m 3 the systemic parental NOAEL is 500 ml/
m 3 .
Histopathological examinations in the 6-week inhalation study
with 4-methyl-2-pentanol (Blair, 1982 as cited in OECD/SIDS,
2007) showed no adverse effects on the reproductive organs of
male and female rats up to the highest concentration tested
(886 ml/m 3 ). For further details see Section 5.2.1.2.
5.5.1.5.3. Tertiary alcohols. No studies were available.
5.5.2. Developmental toxicity
5.5.2.1. Dermal. 2-Ethyl-1-hexanol (99.72% pure) was administered
on the clipped dorsal skin by occlusive cover to F344 rats 6 h per
day from gestation days 6–15 at doses of 0, 0.5, 1.0, 2.0, or
3.0 ml/kg body weight/day (0, 420, 840, 1680, or 2520 mg/kg body
weight/day) in a range-finding study (8/group). In the main study
(25/group) doses of 0, 0.3, 1.0, and 3.0 ml/kg body weight/day (0,
252, 840, or 2520 mg/kg body weight/day) were applied. Persistent
exfoliation, crusting, and erythema on the application site were
seen in both studies from 840 mg/kg body weight/day. Maternal
weight gain was reduced at 1680 and 2520 mg/kg body weight/
day. The NOAELs for maternal toxicity were 252 mg/kg body
weight/day based on skin irritation and 840 mg/kg body weight/
day based on systemic toxicity. The developmental NOAEL was
the highest tested dose of 2520 mg/kg body weight/day (Fisher
et al., 1989; Tyl et al., 1992).

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46 S21
Table 4-1
Mutagenicity and genotoxicity: in vitro studies.
Material Test system Concentration Results References
Subgroup: primary
2-Ethyl-1-hexanol Rec-assay Bacillus subtilis H17, M45 500 lg/disk in DMSO Negative Tomita et al. (1982)
Urine of 2-ethyl-1-hexanol
treated rats (1000 mg/kg
body weight for 15 days)
Rec-assay Bacillus subtilis HA101, Rec-4 Diluted in DMSO to make the
inhibition circle between I.D. 9 and
40 mm
Ames assay with and without S9
activation (preincubation method)
Ames assay with and without S9
activation (preincubation method)
Ames assay with and without S9
activation (preincubation method)
Ames assay with and without S9
activation (preincubation method)
Ames assay with and without S9
activation (method unspecified)
Ames assay with and without S9
activation (preincubation method)
Ames assay with and without S9
activation (preincubation method)
L5178Y TK +/ mouse lymphoma
mutagenicity assay
S. typhimurium TA98, TA100, TA1537,
TA1538, TA 1535, E. coli WP2uvrA
S. typhimurium TA98, TA100, TA1535,
TA1537
S. typhimurium TA98, TA100, TA1535,
TA1537
S. typhimurium TA98, TA100, TA1535,
TA1537, 1538, 2637
1–1000 lg/plate in DMSO, growth
inhibition P500 lg/plate
Positive Saido et al. (2003)
Not mutagenic Shimizu et al. (1985)
3.3–333 lg/plate in DMSO Not mutagenic Zeiger et al. (1982)
3.3–220 lg/plate in DMSO Not mutagenic Zeiger et al. (1985)
100–2000 lg/plate in DMSO, tested
up to cytotoxic concentrations
Not mutagenic Agarwal et al. (1985)
S. typhimurium (unspecified) n.f.i. Not mutagenic Barber et al. (1985)
S. typhimurium TA98, TA100, TA1535,
TA1537, 1538
0.01–1.0 ll/plate in DMSO, cytotoxic
concentration P1.0 ll/plate
Not mutagenic Kirby et al. (1983)
S. typhimurium TA98, TA100 0.1–10.0 lM, n.f.i. Not mutagenic Warren et al. (1982)
L5178Y mouse lymphoma cells 0.013–1.0 ll/ml in DMSO, cytotoxic
concentration P1.0 ll/ml
Not mutagenic Kirby et al. (1983)
8-Azaguanine resistance assay S. typhimurium TA100 0.5–1.5 lM, n.f.i. Mutagenic Seed (1982)
Hodgson et al. (1982)
UDS assay Primary rat hepatocytes cultures
prepared from Fischer 344 rats
Cells were treated simultaneously
with test compound and tritiated
thymidine for 1 h, n.f.i.
Did not induce detectable levels of
UDS
Chromosomal aberration assay Chinese hamster ovary cells 1.5–2.8 mM Did not induce an increased
frequency of chromosomal
aberrations compared to the control;
50% kill at 2.5 mM
Ames assay with and without S9
activation (standard plate assay)
S. typhimurium TA98, TA100, TA1535,
TA1537, TA 1538
Isoamyl alcohol Comet assay Chinese hamster V79 fibroblast cells,
human lung carcinoma epithelial cell
line A549, and human peripheral
blood cells (pB)
Isotridecan-1-ol (isomeric
mixture)
Up to 2 ml undiluted urine, negative
and positive controls: urine of
untreated rats and
8-hydroxyquinoline
umu test: Light absorption S. typhimurium TA1535/pSK1002 Concentrations in which growth
inhibition 650% (n.f.i.)
umu test: Luminiscent S. typhimurium TA1535/pTL210 concentrations in which growth
inhibition 650% (n.f.i.)
Micronucleus test with and without
S9 activation
HPRT test with and without S9
activation
Ames assay with and without S9
activation
Phillips et al. (1982)
Not mutagenic DiVincenzo et al. (1985)
0, 23, 46, 91 mM DNA damage at at cytotoxic
concentrations (91 mM in V79 and
A549 cells), extremely cytotoxic in pB
Kreja and Seidel (2001, 2002)
(analyses not possible)
Negative Nakajima et al. (2006)
Positive
Chinese hamster V79 fibroblast cells 0, 5, 9, 23 mM Not genotoxic Kreja and Seidel (2002)
Chinese hamster V79 fibroblast cells Up to 51.5 mM (highest non-toxic
concentration)
S. typhimurium TA98, TA100, TA1535,
TA1537
Not mutagenic Kreja and Seidel (2002)
20-5000 lg/plate no cytotoxicity Not mutagenic RIFM (1989)
2-Methylbutanol umu test: Light absorption S. typhimurium TA1535/pSK1002 Concentrations in which growth Negative Nakajima et al. (2006)
umu test: Luminiscent S. typhimurium TA1535/pTL210 inhibition 650% (n.f.i.)
Positive
Comet assay Chinese hamster V79 fibroblast cells,
human lung carcinoma epithelial cell
line A549, and human peripheral
blood cells (pB)
0, 45, 90 mM DNA damage at cytotoxic
concentrations (45 mM in A549,
90 mM in V79 cells), extremely
cytotoxic in pB (analyses not
possible)
Kreja and Seidel (2001, 2002)
(continued on next page)

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D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
Table 4-1 (continued)
Material Test system Concentration Results References
Micronucleus test with and without
S9 activation
HPRT test with and without S9
activation
3,5,5-Trimethyl-1-hexanol Ames assay (preincubation assay)
with and without metabolic
activation OECD TG 471, 472
Chromosomal aberration and
polyploidy OECD TG 473
Chinese hamster V79 fibroblast cells 0, 23, 45 mM Not genotoxic Kreja and Seidel (2002)
Chinese hamster V79 fibroblast cells Up to 46 mM (highest non-toxic
concentration)
S. typhimurium TA98, TA100, TA1535,
TA1537, E. coli WP2uvrA
up to 500 lg/plate cytotoxicity:
P150 lg/plate (±S9)
Chinese hamster lung cells (CHL/IU) up to 100 lg/ml cytotoxicity:
200 lg/ml
Not mutagenic Kreja and Seidel (2002)
Not mutagenic MHW, Japan (1997c) as cited
in OECD/SIDS (2003)
Not genotoxic MHW, Japan (1997d) as cited
in OECD/SIDS (2003)
Subgroup: secondary
2,6-Dimethyl-4-heptanol Ames assay with and without S9
activation (standard plate assay)
2,6-Dimethylheptan-4-one Mitotic gene conversion assay with
and without S9
4-Hydroxy-4-methyl-2-
pentanone
Ames assay with and without S9
activation (standard plate assay)
Ames assay with and without S9
activation (standard plate assay)
S. typhimurium TA98, TA100, TA1537,
TA1538, TA 1535, E.coli WP2uvrA
3.33–1000 lg/plate with S9 mix in
DMSO,
1.00–500 lg/plate iwith S9 mix in
DMSO, cytotoxic concentration:
P333 lg/plate
Saccharomyces cerevisiae 0.01–5.0 mg/ml, cytotoxicity at
0.5 mg/ml with S9, at 5.0 without S9
S. typhimurium TA98, TA100, TA1535,
TA1537, TA 1538, E.coli WP2uvrA
31.25-4000 lg/plate in DMSO,
cytotoxic concentration: P500 lg/
plate
S. typhimurium n.f.i. 1–333 lg/plate, no cytotoxicity
observed
Cytogenetic assay Rat liver cell (RL4) 62.5–500 lg/ml, cytotoxicity at the
highest dose level tested
Ames assay with and without
metabolic activation
Chromosomal aberrations and
polyploidy OECD TG 473
S. typhimurium TA98, TA100, TA1535,
TA1537, E. coli WP2uvr A
313–5000 lg/plate no cytotoxicity
was observed
Chinese hamster lung cells (CHL/IU) 300–1200 lg/ml no cytotoxicity
observed at the highest concentration
Not mutagenic Mecchi (2002) as cited in
DOW (2003)
Negative Mortelmans et al. (1986)
Not mutagenic Brooks et al. (1985) as cited
in OECD/SIDS (2004) Brooks
et al. (1988)
Not mutagenic Mortelmans et al. (1986)
No increased incidence of
chromosome aberrations
Brooks et al. (1985) as cited
in OECD/SIDS (2004) Brooks
et al. (1988)
Not mutagenic MHW, Japan (1997) as cited
in OECD/SIDS (2007)
polyploidy increase at 600 and
1200 lg/ml, without dosedependence
not genotoxic
MHW, Japan, 1997, as cited
in OECD/SIDS (2007)
4-Methyl-2-pentanone UDS n.f.i. n.f.i. Negative IPCS, 1990 as cited in
OECD/SIDS (2004)
Ames assay n.f.i. n.f.i. Negative IPCS (1990) as cited in
OECD/SIDS (2004)
Mouse lymphoma test n.f.i. n.f.i. Equivocal IPCS (1990) as cited in
OECD/SIDS (2004)
4-Methyl-2-pentanol Ames assay with and without S9
activation
3,4,5,6,6-
Pentamethylheptan-2-ol
(55–80%) and 3,4,5,6,6-
pentamethylheptan-2-
on (20–45%)
Ames assay with and without
metabolic activation
Gene mutation with and without
metabolic activation
S. typhimurium TA98, TA100, TA1535,
TA1537, TA1538, E. coli WP2uvr A
S. typhimurium TA98, TA100, TA1535,
TA1537, TA1538, E. coli WP2 uvr A
pkm 101
up to 5000 lg/plate cytotoxicity:
5000 lg/plate (±S9)
31.25–4000 lg/plate no cytotoxicity
was observed
Saccharomyces cerevisiae JD1 10–5000 lg/plate cytotoxicity:
5000 lg/plate
Cytogenetic assay Rat liver cell (RL4) 0, 0.5, 1, 2 mg/ml no cytotoxicity was
observed
Ames assay with and without
metabolic activation (plate
incorporation test)
S. typhimurium TA98, TA100, TA1535,
TA1537, TA1538, E. coli WP2 uvrA
1. test: up to 1000 lg/plate
2. test: up to 100 lg/plate
cytotoxicity: P500 lg/plate
Not mutagenic Shimizu et al. (1985)
Not mutagenic Clare (1983) as cited in
OECD/SIDS (2007)
Not mutagenic Clare (1983) as cited in
OECD/SIDS (2007)
Negative Clare (1983) as cited in
OECD/SIDS (2007)
Not mutagenic RIFM (1985b)
DMSO: dimethylsulfoxide, n.f.i.: no further information, n.s.: not statistically significant.

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46 S23
Table 4-2
Mutagenicity and genotoxicity: in vivo studies.
Material Test system Species (No./dose) Dose/Concentration Results References
Subgroup: primary
2-Ethyl-1-hexanol DNA binding in vivo by [ 14 C] labeled
2-ethyl-1-hexanol; 16 h after the
administration of the radiolabeled
test substance: isolation of liver DNA
and analyzing for radioactivity
DNA binding in vivo by [ 14 C] labeled
2-ethyl-1-hexanol, 24 h after the
administration of the radiolabeled
test substance: isolation of liver DNA
and analyzing for radioactivity
Bone marrow micronucleus assay,
n.f.i.
Cytogenetic assay with bone marrow
cells
2 Female Fischer 344 rats
and 2 female NMRI mice
Diet containing 1% di(2-ethylhexyl)
phthalate (rat) or di(2-ethylhexyl) adipate
(mouse) for 4 weeks; radiolabeled [ 14 C] 2-
ethyl-1-hexanol was administered by
gavage (rat: 51.1 or 53.4 mg/kg body
weight; mouse: 120.2 or 109.5 mg/kg
body weight)
Male Fischer rat, n.f.i. Animals were fed a diet containing 1%
di(2-ethylhexyl) phthalate for 11 days ad
libitum. On day 10 they were given a
single oral dose of 100 lCi [1- 14 C] 2-ethyl-
1-hexanol and on day 11 they were
sacrificed
B6C3F1 mouse, n.f.i. Test protocol according to standard tests
performed by Litton Bionetics Inc., n.f.i.
5 Fischer 344 rat/group Oral gavage for 5 consecutive days with
0.02, 0.07, and 0.21 ml/kg body weight/
day (17, 58, 174 mg/kg body weight/
day) = up to 1/10 of the 5-day-LD50
Dominant lethal test Male ICR/SIM mouse n.f.i. 250, 500, and 1000 mg/kg body weight/
day (based on 5-day-LD50) for 5
consecutive days, after treatment each
male was housed with 2 virgin femals per
week for 8 consecutive days, sacrifice of
the females on days 14–17 of caging with
the males; positive control:
trimehtylenemelamine
Isoamyl alcohol Micronucleus Test with bone marrow
cells
NMRI mice (5/sex/dose) 500, 1000, or 2000 mg/kg body weight/
day
No indication for a covalent binding
of 2-ethyl-1-hexanol to liver DNA of
rats or mice; most if not all
radioactivity in liver DNA was due to
biosynthetic incorporation
No binding of the labeled test
substance to liver DNA
Däniken et al. (1984)
Albro et al. (1982)
Not genotoxic, n.f.i. Astill et al. (1986); Barber et al.
(1985)
No increase in chromatid and
chromosome breaks compared to the
controls; mitotic index was not
affected, no toxicity observed, no
reliable negative result
No dominant lethal mutations;
fertility indices and average numbers
of dead and total implants per
pregnancy were within the normal
range
Putman et al. (1983)
Rushbrook et al. (1982)
Non-mutagenic RIFM (2008)
Subgroup: secondary
4-Methyl-2-pentanone Micronucleus test n.f.i. n.f.i. Negative IPCS (1990) as cited in OECD/
SIDS (2004)
3,4,5,6,6-
Pentamethylheptan-2-ol
Bone marrow micronucleus assay
(i.p.), sacrified: 30, 48, 72 h after
application
Mouse (5/sex/dose) 0, 900 mg/kg body weight in corn oil Not genotoxic PCE/NCE reduced 48
and 72 h after dosing
RIFM (1985d)
n.f.i.: no further information, PCE: polychromatic erythrocytes, NCE: normochromatic erythrocytes.

S24
D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
5.5.2.2. Oral.
5.5.2.2.1. Primary alcohols. Wistar rats were given a single dose
of 6.25 or 12.5 mmol 2-ethyl-1-hexanol/kg body weight (833 or
1666 mg/kg body weight) by gavage on day 12 of pregnancy, and
underwent caesarean section on day 20 of pregnancy. At the higher
dose, 22.2% of the surviving fetuses had malformations (lower dose
group 2% and controls 0%). These included hydronephrosis (7.8%),
tail anomalies (4.9%), malformed limbs (9.7%), and ‘‘others” (1%).
In the higher dose group the average fetal weight was reduced.
Implantation index, numbers of dead and resorbed fetuses were
unaffected. Although the dose of 1666 mg/kg body weight is
around half of the oral LD 50 , no maternal toxicity was reported
(Ritter et al., 1987).
Pregnant Sprague–Dawley rats (6/group) were gavaged with a
single dose of 0, 6.25, 9.38, or 12.5 mmol 2-ethyl-1-hexanol/kg
body weight (equivalent to 0, 813, 1219, and 1625 mg/kg body
weight) in corn oil on gestation day 11.5, followed 8 h later by
32 lCi 65 Zn and killed on gestation day 12.5. From 1219 mg/kg
body weight the maternal food intake was reduced, maternal liver
metallothionein and 65 Zn concentrations were higher, whereas in
the embryos the 65 Zn content was lower than in animals which
did not receive 2-ethyl-1-hexanol. The percentage of resorptions
was not affected by the test substance (Bui et al., 1998).
2-Ethyl-1-hexanol was administered daily by gavage to Wistar
rats (10/group) from gestation days 6 to 19 at doses of 0, 1, 5, or
10 mmol/kg body weight/day (equivalent to 0, 130, 650, and
1300 mg/kg body weight/day). At the lowest dose no maternal
and fetal effects occurred. At 650 mg/kg body weight/day, fetus
weights were significantly lower and the incidence of skeletal variations
and retardations was increased. At 1300 mg/kg body
weight/day maternal body weight measured on days 15 and 20
was significantly reduced; clinical signs (salivation, CNS depression,
nasal discharge) were observed, and 6 dams died. Postimplantation
losses, resorptions, number, and percent of fetuses
and litters with malformations and variations, and number and
percent of fetuses with retardations were increased. The fetal
weight was decreased. The maternal and developmental NOAEL
were 130 mg/kg body weight/day each (Hellwig and Jäckh, 1997).
Groups of 28 CD-1 Swiss mice were given >99% pure 2-ethyl-1-
hexanol microencapsulated in their diet at concentrations of 0%,
0.009%, 0.03%, and 0.09% from days 0 to 17 of pregnancy. This corresponded
to calculated doses of 0.13, 43, and 129 mg/kg body
weight/day. No maternal toxicity was observed and the birth rate
was 93–96% in all groups. All of the litters survived and all gestational
parameters were normal. There were no external, visceral,
or skeletal malformations and no increase in variations occurred.
The authors concluded that 2-ethyl-1-hexanol plays essentially
no role in the expression of DEHP-induced maternal and developmental
toxicity (NTP, 1991; Price et al., 1991). As no toxic doses
were reached, no conclusion on the potential of developmental
toxicity of 2-ethyl-1-hexanol in mice can be drawn from this study.
In a screening test, mice (Charles River CD-1) were given
1525 mg 2-ethyl-1-hexanol/kg body weight/day by gavage from
days 7 to 14 of pregnancy (50 animals treated and 50 controls).
The dams and pups were observed until day 3 of lactation. Signs
of toxicity in the dams included significantly reduced body weight
and movement, ataxia, hypothermia, unkempt coats, and blood in
the urine. Seventeen animals died of exposure-related causes. The
number of live pups and their weight were significantly reduced
(Hardin et al., 1987). A NOAEL cannot be deduced from this study.
Twenty-five pregnant Wistar rats were gavaged with 0 (corn
oil), 100, 500, or 1000 mg/kg body weight/day on gestation days
6–15. The test material was a mixture of C7–9 branched alcohols,
with isooctyl alcohol as the main component (CAS No. 68526-83-
0). In the mid- and high-dose groups statistically significant increases
in the number of lumbar ribs were observed. The authors
state that, due to the lack of embryotoxicity these findings were
attributed to maternal toxicity observed during treatment. However,
in the 500 mg/kg body weight/day group no maternal toxicity
was reported. In high-dosed dams emaciation, rales, hypoactivity,
decreased food consumption, and body weight gain were observed.
The total number of fetuses with skeletal variations and with hypoplastic
skull bones was noted. These findings exceeded the historical
control range of the laboratory but were not observed with
litter-based analysis. The maternal NOAEL was set at 500 mg/kg
body weight/day and the fetal NOAEL at 1000 mg/kg body
weight/day (EBSI, 1994a, as cited in Nishimura et al., 1994). As increased
incidences of lumbar ribs were seen from 500 mg/kg body
weight/day at which dose no maternal toxicity was reported, the
NOAEL for developmental toxicity should better be evaluated as
100 mg/kg body weight/day.
Two different isomeric mixes of isononyl alcohol (isononanol
type 1 and isononanol type 2, CAS No. 68515-81-1 for both) and
isodecyl alcohol were administered by gavage to Wistar rats
Table 5-1
Carcinogenicity studies.
Material Method Dose Species (No./dose) Results References
Subgroup: primary
2-Ethyl-1-hexanol
Cell transformation
assay with and
without metabolic
activation
Cell transformation,
anchorage
independence,
without metabolic
activation
Oral (gavage),
5 days/week,
18 months
Oral (gavage),
5 days/w, 24 months
96–180 nl/ml; survival:
31.7–72% in the
concomitant cytotoxicity
test, positive control:
cyclophosphamide
4–77 10 7 mM, no
information on cytotoxicity
0, 50, 200, 750 mg/kg body
weight/day
0, 50, 150, 500 mg/kg body
weight/day
BALB 3T3 cells Negative Barber et al. (1985) and
RIFM (1983b)
JB6 cell line of
mouse epidermis
cells
B6C3F1 mouse,
50/sex/group
F344 rat, 50/sex/
group
Negative Ward et al. (1986)
750 mg/kg body weight/day:
weak hepatocellular carcinoma
increase (f), body weight gain
decrease, mortality increase
P150 mg/kg body weight/day:
body weight gain decrease,
lethargy, unkemptness 500 mg/
kg body weight/day: mortality:
52% f
Astill et al. (1996b)
Astill et al. (1996b)

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46 S25
Table 6-1
Reproductive and developmental toxicity studies - dermal.
Material Method Concentration/dose Species (No./dose) Results References
2-Ethyl-1-hexanol
Occlusive, 6 h/day,
on gestation days
6–15, caesarean
section at day 21
Range-finding study: 0, 0.5, 1.0,
2.0, and 3.0 ml/kg body weight/
day (0, 420, 840, 1680, or
2520 mg/kg body weight/day)
Main study: 25/group 99.72%
pure 0, 0.3, 1.0, and 3.0 ml/kg
body weight/day (0, 252, 840, or
2520 mg/kg body weight/day)
F344 rats (range-finder:
8 f/group; main study:
25 f/group)
NOAEL maternal toxicity: 252 mg/kg
body weight/day based on skin
irritation and 840 mg/kg body
weight/day based on systemic
toxicity NOAEL developmental
toxicity: 2520 mg/kg body weight/
day
Maternal: P840 mg/kg body weight/
day: Persistent exfoliation and
crusting and erythema at application
site; maternal liver, kidney, thymus,
spleen, adrenal, and uterine weights
and gestational and fetal parameters
were unaffected by treatment;
P1680 mg/kg body weight/day:
weight gain decrease
Fetal: no treatment-related increases
in incidence of individual or pooled
external, visceral, or skeletal
malformations or variations
Deisinger et al. (1994);
Tyl et al. (1992)
(10/group) daily on gestation days 6–15. The doses for the isononyl
alcohols were 0, 1, 5, 7.5, and 10 mmol/kg body weight/day (0, 144,
720, 1080, and 1440 mg/kg body weight/day), for isodecyl alcohol
0, 1, 5, and 10 mmol/kg body weight/day (0, 158, 790, and
1580 mg/kg body weight/day). Isononyl alcohol 1 mainly consists
of dimethyl heptanols. Isononyl alcohol 2 mainly consists of dimethyl
heptanols and methyl octanols. The test procedure was
according to OECD TG 414 with the exception that 10 instead of
20 animals per dose level were used. At the lowest dose of isononyl
alcohol 1 there was an equivocal increase in the incidence of fetuses
with hydroureter (11%, which was only slightly above the
highest incidence of 4 control groups used in the study, 9.2%).
The highest historical control incidence was reported to be 7.7%
for studies conducted in the same time interval as the study under
question. A clear dose–response was not seen. Therefore, a substance-related
effect is questionable. At the lowest dose of isononyl
alcohol 2 no maternal and fetal toxicity was seen. At a dose of
720 mg/kg body weight/day and more of isononyl alcohols 1 and
2, signs of maternal and developmental toxicity, including decreased
body weight, increased resorption rates, and increased
skeletal variations and retardations were observed. At doses of
1080 mg/kg body weight/day and more the incidences of malformations
were elevated. For isodecyl alcohol, maternal toxicity (reduced
body weight gain and clinical signs) was evident at 790 mg/
kg body weight/day and more. Developmental toxicity including
reduced mean fetal body weight and skeletal retardations were observed
only in the highest dose group. The maternal NOAEL for
isononyl alcohol 1 and isononyl alcohol 2 is 144 mg/kg body
weight/day and for isodecyl alcohol 158 mg/kg body weight/day.
The NOAEL for developmental toxicity for isononyl alcohol 1 and
2 is 144 mg/kg body weight/day and for isodecyl alcohol 790 mg/
kg body weight/day. Isononyl and isodecyl alcohol are developmental
toxins only at doses that produce maternal toxicity (Hellwig
and Jäckh, 1997; RIFM, 1991a).
In a combined repeated dose and reproductive/developmental
toxicity screening test with gavage application of 3,5,5-trimethyl-
1-hexanol (OECD TG 422) (see Section 5.2.1.1) the following results
concerning developmental toxicity were observed: the number of
pups born alive diminished in the 60 and 300 mg/kg body
weight/day groups. In the high-dose group total litter loss was observed
in two dams, the viability of neonates on day 4 of lactation
was lower, and male and female pups showed lower body weights
on day 0 of lactation (MHW, Japan, 1997b as cited in OECD/SIDS,
2003). Therefore, the NOAEL for systemic toxicity and developmental
toxicity were considered 12 mg/kg body weight/day. Skeletal
and visceral effects were not investigated in the pups.
5.5.2.2.2. Secondary alcohols. In the combined repeated dose
and reproductive/developmental toxicity screening test with gavage
application of 4-hydroxy-4-methyl-2-pentanone [OECD TG
422] (see Sections 5.2.1.1 and 5.5.2), a tendency for a decrease of
developmental parameters was observed at the highest dose of
1000 mg/kg body weight/day. These effects included the total
number of pups born, delivery index, live birth index, number of
pups alive and viability index on day 4 of lactation The NOAEL
for developmental toxicity was 300 mg/kg body weight/day. The
NOAEL for maternal toxicity was 100 mg/kg body weight/day
(MHW, Japan 1997, as cited in OECD/SIDS, 2007). OECD TG 422
does not provide for an evaluation of skeletal and visceral effects
in pups.
2,6-Dimethylheptan-4-one has been assessed in a reproduction/
developmental toxicity screening test 20 rats (10/sex) were given
0, 100, 300, or 1000 mg 2,6-dimethylheptan-4-one/kg body
weight/day in corn oil by gavage from 2 weeks prior to mating
throughout pregnancy until weaning day 5 post partum when
the dams and offspring were sacrificed. Two dams at the top dose
level died during lactation due to the test substance. There was no
evidence of an effect on any of the reproductive parameters investigated
or on any of the surviving litters. The NOAEL for developmental
effects is the highest tested dose of 1000 mg 2,6-
dimethylheptan-4-one/kg body weight/day, with a parental NOAEL
of 300 mg/kg body weight/day (Shell HSE, 1996 as cited in OECD/
SIDS, 2004). OECD TG 421 does not provide for an evaluation of
skeletal and visceral effects in pups.
5.5.2.2.3. Tertiary alcohols. No studies were available.
5.5.2.3. Inhalation.
5.5.2.3.1. Primary alcohols. Pregnant Wistar rats (20–25) were
whole body exposed 6 h per day on gestation days 6–15 to 0,
510, 2500, or 9800 mg isoamyl alcohol/m 3 (0, 138, 675, and
2646 ml/m 3 ). Body weight gain was decreased at the highest concentration
between days 6 and 9 but there were no compound-related
effects on conception rate, mean number of corpora lutea,
implantation sites, pre- and post-implantation losses, and number
of resorptions, viable fetuses, sex ratio, mean fetal, and placental
weight. No external, visceral, or skeletal malformations were observed.
The NOAEL for maternal toxicity was 2500 mg/m 3
(675 ml/m 3 ) and the NOAEL for developmental toxicity 9800 mg/
m 3 (2646 ml/m 3 ) (Klimisch and Hellwig, 1995).

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D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
Table 6-2
Reproductive and developmental toxicity studies – oral.
Material Method Concentration/dose Species (No./dose) Results References
Subgroup: primary
2-Ethyl-1-hexanol Gavage, 3 days/week, 3-day old males
0, 167 mg/kg body
weight/day
Gavage, 5 days, 35-day 2.7 mmol/kg body
old male rats
weight/day (350 mg/kg
body weight/day)
Gavage on day 12 0 (untreated), 6.25 or
Gavage, on gestation
day 11.5; after 8 h
intubated with 32 lCi
65 Zn, killed on
gestation day 12.5
Gavage from days 6 to
19 of pregnancy
Days 0–17 of
pregnancy
12.5 mmol (833,
1666 mg/kg body
weight/day), undiluted
0, 6.25, 9.38 or
12.5 mmol 2-ethy-1-
hexanol/kg body
weight in corn oil
(equivalent to 0, 813,
1219, 1625 mg/kg body
weight)
0, 1, 5, and 10 mmol/kg
body weight/day (0,
130, 650, and 1300 mg/
kg body weight/day)
Diet: 0%, 0.009%, 0.03%,
and 0.09%
(microencapsulated)
(0.13, 43 and 129 mg/
kg body weight/day)
>99% pure test
substance
CD Sprague–Dawley rats (4 m/group) No effect on Sertoli cells and gonocytes Li et al. (2000)
Sprague–Dawley rats No testicular damage Sjoberg et al. (1986)
Wistar rats (7 f/group) Maternal: no maternal toxicity was
reported
Fetal: 1666 mg/kg body weight/day: 22.2%
of the surviving fetuses had
malformations (lower dose group 2%,
controls 0%). These included
hydronephrosis (7.8%), tail anomalies
(4.9%), malformed limbs (9.7%) and
‘‘others” (1%); average fetal weight
decreased
Implantation index, average fetal weight,
numbers of dead and resorbed fetuses
were not affected
Sprague–Dawley rats (6 f/group) Maternal: P1219 mg/kg body weight:
maternal food intake decreased; 1625 mg/
kg body weight: percentage of 65 Zn
retained in maternal liver increase
Fetal: the percentage of resorptions was
not affected
1625 mg/kg body weight: percentage of
65 Zn retained in the embryos decreased
Wistar rats (10 f/group) NOAEL maternal and developmental
toxicity: 130 mg/kg body weight/day
Maternal: P650 mg/kg body weight/day:
1300 mg/kg body weight/day: body
weight decreased; mortality increased
Fetal: P650 mg/kg body weight/day:
weight decreased, skeletal variations and
retardation increased
1300 mg/kg body weight/day: postimplantation
loss, resorptions, number
and percent fetuses and litters with
malformations and variations, and
number and percentage of fetuses with
retardations increased; fetal weight
decreased
CD-1 Swiss mice (28 f/group) NOAEL maternal and developmental
toxicity: 129 mg/kg body weight/day but
no toxic dose tested
No maternal toxicity; all of the litters
survived and all gestational parameters
were normal
Ritter et al. (1987)
Bui et al. (1998); Taubeneck et al.
(1996)
Hellwig and Jäckh (1997)
NTP (1991) and Price et al. (1991)

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46 S27
Isooctyl alcohol (C7–9
alcohols, branched
(CAS No. 68526-83-
0))
Isotridecan-1-ol
(isomeric mixture)
Isononyl alcohol
(Isononanol type 1
(CAS No. 68515-81-
1))
Gavage from days 7 to
14 of pregnancy; the
dams and pups were
observed until day 3 of
lactation
0, 1525 mg/kg body
weight/day in corn oil
Gavage, days 6–15 p.c.,
according to OECD TG
414
0, 100, 500, 1000 mg/
kg body weight/day in
corn oil
Gavage, days 6–19 p.c. 0 (olive oil), 60, 250, or
750
Gavage, days 6–15 p.c.
according to OECD TG
414
0 (control 1: water,
control 2: water with
0.005% Cremophor EL),
1, 5, and 10 mmol/kg
body weight/day (0,
144, 720, and 1440 mg/
kg body weight/day) in
aqueous Cremophor EL
Supplementary study:
0 (control 1: water,
control 2: water with
0.005% Cremophor EL)
and 7.5 mmol/kg body
weight/day (0,
1080 mg/kg body
weight/day) because of
mortality of all dams at
10 mmol/kg (1440 mg/
kg) body weight/day
Charles River CD-1 mice (50 f/group) NOAEL for maternal/developmental
toxicity cannot be derived
Sprague–Dawley rat
(25 f/group)
Maternal: 1525 mg/kg/d: 17/49 died
(controls 0), reduced movement, ataxia,
hypothermia, unkempt coats and blood in
the urine, body weight and fertility and
pregnancy index decrease
Fetal: 1525 mg/kg/day: number of live
pups and in their weight decrease. No
further parameters were considered in
this study
NOAEL maternal toxicity: 500 mg/kg body
weight/day
NOAEL developmental toxicity: 100 mg/kg
body weight/day
Maternal: 1000 mg/kg: food consumption
decreased, body weight gain from GD6–9
and GD6–15 decreased, clinical signs
(emaciation, rales, hypoactivity,
abdominal/anogenital staining, little or no
stool)
Fetal: P500 mg/kg: number of lumbar ribs
increased
1000 mg/kg body weight/day: number of
fetuses with skeletal variations increased,
hypoplastic skull bones increased only on
a per-fetus basis
Hardin et al. (1987)
Wistar rats (25/f/group) NOAEL for maternal toxicity: 250 mg/kg RIFM (2003b)
NOAEL for developmental toxicity:
750 mg/kg
Maternal: 750 mg/kg: transient
salivation;11% reduction of food
consumption (6–10 p..c); increased
alanine aminotransferase values;
increased triglycerides (14%) and relative
liver weights (18%); decreased total
protein and globulin concentrations
250 mg/kg: transient salivation
Fetal: 750 mg/kg body weight/day: no
effects
Wistar rats (10 f/group) NOAEL for maternal toxicity: 144 mg/kg
body weight/day NOAEL for
developmental toxicity: 144 mg/kg body
weight/day
EBSI (1994a) as cited in Exxon
(2001a)
Hellwig and Jäckh (1997) and EPA,
1991
Maternal: P720 mg/kg: food consumption
(days 6–10 p.c.) decreased, clinical signs
(apathy, nasal discharge)
1080 mg/kg: severe maternal signs (n.f.i.),
mortality (1/10)
1440 mg/kg: mortality (10/10)
Fetal: 144 mg/kg body weight/day: fetuses
with hydroureter (8/73; 11.0%, control 1:
0/68, control 2: 3/69, 4.3%), no further
effects
(continued on next page)

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D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
Table 6-2 (continued)
Material Method Concentration/dose Species (No./dose) Results References
Isodecyl alcohol Gavage, days 6–15 p.c.,
according to OECD TG
414 (10 instead of 20
recommended
animals/group)
3,5,5-Trimethyl-1-
hexanol
Gavage, males:
46 days, females: from
14 days before mating
to day 3 of lactation,
OECD TG 422
0, 1, 5, and 10 mmol/kg
body weight/day (0,
158, 790, and 1580 mg/
kg body weight/day) in
aqueous Cremophor EL
0, 12, 60, 300 mg/kg
body weight/day in
olive oil
720 mg/kg body weight/day: fetuses with
hydroureter (8/67, 12.0%), fetal number
decreased and % fetuses with skeletal
variations and retardations increased
1080 mg/kg: fetuses with hydroureter (3/
37, 8.1%, control 1: 6/65, 9.2%, control 2: 2/
58, 3.4%); mean uterine and fetal weights
decreased, resorptions increased, postimplantation
loss increased, number and
% fetuses and litters with malformations
increased (mainly related to the heart),
number and % fetuses with retardations
increase, skeletal variation increase
(rudimentary-cervical rib(s) increased
(11/0 control 1, 11/1 control 2))
1440 mg/kg body weight/day:
examination of fetuses not possible
because of maternal death
Wistar rats (10 f/group) NOAEL maternal toxicity: 158 mg/kg body
weight/day
NOAEL developmental toxicity: 790 mg/
kg body weight/day
Maternal: P790 mg/kg: food consumption
decreased, body weight on days 15 and 20
decreased, clinical symptoms (nasal
discharge, salivation, and CNS depression)
1580 mg/kg: mortality increased
Fetal: 1580 mg/kg: mean uterine and fetal
weights decreased, resorptions increased,
postimplantation loss increased, number
and % fetuses with malformations and
retardations increased
SD (Crj:CD) rat (12/sex/dose) NOAEL systemic toxicity males and
females: 12 mg/kg body weight/day
NOAEL fertility: 12 mg/kg body weight/
day (females)
300 mg/kg body weight/day (males)
NOAEL developmental toxicity: 12 mg/kg
body weight
Parental: P12 mg/kg body weight/day:
renal hyaline droplets, eosinophilic bodies
(m)
P60 mg/kg body weight/day: rel. liver
weight increase (m,f), abs. and rel. kidney
weight increase (m), pale discoloration of
kidneys (m), renal tubular epithelial
regeneration (m), formation of granular
casts in kidney (m), renal epithelial fatty
change (f); implantation index decrease (f)
300 mg/kg body weight/day: 1 f died, 3 f
killed (weakness); body weights increase
(m), food consumption increase (m), body
weights decrease (f), food consumption
decrease (f); urine volume increase (m),
water consumption increase (m); red
blood cell counts decrease (m), hematocrit
Hellwig and Jäckh (1997)
MHW, Japan (1997b) as cited in
OECD/SIDS (2003)

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46 S29
decrease (m), hemoglobin decrease (m),
BUN decrease (m), chloride decrease (m)
abs. liver weight increase (m,f), rel. kidney
weight increase (f), swelling of kidney (m),
yellowish white discoloration of liver (f),
irregularity in shape of follicles (m),
columnar change of follicular epithelium
(m), thyroid colloid decrease (m), thymus
atrophy (f); total litter loss in 2 dams
Fetal: P60 mg/kg body weight/day:
decreased pups born alive
300 mg/kg body weight/day: viability of
neonates on day 4 of lactation decreased,
body weights of male and female pups ?
decreased
Subgroup: secondary
2,6-Dimethylheptan-4-
one
4-Hydroxy-4-methyl-2-
pentanone
Gavage, from 2 weeks
prior to mating
throughout pregnancy
until weaning day 5
post partum (OECD TG
421)
OECD TG 422
(screening test): males:
44 days, females: from
14 days before mating
to day 3 of lactation
0 (vehicle), 100, 300,
1000 mg/kg body
weight/day in corn oil
0, 30, 100, 300,
1000 mg/kg body
weight/day in water
Alpk:ApfsSD rats (10/sex/group) NOAEL parental systemic toxicity:
300 mg/kg body weight/day
NOAEL developmental/reproductive
effects: 1000 mg/kg body weight/day
Maternal: 1000 mg/kg body weight/day:
two dams died during lactation,
attributable to the test substance. There
was no effect on the number of
pregnancies, positive smears, litters born,
number of implantations or proportion of
pups born live in any dose group
Paternal: 1000 mg/kg body weight/day:
male body weight gains decrease
No changes in organ weight and no
significant histopathological changes in
the male or female reproductive organs;
no evidence of an effect on any of the
reproductive parameters investigated or
on any of the surviving litters
Crj:CD(SD) rat (10/sex/dose) NOAEL parental systemic toxicity:
100 mg/kg body weight/day
NOAEL for fertility and developmental
toxicity: 300 mg/kg body weight/day
Parental: tendency for lower reproductive
indices (fertility and implants) (n.f.i.)
Fetal:1000 mg/kg body weight/day:
tendency for decrease of the following
parameters: total number of pups born,
delivery index, live birth index, number of
pups alive, viability index on day 4 of
lactation (n.f.i.)
f: female, m: male, n.f.i.: no further information, n.s.: not statistically significant, p.c.: post coitum
Shell HSE (1996) as cited in OECD/
SIDS (2003)
MHW, Japan (1997) as cited in OECD/
SIDS (2007)

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D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
Table 6-3
Reproductive and developmental toxicity studies – inhalation.
Material Method Concentration/dose Species (No./dose) Results References
Subgroup: primary
2-Ethyl-1-hexanol Whole body exposure from day 0
to 19 of pregnancy
Isoamyl alcohol Inhalation, days 6 through GD15,
6 h/day, caesarean section on
day 20 GD, OECD TG 414
Inhalation, days 7 through 19 pi,
6 h/day, caesarean section on
day 29 pi OECD TG 414
0, 850 mg/m 3 (160 ml/m 3 )
the maximum vapor
concentration that could
be achieved without
increasing exposure
chamber temperature
above 80°F
0, 510, 2500, 9800 mg/m 3
(0, 138, 675, 2646 ml/m 3 )
0, 510, 2510, 9800 mg/m 3
(0, 138, 678, 2646 ml/m 3 )
Sprague–Dawley rats
(15 f/group)
Wistar female rat
(20–25 f/group)
Himalayan female
rabbit (15 f/group)
NOAEL 160 ml/m 3 Nelson et al. (1989)
Maternal: 160 ml/m 3 : no maternal toxicity
Fetal: 160 ml/m 3 : no significant differences in
corpora lutea per litter, resorptions per litter,
numbers of females or males per litter, or fetal
weight of females or males, and no external,
visceral, or skeletal malformations
NOAEL maternal toxicity: 675 ml/m 3 Klimisch and Hellwig (1995)
NOAEL developmental toxicity: 2646 ml/m 3 RIFM (1990a)
Maternal: 2646 ml/m 3 : body weight gain (days 6–
9)decreased; no test substance-related clinical signs
Fetal: no litter parameters affected; no gross
external, soft tissue, or skeletal fetal alterations
NOAEL maternal toxicity: 678 ml/m 3 Klimisch and Hellwig (1995)
NOAEL developmental toxicity: 2646 ml/m 3 RIFM (1990b)
Maternal: 2646 ml/m 3 : body weight gain (days 7–
10) decreased; eye irritation (redness, lid closure,
slight discharge)
Fetal: no litter parameters affected; no gross
external, soft tissue, or skeletal fetal alterations
Subgroup: secondary
4-Methyl-2-pentanone Inhalation Two-generation study, exposure 0, 500, 1000, or
2000 ml/m 3 (0, 2050,
4090, or 8180 mg/m 3 )
6 h/day, 7 days/w (30/sex/group)
Sprague–Dawley rat NOAEL systemic toxicity: 1000 ml/m 3 (excluding
male nephropathy)
NOAEL reproductive toxicity: 2000 ml/m 3
duration (F 0 ,F 1 ): F 0 adults: P500 ml/m 3 : centrilobular hepatocellular
hypertrophy only in males, abs./rel. kidney weights
Males: 70 d prior to end through
increase (m)
mating period
Females: 70 d prior to mating to
day 20 of gestation, resumed at
5 days of lactation
US EPA OPPTS Guideline 870-
3800
1000 ml/m 3 : nephropathy (basophilic tubules with
inflammation and thickening of the tubular
basement membrane) (m), sedative effect (absent
or reduced reaction to auditory startle stimulus
(normalized 1 h after end of exposure))
2000 ml/m 3 : body weight gain decrease (f); abs.
and rel. liver weights increase (m,f)
Nemec et al. (2004)

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46 S31
Inhalation, days 6–15 p.c.,
6 h/day, duration of study:
21 days, according to OECD TG
414
Inhalation, days 6–15 p.c.,
6 h/day, duration of study:
18 days, according to OECD TG
414
0 (air), 300, 1000,
3000 ml/m 3 (0, 1230,
4090, 123,000 mg/m 3 )
0 (air), 300, 1000,
3000 ml/m 3 (0, 1230,
4090, 123,000 mg/m 3 )
Fischer 344 rat
(35 f/group)
F 1 adults: P500 ml/m 3 : kidney changes (alpha-2uglobulin
nephropathy) (m)
P1000 ml/m 3 : sedative effect (s.a.) (m),
centrilobular hepatocellular hypertrophy (m)
2000 ml/m 3 : absent or reduced reaction to auditory
startle stimulus (ameliorated 1 h after end of
exposure) (f); 1 m died on PND 22, clinical signs of
neurotoxicity (i.e., rocking, prostration, half-closed
eyelids) approx. 1 h post-exposure (PND
22) ) exposures for all groups of F1 weanlings
suspended through PND 27; body weight gain
(transient) decrease (m,f); abs. and rel. liver
weights increase (m, f), centrilobular hepatocellular
hypertrophy (m)
F1/F2 Offspring: reproductive parameters unaffected
NOAEL maternal toxicity: 1000 ml/m 3 Tyl et al. (1987)
NOAEL developmental toxicity: 1000 ml/m 3
Maternal: 3000 ml/m 3 : neuromuscular effects (e.g.
loss of coordination, paresis); body weight and body
weight gain decreased, food consumption
decreased, rel. kidney weights increased
Fetal: 3000 ml/m 3 : body weight per litter decreased,
skeletal ossification retarded, unilateral
rudimentary rib at the first lumbar arch increased
CD-1 mice (30 f/group) NOAEL maternal toxicity: 1000 ml/m 3 Tyl et al., (1987)
NOAEL developmental toxicity: 1000 ml/m 3
Maternal: 3000 ml/m 3 : 3 dams died on GD 6;
neuromuscular effects, abs. and rel. liver weights
increased
Fetal: 3000 ml/m 3 : body weight per litter decreased,
number of dead fetuses increased, visceral
variations (dilated lateral ventricles of the
cerebrum and dilated renal blood vessels)
increased, skeletal variations (vertebrae, sternbrae,
and distal limbs) increased, skeletal ossification
retarded
DEHP: di(2-ethylhexyl) phthalate, f: female, GD: gestation day, m: male, s.a.: see above, n.f.i.: no further information, MEHP: mono(2-ethylhexyl) phthalate, n.s.: not statistically significant, p.c.: post-coitum, pi: post-insemination.
4-Methyl-2-pentanone is not a fragrance material, but is structurally related.

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D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
The same test procedure was performed with 14–15 pregnant
Himalayan rabbits. The animals were exposed to 0, 510, 2510, or
9800 mg isoamyl alcohol/m 3 (0, 138, 678, and 2646 ml/m 3 ) from
day 7 to day 19 post-insemination. In dams exposed to the highest
concentration body weight gain was decreased between days 7 and
10 post insemination and irritant eye effects (reddish, lid closure,
and slight discharge) were noted. Histopathological examination
of the dams revealed no substance-related effects. The reproduction
parameters (e.g. mean number of corpora lutea, implantation
sites, values calculated for the pre- and post-implantation losses,
and number of resorptions) and malformations (external, visceral,
or skeletal) were within the levels of the concurrent control group
or of historical control groups. The maternal NOAEL was 2500 mg/
m 3 (678 ml/m 3 ) and the NOAEL for developmental toxicity was
9800 mg/m 3 (2646 ml/m 3 ) (Klimisch and Hellwig, 1995).
Fifteen pregnant Sprague–Dawley rats were exposed (whole
body) 7 h per day on gestation days 0–19 to 850 mg 2-ethyl-1-hexanol/m
3 (160 ml/m 3 ), the maximum vapor concentration that
could be achieved without increasing exposure chamber temperature
above 80 ° F. After caesarean section on day 20, one-half of the
fetuses were examined for skeletal malformations, the other half
for visceral malformations. Aside from a decrease in feed consumption
in dams compared to control, there were no significant differences
in maternal, reproductive, or developmental parameters
(Nelson et al., 1989). The NOAEL for maternal and developmental
toxicity was 850 mg/m 3 (160 ml/m 3 ).
5.5.2.3.2. Secondary alcohols. Thirty-five pregnant Fischer 344
rats or 30 pregnant CD-1 mice were exposed 6 h per day on gestation
days 6–15 to 0, 300, 1000, and 3000 ml 4-methyl-2-pentanone/
m 3 (0, 1230, 4090, and 12,300 mg/m 3 ). Maternal toxicity (neuromuscular
effects, e.g. loss of coordination or paresis) was observed
in both species after exposure to the highest concentration. Rat
dams showed reductions in body weights, body weight gain, and
food consumption. The relative kidney weights were elevated. In
mice, three dams died at the first exposure and the relative and
absolute liver weights were increased. Reduced fetal body weight
per litter and delayed skeletal ossification was observed in both
species at the highest concentration. Rat fetuses showed an increased
incidence of unilateral rudimentary rib at the first lumbar
arch. In mice, the number of dead fetuses as well as visceral and
skeletal variations was increased. The NOAELs for maternal and fetal
toxicity were 1000 ml/m 3 for both species (Tyl et al., 1987 as cited
in OECD/SIDS, 2007).
5.5.2.3.3. Tertiary alcohols. No studies were available.
5.6. Skin irritation
5.6.1. Human studies
Seven alcohols with saturated branched chain under review
with a worldwide use of greater than 0.01 tons per year have been
well studied for their potential to produce dermal irritation in humans
(see Table 7-1).
The following substances did not induce skin irritation in pretests
for a maximization study with single occlusive application
for 48 h with the highest concentrations tested, i.e., 20% 3,6-dimethyl-3-octanol
(RIFM, 1972a, 1973c), 10% 3,7-dimethyl-7-methoxyoctan-2-ol
(RIFM, 1982b), 10% 2,6-dimethyl-2-heptanol (RIFM,
1976b, 1983a), 8% isoamyl alcohol (RIFM, 1976b), 8% 3,5,5-trimethyl-1-hexanol
(RIFM, 1977b), and 4% 2-ethyl-1-hexanol (RIFM,
1976c).
No irritation was observed with 2% 2,6-dimethyl-2-heptanol
during the induction phase of a human repeat insult patch test
(HRIPT) in 10 healthy male and female volunteers (RIFM, 1969).
The repeated application of 15% 3,4,5,6,6-pentamethylheptan-2-
ol during the induction phase of a HRIPT led to erythema (6 grade
1 of 4, 4 grade 2 of 4) in 5 of 51 volunteers (RIFM, 1983c).
A patch test (5 min under occlusion) was conducted on 12
healthy volunteers and with 3 or 12 subjects of oriental ancestry
with a 75% aqueous solution of isoamyl alcohol. Irritation reactions
were observed in all volunteers (Wilkin and Fortner, 1985a,b; Wilkin
and Stewart, 1987).
Further details on studies of dermal irritation in humans are
provided in Table 7-1.
5.6.2. Animal studies
Twelve of the alcohols under review with a worldwide use of
greater than 0.01 tons per year have been tested in animal models
of skin irritation using rabbits, rats, or guinea pigs. Studies with
single application are summarized in Table 7-2-1 and studies with
repeated application are shown in Table 7-2-2.
A single application of neat 3,4,5,6,6-pentamethylheptan-2-ol
did not produce dermal irritation in rabbits (RIFM, 1984b) and rats
(RIFM, 1985a). If applied undiluted as a single application, 2-ethyl-
1-butanol, 2-ethyl-1-hexanol, isoamyl alcohol, 2-methylbutanol,
3,5,5-trimethyl-1-hexanol, 2,6-dimethyl-4-heptanol, 4-methyl-2-
pentanol, 2,6-dimethyl-2-heptanol, and 3,6-dimethyl-3-octanol
(McOmie and Anderson, 1949; RIFM, 1973a, 1976a, 1977a; Scala
and Burtis, 1973; Cornu et al., 1992, 1984, 1978) led to slight or
moderate irritation in all studies with rabbits irrespectively of
the method used. As an exception undiluted 2,6-dimethyl-2-heptanol
was strongly irritating after 24 h occlusive application (RIFM,
1979a). The diluted substances led to no or only slight effects in
rabbits or guinea pigs: 3,6-dimethyl-3-octanol 15% no to slight
reactions (RIFM, 1970), 2,6-dimethyl-2-heptanol 10% no reaction
(RIFM, 1981a), 3,7-dimethyl-7-methoxyoctan-2-ol 1% slight reaction
(RIFM, 1973e).
Five percent 3,7-dimethyl-7-methoxyoctan-2-ol did not produce
dermal irritation in guinea pigs after repeated application
(RIFM, 1973d). Repeated application of neat 2-ethyl-1-hexanol
led to slight dermal irritation in rats (Schmidt et al., 1973). Moderate
or strong irritation was observed after repeated applications of
undiluted 2,6-dimethyl-4-heptanol, 4-methyl-2-pentanol, and
3,4,5,6,6-pentamethylheptan-2-ol (also diluted) in rabbits (McOmie
and Anderson, 1949; RIFM, 1985c, 1986a). Toxicity studies
with repeated dermal application (see Section 5.2.1) also showed
dermal irritation especially with 3,4,5,6,6-pentamethylheptan-2-
ol. These studies were performed with high doses under occlusion
and are therefore not representative of human exposure.
5.7. Mucous membrane irritation
5.7.1. Sensory irritation
5.7.1.1. Human data. The results of the human irritation studies are
summarized in Table 8.
Human male volunteers (with and without self-reported multiple
chemical sensitivity) were exposed to 2-ethyl-1-hexanol by
inhalation for 4 h (exposure chamber). Fluctuating concentrations
(time weighted average concentrations: 1.5 (control), 10, and
20 ml/m 3 ) were used in the first experiment, and similar but constant
vapor concentrations in a second experiment. Olfactory- and
trigeminal-mediated symptoms and intensities of odor, eye, and
nasal irritation were recorded. Self-reported nasal and eye irritation
and perceived odor intensity were increased and concentration-related
at concentrations of 10 ml/m 3 or more. Self-reported
chemical sensitivity had only minor effects on chemosensory
symptoms in the second experiment (constant concentrations)
and no effect on intensity ratings in either experiment (van Thriel
et al., 2005).
An average of 12 subjects were exposed by inhalation to 2,6-dimethyl-4-heptanol
for 15 min. At 5 ml/m 3 or more, eye irritation
was observed, and at 10 ml/m 3 nose and throat irritation. The sensory
response limit was reported to be less than 5 ml/m 3 (Silver-

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46 S33
man et al., 1946). In the same study 4-methyl-2-pentanol led to
eye irritation at 50 ml/m 3 and higher concentrations resulted in
nose and throat irritation. The NOEL was 25 ml/m 3 (Silverman
et al., 1946).
5.7.1.2. Animal data. Sensory irritation was evaluated in 4 Swiss
male mice via measurement of changes in respiratory rate during
a 10-min exposure to isoamyl alcohol. The concentration of isoamyl
alcohol that caused a 50% decrease in the respiratory rate
(RD 50 ) of mice was 4452 ml/m 3 with 95% confidence limits of
2885–12,459 ml/m 3 (Kane et al., 1980). Another study reported a
RD 50 value of 2624 mg/m 3 (729 ml/m 3 ) (Korpi et al., 1999).
After a 5-min exposure to 4-methyl-2-pentanol the RD 50 for
mice was 420 ml/m 3 (6 animals/group) (Muller and Greff, 1984
as cited in Greim, 2002).
5.7.2. Eye irritation
No human studies on eye irritation are available. An overview of
in vivo studies on eye irritation in rabbits can be found in Table 9.
Several in vitro tests to investigate the eye irritation potential
did show an irritating effect of 2-ethyl-1-hexanol (Adriaens and
Remon, 2002; Adriaens et al., 2005; Casterton et al., 1996; Gautheron
et al., 1994; Gilleron et al., 1997; Goethem et al., 2006; Kennah
et al., 1989a).
For 3,7-dimethyl-7-methoxyoctan-2-ol only one study with a
1% solution in propylene glycol was available, in which the substance
did not cause irritating effects (RIFM, 1973e).
In 4 of 5 studies, isotridecan-1-ol (isomeric mixture) elicited no
eye irritation in rabbits (Greim, 2000). Further information about
the test method and the concentration were not given. The undiluted
substance was moderately irritating to the rabbit eye in
one study (Greim, 2000; Scala and Burtis, 1973).
Undiluted 3,6-dimethyl-3-octanol was evaluated as an eye irritant.
The substance led to redness and chemosis of the conjunctiva,
slight corneal opacity, and swelling of the iris. The effects were not
reversible within 3 days (RIFM, 1970).
In three studies undiluted 2-ethyl-1-hexanol was moderately
irritating to the rabbit eye (Carpenter and Smyth, 1946; Schmidt
et al., 1973; Smyth et al., 1969). Observed effects were conjunctival
redness and swelling, lacrimation, and discharge. The effects did
not clear within 96 h. Corneal effects were not found (Schmidt
et al., 1973). In three other studies, the undiluted substance was
classified as a severe eye irritant (Kennah et al., 1989b; RIFM,
1978b; Scala and Burtis, 1973). These studies resulted in dullness
and vascularization of the cornea (Scala and Burtis, 1973). The corneal
effects were persistent (RIFM, 1978b). In addition, iritis, conjunctival
erythema, chemosis, and discharge appeared (Scala and
Burtis, 1973).
Undiluted 2,6-dimethyl-2-heptanol, 2,6-dimethyl-4-heptanol,
4-methyl-2-pentanol, and 3,4,5,6,6-pentamethylheptan-2-ol were
moderate eye irritants (McOmie and Anderson, 1949; RIFM,
1979a, 1984c; Smyth et al., 1951). The substances caused conjunctivitis
with edema and corneal injury. The effects disappeared
within 7 days (McOmie and Anderson, 1949; RIFM, 1984c) except
for those caused by 2,6-dimethyl-2-heptanol (RIFM, 1979a).
Undiluted 2-ethyl-1-butanol, isoamyl alcohol, and 2-methylbutanol
were highly irritating to the rabbit eye (Smyth et al., 1954,
1962, 1969).
5.8. Skin sensitization
5.8.1. Human studies
Seven of the alcohols under review with a worldwide use of
greater than 0.01 tons per year have been evaluated for their potential
to induce sensitization in humans (see Tables 10-1 and
10-2).
In both subgroups of primary and secondary alcohols no evidence
of a sensitizing effect in a maximization test or in a human
repeated insult patch test (HRIPT) with volunteers was observed
with 4% 2-ethyl-1-hexanol (RIFM, 1976c), 8% isoamyl alcohol
(RIFM, 1976b), 8% 3,5,5-trimethyl-1-hexanol (RIFM, 1977b), 10%
3,7-dimethyl-7-methoxyoctan-2-ol (RIFM, 1982b), and 15%
3,4,5,6,6-pentamethylheptan-2-ol (RIFM, 1983c). In the subgroup
of tertiary alcohols 2,6-dimethyl-2-heptanol did not induce positive
reactions in a maximization test (10%, RIFM, 1976b) or a HRIPT
(2%, RIFM, 1969). In a maximization test with 20% 3,6-dimethyl-3-
octanol in petrolatum (RIFM, 1972a), 4 of 25 volunteers exhibited
positive reactions 24 and 48 h after challenge. However, since
these four subjects also reacted strongly to a control material it
was concluded that the reactions observed were due to a ‘‘spill
over” effect from the other material. In a second test with 10% in
petrolatum, the positive reactions could not be confirmed (RIFM,
1973c).
With a sub-irritating concentration (no further information) of
3,7-dimethyl-7-methoxyoctan-2-ol in petrolatum, 0.9% positive
reactions (2 patients) were found in patch tests with 218 patients
with proven sensitization to fragrance materials (Table 10-2; Larsen
et al., 2002).
5.8.2. Animal studies
Results of available animal studies are shown in Table 10-3. In
comparison to humans, limited data on sensitization in animals
are available. Only one secondary and one tertiary alcohol were
tested.
2,6-Dimethyl-2-heptanol was negative in guinea pigs at a concentration
of 10% (Watanabe et al., 1988). No delayed-type hypersensitivity
was observed for 3,7-dimethyl-7-methoxyoctan-2-ol in
the same species (RIFM, 1973d).
5.9. Phototoxicity and photoallergenicity
Limited data were available with regard to the phototoxicity
and photoallergenicity of the alcohols with saturated branched
chain (see Table 11). From human or animal studies reliable data
were available only on the phototoxicity and photoallergenicity
of the tertiary alcohol 2,6-dimethyl-2-heptanol.
No phototoxic reactions were observed in 6 healthy female volunteers
exposed to 10% 2,6-dimethyl-2-heptanol in 1:1 ethanol/
acetone, followed by irradiation by UVA (RIFM, 1983a).
In the only animal phototoxicity study, 10% 2,6-dimethyl-2-
heptanol in ethanol produced no phototoxic reactions after UVA
or UVB irradiation in guinea pigs (RIFM, 1981a).
No studies have been performed which investigate the photoallergic
potential in humans.
2,6-Dimethyl-2-heptanol was tested for its photoallergenicity
in a reliable test with guinea pigs (RIFM, 1981b). No photoallergenicity
was seen in the animals induced with 10% in rectified alcohol,
followed by irradiation with UVB and UVA (9 times in 18 days),
and challenged after a 10-day rest with 10% of the test substance in
rectified alcohol and irradiation.
As the alcohols under review do not contain double bonds, they
cannot absorb UVA or UVB light. Indeed, UV spectra have been
obtained for 12 materials (2-ethyl-1-hexanol, isoamyl alcohol,
isotridecan-1-ol (isomeric mixture), 2-methylbutanol, 3-methyl-
1-pentanol, 2-methylundecanol, 3,5,5-trimethyl-1-hexanol, 2,6-dimethyl-4-heptanol,
3,7-dimethyl-7-methoxyoctan-2-ol, 6,8-dimethylnonan-2-ol,
3,4,5,6,6-pentamethylheptan-2-ol, and 2,6-
dimethyl-2-heptanol). Five materials did not absorb UV light, the
remaining 5 peaked in the UVC range (

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D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
Table 7-1
Skin irritation studies in humans.
Material Method Concentration Subjects Results References
Subgroup: primary
2-Ethyl-1-hexanol 48 h, occlusive (pretest
for a maximization
study)
Isoamyl alcohol 48 h, occlusive (pretest
for a maximization
study)
3-Methyl-1-pentanol 24 h, occlusive (pretest
for a HRIPT)
4% in petrolatum 29 healthy male volunteers No irritation RIFM (1976c)
8% in petrolatum 25 healthy volunteers No irritation RIFM (1976b)
5 min, occlusive 75% in water 12 volunteers Irritation in all 12
volunteers
5 min, occlusive 75% in water 12 volunteers (oriental) Irritation in all 12
volunteers
5 min, occlusive 75% in water 3 volunteers (oriental) Irritation in all 3
volunteers
3,5,5-Trimethyl-1-hexanol 48 h, occlusive (pretest
for a maximization
study)
0.5% in alcohol SDA 39 C 41 healthy volunteers Little or no irritation RIFM (1973f)
Wilkin and Stewart (1987)
8%, in petrolatum 25 healthy volunteers No irritation RIFM (1977b)
Wilkin and Fortner (1985a)
Wilkin and Fortner (1985b)
Subgroup: secondary
3,7-Dimethyl-7-methoxyoctan-2-ol 48 h, occlusive (pretest
for a maximization
study)
3,4,5,6,6-Pentamethylheptan-2-ol During the induction
phase of a repeated
insult patch test
(HRIPT): 9 applications
with a duration of 24 h
within a 3-week
period, occlusive,
0.2 ml, observations on
the application days
10%, petrolatum 27 healthy male and female volunteers No irritation RIFM (1982b)
15% v/v solution in ethanol SDA 39C (99%) 51 healthy male and female volunteers 10/48 positive
reactions: 5 grade 1
reactions (erythema
confined to the contact
site and exceeding that
of the untreated skin)
and 5 grade 2 reactions
(erythema confined to
the contact site and
definitely exceeding
that of the untreated
skin; papules may or
may not be present)
RIFM (1983c)
Subgroup: tertiary
2,6-Dimethyl-2-heptanol 48 h, occlusive (pretest
for a maximization
study)
0.025 ml/2 cm 2 ,
occlusive, up to 72 h
Induction phase of
HRIPT
3,6-Dimethyl-3-octanol a 48 h, occlusive (pretest
for a maximization
study)
48 h, occlusive (pretest
for a maximization
study)
3-Methyloctan-3-ol a 48 h, occlusive (pretest
for a maximization
study)
10% in petrolatum 25 healthy volunteers No irritation RIFM (1976b)
10% in 1:1 ethanol/acetone 6 healthy female volunteers No irritation RIFM (1983a)
2% in dimethyl phthalate 10 healthy male and female volunteers No irritation RIFM (1969)
10% in petrolatum 5 healthy male volunteers No irritation RIFM (1973c)
20% in petrolatum 5 healthy male volunteers No irritation RIFM (1972a)
10% in petrolatum 29 healthy volunteers No irritation RIFM (1978a)
a
No relevant use was reported.

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46 S35
Table 7-2-1
Skin irritation studies in animals, single application.
Material Method Concentration Species Results References
Subgroup: primary
2-Ethyl-1-butanol 24 h, uncovered, 0.01 ml sample on
the clipped skin
Undiluted Rabbit (n = 5) An average reaction to a trace of capillary injection Smyth et al. (1954)
2-Ethyl-1-hexanol 5000 mg/kg, n.f.i. Undiluted Rabbit (n = 10) Moderate redness and edema in 10/10 RIFM (1977a)
Rabbit (n = 5) Moderate irritation observed Smyth et al. (1969)
24 h, uncovered, 0.01 ml sample on
the clipped skin
24 h, occlusive, 0.1, 0.316, 1.0,
3.16 mg/kg body weight, on the
clipped intact skin, observations daily
up to 7 days
Undiluted or as a solution in water,
propylene glycol or acetone
Undiluted Rabbit (n = 4) Moderate irritation: moderate erythema, moderate
edema, atonia, blanching, desquamation,
coriaceousness, necrosis, and eschar
Scala and Burtis (1973)
Isoamyl alcohol Single application of 5.0 g/kg Undiluted Rabbit (n = 10) Marked erythema and moderate edema RIFM (1976a)
Single application Undiluted Rabbit (n = 6) Very irritating RIFM (1979c)
isotridecan-1-ol (mixed
isomers)
24 h, uncovered, 0.01 ml sample on
the clipped skin
Single occlusive patch for 24 h to
intact skin of 4 rabbits
Single uncovered application of
0.01 ml for 24 h
Percutaneously to the intact dorsal
skin for 20 h
Undiluted or as a solution in water,
propylene glycol or acetone
Rabbit (n = 5) Irritation was observed Smyth et al. (1969)
Undiluted Rabbits Moderately irritating Scala and Burtis (1973)
Undiluted Rabbits Moderately irritating Smyth et al. (1962)
Undiluted Rabbits Severe erythema and distinct edema at 24 h distinct
scarring and severe scaling at 8 days
4-h semi-occlusive irritation Undiluted Rabbits Slight to marked erythema, slight or moderate
edema and scaling
2-Methylbutanol 24 h, uncovered, 0.01 ml sample on
the clipped skin
Undiluted Rabbit (n = 5) Irritation defined as the least visible capillary
injection from the undiluted material
RIFM (1963d,e)
RIFM (2003a)
Smyth et al. (1962)
n.f.i. Undiluted Rabbit (n = 2) Moderately irritating RIFM (1979b)
3-Methyl-1-pentanol 0.5 ml application, 24 h contact, 0.5% in alcohol SDA 39C Rabbit (n = 3) No erythema and edema observed RIFM (1972c)
observed again at 48 h
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
RIFM (1977a)
Subgroup: secondary
2,6-Dimethyl-4-heptanol Neat application as part ofl LD 50 Undiluted Rabbit (n = 5) No irritation Smyth et al. (1949)
4 h, semi-occlusive, 3.9-9.4 ml/kg body weight on the shaved skin
Undiluted Rabbit (n = 5) 2/5 some erythema and slight edema McOmie and Anderson
(1949)
3,7-Dimethyl-7-
methoxyoctan-2-ol
24 h, occlusive, 0.5 ml, abraded and
intact skin, observations after 24,
72 h
1% in propylene glycol Rabbit (n = 6) Mildly irritating, PII 0.5, 5/6 very slight erythema in
the intact and abraded sites after 24 h, 1/6 very
slight erythema in the intact and abraded sites after
72 h
4-Methyl-2-pentanol Details of the method not reported Concentration and vehicle not reported Rabbit, n.f.i. 2/10 defined as an average reaction equivalent to a
trace of capillary injection
3,4,5,6,6-
Pentamethylheptan-2-ol
0.25 h, observation period of 10 days,
n.f.i.
7 applications (5 h) to the intact skin
for 21 days
4 h, occlusive, 0.5 ml, clipped skin,
observations at 24, 48, 72 h
24 h, occlusive, 2000 mg/kg body
weight, observations at 24 h, and
daily for 14 days
Undiluted Rabbit (n = 3) Immediate slight erythema and delayed moderate
erythema with drying of surface
Undiluted Rabbits (n = 2) Erythema, flaking, and cracking of the skin with
bleeding fissures by the 7th exposure
RIFM (1973e)
Smyth et al. (1951)
McOmie and Anderson
(1949)
McOmie and Anderson
(1949)
Undiluted Rabbit (n = 6) No irritation RIFM (1984b)
Undiluted Rats (n = 5/sex) No irritation RIFM (1985a)
Subgroup: tertiary
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
slight edema, 9/10 moderate edema
RIFM (1976a)
(continued on next page)

S36
D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
the UV spectra and review of phototoxic/photoallergy data, the
materials in this group would not be expected to elicit phototoxicity
or photoallergy under the current conditions of use as a fragrance
ingredient.
Table 7-2-1 (continued)
Material Method Concentration Species Results References
RIFM (1979a)
Undiluted Rabbit (n = 6) PII 5.1, strongly irritating, after 24 h on intact skin:
6/6 strong redness, 5/6 slight edema, 1/6 strong
edema, slight redness already after 5 min reversible
within 8 days, redness after 24 h application not
reversible within 8 days
1, 5, 15 min, 2, 20 h, intact and
abraded skin, observations after 24 h,
48 h, 8 days; (Federal Register 38, No.
187, § 1500.41, S. 27019, 27. Sept.
1973)
No irritation RIFM (1981a)
10% in ethanol Albino guinea-pig
(n =8)
4 h, patch test, observations after 4 h,
24 h, 48 h (control of a phototoxicity
study)
RIFM (1973a)
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:
moderate edema
RIFM (1970)
Undiluted, 15% in distilled water Rabbit (n = 6) Undiluted PII: 3.4, very slight to moderate/severe
erythema, very slight to slight edema, no
observations were made after 3 days; 15% PII: 2.0,
very slight to well-defined erythema no edema to
very slight edema, 3/6 animals were not entirely
recovered within 7 days a score of 5 or more is
regarded as signifying a primary skin irritant
24 h, occlusive, 0.5 ml, intact and
abraded skin, observations at 24, 48,
72 h
RIFM (1978c)
3-Methyloctan-3-ol a 5000 mg/kg body weight Undiluted Rabbit (n = 10) 4/10: slight redness, 4/10: moderate redness, 2/10:
slight edema, 8/10: moderate edema
n.f.i.: no further information, PII: primary irritation index.
a
No relevant use was reported.
5.10. Miscellaneous studies
To address hepatotoxicity, several miscellaneous studies were
conducted. Ex vivo studies on the mechanism of hepatotoxicity
were conducted with 2-ethyl-1-hexanol, 2-methylbutanol, and
isoamyl alcohol, in vitro enzyme induction and peroxisome proliferation
studies were conducted with 2-ethyl-1-hexanol and isoamyl
alcohol and in vivo repeated dose toxicity studies with 2-
ethyl-1-hexanol, isoamyl alcohol, isodecyl alcohol, isononyl alcohol,
isooctane-1-ol (isomeric mixture) and 3,5,5-trimethyl-1-hexanol
were performed. These studies are not summarized here but
may be found in detail in individual Fragrance Material Reviews
(McGinty et al., 2010a,b,c,d,e,f,g,h,i,j,k,l,m,n,o,p,q). The data show
that 2-ethyl-1-hexanol is a peroxisome proliferator and that 2-
ethyl-1-hexanol, 2-methylbutanol, and isoamyl alcohol induce liver
enzymes.
6. Conclusion
The compounds assessed in this group have a close structural
relationship, similar metabolism, and toxicity profiles.
Data on metabolism for the compounds under review are available
only for the primary alcohols 2-ethyl-1-butanol, 2-ethyl-1-
hexanol, isoamyl alcohol, 2-methylbutanol, and for the secondary
alcohol 4-methyl-2-pentanol.
The major pathways of metabolism and fate which are common
to the primary, secondary and tertiary alcohols in this group are:
– conjugation of the alcohol group with glucuronic acid;
– oxidation of the alcohol group;
– side-chain oxidation yielding polar metabolites, which may be
conjugated and excreted – or further oxidation to an aldehyde,
a carboxylic acid, and to CO 2 ;
– excretion of the unchanged parent compound.
In most cases metabolism yields innocuous substances, which
are excreted in the urine and feces.
Because there is insufficient information for many of the 20
alcohols with saturated branched chain under review, the database
is supplemented with studies of 3 metabolites of these alcohols.
The Panel is of the opinion that there are no safety concerns
regarding alcohols branched chain saturated under the present declared
levels of use and exposure. These materials have not been
evaluated at levels other than reported in this group summary.
Use of these materials at higher maximum dermal levels or higher
systemic exposure levels requires re-evaluation by the Panel. This
conclusion was based on the following reasons:
No, or only minimal, evidence of skin irritation in humans was
caused by 6 compounds tested at concentrations of 2–10%. Due
to the structural similarities, compounds not tested for skin irritation
in humans are expected to show similar properties with
respect to this endpoint. Therefore, the alcohols under review pose
no concern provided concentrations in end products are in the
range of 2–10%, which is above the current concentrations of use.
The 11 materials evaluated for eye irritation showed that the
undiluted materials cause moderate to severe eye irritation.
However, since these materials are not used undiluted they
pose no concern for eye irritation at the concentrations currently
in use in end products (0.001–1.7%).

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46 S37
Table 7-2-2
Skin irritation studies in animals, repeated application.
Material Method Concentration Species Results References
Subgroup: primary
2-Ethyl-1-hexanol 12 applications, over a period of 12 days, uncovered,
2 ml/kg body weight/day on the shaved skin,
observations daily
Undiluted Rat (n = 10) After 10 days slight redness and scabbing Schmidt et al.
(1973)
Subgroup: secondary
2,6-Dimethyl-4-heptanol 7 applications, 5–12 h duration over a period of 15–
21 days, uncovered, 3.0 ml/kg on 100 cm 2 ,
nonabraded skin, observations daily
3,7-Dimethyl-7-methoxyoctan-2-ol 10 applications, 24 h duration on alternate days
during a 3-week period, occlusive, 0.2 ml, shaved
skin, observations
4-Methyl-2-pentanol 5 applications, 5–12 h duration over a period of 15–
21 days, uncovered, 3.0 ml/kg on 100 cm 2 ,
nonabraded skin, observations daily
3,4,5,6,6-Pentamethylheptan-2-ol 9–28 applications, 6 h duration over a period of
28 days, occlusive, nonabraded and clipped skin,
observations daily
Daily applications for 6 h, duration over 28 days,
occlusive, 1000 mg/kg body weight/dayay,
nonabraded skin, observations daily
Undiluted Rabbit (n = 2) definite erythema after 2nd exposure; areas of flaking
after 4th exposure; cracking of skin, fissures with some
bleeding after 7th exposure
2.5, 5% in water,
applications 1–7:
5%, applications
8–10: 2.5%
Guinea pig (n = 10) No irritation, isolated occurences of slight erythema
during the treatment period
Undiluted Rabbit (n = 3) Severe drying of the skin with some sloughing and
cracking
Undiluted, 1.5%,
5%, 15%, 50%
dissolved in 1%
w/v aqueous
methylcellulose
(ca. 30, 100, 300,
1000 mg/kg body
weight/dayay)
Rabbit (n = 10/sex) P30 mg/kg body weight/dayay: erythema and edema
increased dose-dependently; P300 mg/kg body weight/
dayay: after 9 treatments the treatment was terminated
as a result of irritation
Undiluted Rabbit (n = 13/sex) Severe and persistent irritation: dermal irritation
progressed rapidly in all animals to well defined to
moderate erythema and edema within one week;
irritation progressed further in several rabbits becoming
severe within 2 weeks of treatment, scab formation
McOmie and
Anderson (1949)
RIFM (1973d)
McOmie and
Anderson (1949)
RIFM (1986a)
RIFM (1985c)

S38
D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
Table 8
Sensory irritation studies in humans
Clinical signs References
Material Dose route No. subjects/
concentration
group
van Thriel et al. (2005)
P10 ml/m 3 : self-reported nasal and eye irritation
and perceived odor intensity increase; no difference
between subjects with and without sMCS
Constant concentrations:
7 males without and
12 males with sMCS
Subgroup: primary
2-Ethyl-1-hexanol Inhalation, exposure, 4 h: constant concentrations:
(1.5, 10, 20 ml/m 3 ) or fluctuating concentrations
(time-weighted average 1.5, 10, 20 ml/m 3 )
Subgroup: secondary
2,6-Dimethyl-4-heptanol Inhalation, exposure for 15 min 12 Eye irritation at 5 and 10 ml/m 3 , nose and throat
irritation at 10 ml/m 3
4-Methyl-2-pentanol Inhalation exposure for 15 min 12 Eye irritation at 50 ml/m 3 , nose and throat
irritation >50 ml/m 3
sMCS: self-reported multiple chemical sensitivity.
These materials have no or low sensitizing potential. Available
data for five of the substances show that they do not possess a
sensitization potential. However, for 3,6-dimethyl-3-octanol, a
low sensitization potential in humans cannot be excluded. Saturated
alcohols do not form hydroperoxides. They oxidize and
become aldehydes or ketones. The use of these materials under
the declared levels of use and exposure will not induce sensitization.
For those individuals who are already sensitized, there is a
possibility that an elicitation reaction may occur. The relationship
between the no effect level for induction and the no effect
level for elicitation is not known for this group of materials.
Based on the lack of structures, which could absorb UVA or UVB
light, and review of phototoxic/photoallergy data, the alcohols
with saturated branch chains would not be expected to elicit
phototoxicity or photoallergy under the current conditions of
use as a fragrance ingredient.
The 15 compounds tested have a low order of acute toxicity.
The seven branched chain saturated alcohols and three of their
metabolites (see Tables in Section 5.2) tested were of low systemic
toxicity after repeated application. Changes indicative of
enzyme induction in the liver (liver enlargement), peroxisome
proliferation and alpha-2u-nephropathy in male rats have been
observed at doses of 60 mg/kg body weight/day and more. The
lowest NOAEL of all the subacute and sub-chronic oral studies
available, which were performed with five of the substances
under review and the metabolite 4-hydroxy-4-methyl-2-pentanone,
is 10 mg/kg body weight/day for 3,5,5-trimethyl-1-hexanol.
This value is taken as representative for all members of
the group as a worst-case. The database does not allow a definite
conclusion that the toxicity after dermal application is
lower than after oral application by gavage (oral bolus dose
vs. slow uptake via the skin). However, at least 3,4,5,6,6-pentamethylheptan-2-ol
had a much higher systemic NOAEL of
1000 mg/kg body weight/day in a subacute dermal study compared
to the lowest oral NOAEL of 10 mg/kg body weight/day
mentioned above. Several subacute and subchronic inhalation
studies showed a lowest NOAEL of 120 ml/m 3 for 2-ethyl-1-
hexanol corresponding to a dose of 175 mg/kg body weight/
day, assuming a body weight of 261 g, a minute volume of
0.2 l for a rat (Bide et al., 2000) and 100% retention. Comparing
the oral worst-case NOAEL of 10 mg/kg body weight/day to the
worst-case daily uptake of 0.14 mg/kg body weight/day which
was estimated for 3,4,5,6,6-pentamethylheptan-2-ol (100% dermal
absorption assumed as worst-case) the margin of safety is
70 (100% oral absorption is assumed as shown with 2-ethyl-1-
hexanol). For the other compounds for which systemic uptake
in consumers (Table 1) has been estimated by RIFM, the margin
of safety is between 90 and 50,000. There is an adequate margin
of safety for the alcohols under review when applied in consumer
products at the current concentrations.
With 3,5,5-trimethyl-1-hexanol adverse effects on reproduction
were noted at a rather low oral dose (60 mg/kg body weight/
day) with a NOAEL of about 10 mg/kg body weight/day. For this
compound the estimated systemic dose is 0.0036 mg/kg body
weight for consumers (Table 1), leading to a margin of safety
of 2700. 2-Ethyl-1-hexanol induced fetotoxic and teratogenic
effects at high doses of 1300 mg/kg body weight/day in rats,
however, none of the group members tested induced adverse
effects on fertility and development at doses or concentrations
that were not toxic to the parental animals. It should be noted
that in a dermal study with 2-ethyl-1-hexanol no adverse
effects on development in rats were seen with the highest dose
of 2520 mg/kg body weight indicating, that dermal exposure is
less effective in producing adverse effects than oral exposure
most probably due to the different pharmacokinetic behavior
for both application routes.

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46 S39
Table 9
Eye irritation studies in rabbits.
Material Method Results References
Subgroup: primary
2-Ethyl-1-butanol Single application, undiluted or diluted in water of
propylene glycol, grading after 18–24 h, n.f.i.
2-Ethyl-1-hexanol Single application of 0.005 ml, undiluted, grading after
18–24 h, n.f.i.
Single application, one drop, undiluted, 50%, 25%, 12.5%
solutions in oil, observations up to 96 h, one rabbit per
concentration
Single application of 0.1 ml, undiluted, observations
after 1, 4, and 24 h, 2, 3, 4, and 7 days, 6 rabbits
Single application of 0.1 ml, undiluted, observations
after 24, 48, and 72 h, 6 rabbits
Single application of 0.1 ml, undiluted and solution in
propylene glycol or water: 110, 14, and 21 days, 6
rabbits
Produced an injury of necrosis to 63–87% of the eye Smyth et al. (1954)
Severe burn Carpenter and Smyth (1946)
Conjunctival redness and swelling, lacrimation,
discharge, no effects on the cornea
Undiluted test substance: effects not reversible within
96 h
Smyth et al. (1969)
Schmidt et al. (1973)
12.5% no effect
Severe eye irritant Scala and Burtis (1973)
Median scores after 24, 72 h, and 7 days: 19, 20, 0
(Draize scores)
Corneal dullness, opacity (widespread corneal opacity),
and vascularization, irititis, conjunctival erythema,
chemosis, and discharge
Persistent corneal effects RIFM (1978b)
Draize scores
24 h: cornea: 17.5, iris: 2.5, conjunctivae: 7.0
48 h: cornea: 10.8, iris: 0.8, conjunctivae: 7.0
72 h: cornea: 7.5, iris: 0.8, conjunctivae: 5.3
Draize scores Kennah et al. (1989b)
100% solution: 51 (severe), 30%: 35 (severe/moderate),
10%: 39 (moderate), 3%: 30 (moderate), 1%: 9 (mild)
Corneal swelling in % of control:
100% solution: 192%; 30%: 190%; 10%: 162%; 3%: 151%;
1%: 94%
Isoamyl alcohol Single application, undiluted or solution in water or
propylene glycol, n.f.i.
Severe burn Smyth et al. (1969)
RIFM (1979c)
Isotridecan-1-ol (isomeric mixture) Single application, undiluted and observations 1, 24, 48,
Irritation was observed. In one animal slight corneal
RIFM (2002b)
72 h and 7 days after application
opacity and loss of corneal tissue
Single application, undiluted, 0.5 ml Small area of necrosis on the eye Smyth et al. (1962)
Single application, undiluted and observations 1 ant 24 h
after application
Slight irritation RIFM (1963d)
RIFM (1963f)
Single application of 0.1 ml, undiluted, observations
Moderately irritating Scala and Burtis (1973)
after 1, 4, and 24 h, 2, 3, 4, and 7 days, 6 rabbits
2-Methylbutanol Single application, undiluted or solution in water or
Resulted in injury where corneal necrosis was observed Smyth et al. (1962)
propylene glycol, observations and grading after 24 h, 6
animals
Single application, undiluted and observations after 24,
48, and 72 h, 6 animals
Turbidity at the cornea, inflammation on the iris, and
redness, swelling, or secretion of the conjunctivae
RIFM (1979b)
Subgroup: secondary
2,6-Dimethyl-4-heptanol Undiluted, 0.5 ml application, n.f.i. An average reaction, at most a very small area of
necrosis resulting from 0.5 ml of undiluted chemical in
the eye
Single application, undiluted, observations after 24 h,
and 72 h, 1 animal
Moderate; some conjunctivitis with some edema and
corneal injury; score 10 after 24 h, returned to score 0
Smyth et al. (1949)
McOmie and Anderson (1949)
(continued on next page)

S40
D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
Table 9 (continued)
Material Method Results References
3,7-Dimethyl-7-methoxyoctan-2-ol 0.1 ml of a solution of 1% in propylene glycol, single
application, observations after 24, 48, and 72 h, 6
animals
4-Methyl-2-pentanol Single application, undiluted or diluted in water or
propylene glycol, grading after 18–24 h, n.f.i.
Single application, undiluted, observations after 1 h, 24,
and 72 h, 3 animals
3,4,5,6,6-Pentamethylheptan-2-ol Single application, undiluted, 0.1 ml, irrigation for 5 min
after 4 s or 30 s, respectively, or without irrigation,
observations after 1 h, 1, 2, 3, 7 days, 3 animals/group
within 72 h
No irritation RIFM (1973b)
5/6 animals: erythema of the conjunctiva, 1/6 animals:
chemosis of the conjunctiva
No corneal or iris involvement
Effects cleared within 3 days
Severe burn from 0.005 ml Smyth et al. (1951)
Moderate; some conjunctivitis with some edema and
corneal injury; score 11 after 1 h, 25 after 24 h, 17 after
72 h
Returned to normal within 7 days
moderately irritating RIFM (1984c)
Without irrigation
3/3 animals: hyperaemia of the conjunctiva after 1 h
1/3 animals: chemosis of the conjunctiva after 1 h
2/3 animals: corneal opacity after 1 h
Returned to normal after 7 days
1/3 animals was sacrificed in a moribund state after
2 days (bacterial infection)
Irrigation after 30 s
3/3 animals: hyperaemia and chemosis of the
conjunctiva after 1 h
Returned to normal within 2 days
Irrigation after 4 s
2/3 animals: hyperaemia of the conjunctiva after 1 h
Returned to normal within 1 day
McOmie and Anderson (1949)
Subgroup: tertiary
2,6-Dimethyl-2-heptanol Single application, undiluted, observations after 24, 48,
72 h, 8 days, 6 animals
3,6-Dimethyl-3-octanol a 10% (5 animals), 15% (6 animals), 50% (1 animal),
undiluted (6 animals), solutions in 1.25% Tween 20,
observations at 24, 48, 72 h
Primary irritation index (PII): 29.8, moderate irritant RIFM (1979a)
After 24 h: 6/6 slight corneal opacity, 2/6 slight iris
effects, 5/6 moderate conjunctival redness, 6/6 moderate
conjunctival swellings, 3/6 conjunctival scars, which
were not reversible within 8 days
primary irritation index (PII): irritant RIFM (1970)
10%: 2.8
15%: 3.6
50%: 4.0
Undiluted: 3.6, ranges of grading: corneal opacity 0–1,
iris swelling 0–1, redness and chemosis of conjunctiva
1–2, not reversible within 3 days
n.f.i.: no further information.
a
No relevant use was reported.

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46 S41
Table 10-1
Skin sensitization studies in humans.
Material Method Concentration Subjects Results References
Subgroup: primary
2-Ethyl-1-hexanol Maximization test 4% in petrolatum 29 healthy volunteers No sensitization reactions RIFM (1976c)
Isoamyl alcohol Maximization test 8% in petrolatum 25 healthy volunteers No sensitization reactions RIFM (1976b)
3-Methyl-1-pentanol HRIPT 0.5% in alcohol SDA 39C 41 healthy volunteers No sensitization reactions RIFM (1973f)
3,5,5-Trimethyl-1-hexanol Maximization test 8% in petrolatum 25 healthy volunteers No sensitization reactions RIFM (1977b)
Subgroup: secondary
3,7-Dimethyl-7-
methoxyoctan-2-ol
3,4,5,6,6-Pentamethylheptan-
2-ol
Maximization test 10% in petrolatum 27 healthy volunteers No sensitization reactions RIFM (1982b)
HRIPT
15% v/v solution in ethanol
SDA 39C (99%)
51 healthy male and
female volunteers
No sensitization reactions
RIFM (1983c)
Subgroup: tertiary
2,6-Dimethyl-2-heptanol Maximization test 10% in petrolatum 25 healthy volunteers No sensitization reactions RIFM (1976b)
HRIPT 2% in dimethyl phthalate 53 healthy volunteers No sensitization reactions RIFM (1969)
(18 males and 35 females)
HRIPT 5% in alcohol SDA 39C 45 healthy volunteers No sensitization reactions RIFM (1971, 1972b)
(33 females, and 12 males)
3,6-Dimethyl-3-octanol a Maximization test 20% in petrolatum 25 healthy male volunteers Inconclusive because subjects RIFM (1972a)
reacted to other test material
on the same Panel
Maximization test 10% in petrolatum 25 healthy male volunteers No sensitization reactions RIFM (1973c)
(this was a retest)
3-Methyloctan-3-ol a Maximization test 10% in petrolatum 29 healthy male volunteers No sensitization reactions RIFM (1978a)
HRIPT: human repeated insult patch test.
a No relevant use was reported.
Table 10-2
Diagnostic patch tests.
Material Method Concentration Subjects Results Reference
Subgroup: secondary
3,7-Dimethyl-7-
methoxyoctan-2-ol
Patch
test
Concentration and vehicle not
reported
218 patients with proven contact dermatitis
were tested with 3,7-dimethyl-7-
methoxyoctan-2-ol
2 positive
reactions
Larsen et al.
(2002)
Table 10-3
Skin sensitization studies in animals.
Material Method Concentration Species Results References
Subgroup: secondary
3,7-Dimethyl-7- According to Food and Drug Administration of the
methoxyoctan- United States of America in ‘‘Appraisal of the Safety of
2-ol
Chemicals in Food, Drugs and Cosmetics” 1959, p. 51,
except that the test material was applied topically and
not injected: induction: 10 applications with 2.5 or 5%
topically, challenge: 2 weeks later with 2.5% in water
Applications 1–7: 5%
(irritating),
applications 8–10: 2.5%
Guinea pig (n = 10)
No delayed-type
hypersensitivity
RIFM
(1973d)
Subgroup: tertiary
2,6-Dimethyl-2-
heptanol
Maximization test
Induction: 10% in FCA
(intradermal),
challenge: 20% in acetone
Guinea pig (10 in test
group, 10 in control
group)
No sensitization
reactions
Watanabe
et al.
(1988)
FCA: Freund’s complete adjuvant.
Available data on genotoxicity for eight alcohols and three
metabolites do not show such a potential in vitro or in vivo.
Due to the structural similarities of the members of this group
of alcohols, and because both terpene alcohols (Belsito et al.,
2008) and unsaturated branched chain alcohols (Belsito et al.,
2008) did not show a genotoxic potential, no genotoxicity is
expected for the other materials of the group.
A valid carcinogenicity study showed that 2-ethyl-1-hexanol is
a weak inducer of liver tumors in female mice. Mechanistic
studies showed that 2-ethyl-1-hexanol is an activator of
PPAR-alpha. These substances can contribute to liver carcinogenesis
by increasing tumor promotion. The relevance of this
mechanism for humans is still a matter of debate. While this
mechanism cannot be completely discounted, it is reasonable
to assume that humans are less sensitive than rodents. In view
of the low use of 2-ethyl-1-hexanol in cosmetic products (0.1–
1 tons/y) and the low systemic exposure estimated by RIFM
(0.0005 mg/kg body weight/day), the margin of exposure is
100,000 compared to the NOAEL for liver carcinomas in mice
of 50 mg/kg body weight, which is considered to be sufficient
for a non-genotoxic compound.
Conflict of interest statement
This research was supported by the Research Institute for Fragrance
Materials, an independent research institute that is funded

S42
D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
Table 11
Phototoxicity and photoallergenicity.
Material Method Concentration Species Results References
Subgroup: tertiary
2,6-Dimethyl-2-heptanol 0.025 ml/test site on the back (36 test sites, 2 cm 2 ),
covered, 30 min later the test sites were exposed to
UVA irradiation (320–400 nm, 1, 2.5, 5, 10, 20 J/cm 2 ),
observations 4, 24, 48 and 72 h after irradiation
Patch applied 48 h, 4 h after the removal of the
patches the animals did receive:
Group A: UVA (320–400 nm), 30 min
Group B: UVB (280–370 nm), 15 min
Group C: no irradiation, Group D: not pretreated and
Radiated from both light sources, observations 4, 24,
48 h after the irradiation
Photoallergy test: induction: 0.1 ml on 8 cm 2 of the
test area, 15 min UVB, 4 h UVA (Westinghouse black
light tubes, from a distance of 25 cm) every 2nd day,
total nine times in 18 days, challenge: after resting
time of 10 days 0.025 ml applied on both flanks, left
flank irradiated as for induction, skin reading 24 and
48 h after challenge
10% in 1:1
ethanol/acetone
6 healthy
volunteers
(females)
10% in ethanol Albino guinea pig
(n = 8/group)
10% in rectified
alcohol
Guinea pig
(n = 8/sex)
Not phototoxic
Not phototoxic, after
4 h 1/8 slight reaction
(in each group), which
was cleared within
24 h
No photoallergenicity
RIFM
(1983a)
RIFM
(1981a)
RIFM
(1981b)
Table 12
Summary of UV spectra data.
Material
UV spectra range of absorption (nm)
2-Ethyl-1-hexanol Peaked at 210–215
Returned to baseline at 400 (with minor absorption 290–400)
Isoamyl alcohol
Does not absorb UV light
Isotridecan-1-ol (isomeric mixture)
Does not absorb UV light
2-Methylbutanol Peaked at 200–215
Returned to baseline at 220–225
3-Methyl-1-pentanol Peaked at 200–210
Returned to baseline at 280–290
2-Methylundecanol Peaked at 200–205
Returned to baseline at 270–280
3,5,5-Trimethyl-1-hexanol
Does not absorb UV light
2,6-Dimethyl-4-heptanol
Does not absorb UV light
3,7-Dimethyl-7-methoxyoctan-2-ol Peaked at 200–210
Returned to baseline at 400 (with minor absorption 290–400)
6,8-Dimethylnonan-2-ol Peaked at 200–210
Returned to baseline 230–240 (with minor absorption 260–320)
3,4,5,6,6-Pentamethylheptan-2-ol Peaked at 200–205
Returned to baseline 264–271
2,6-Dimethyl-2-heptanol
Does not absorb UV light
by the manufacturers of fragrances and consumer products containing
fragrances. The authors are all members of the Expert Panel
of the Research Institute for Fragrance Materials, an independent
group of experts who evaluate the safety of fragrance materials.
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Food and Chemical Toxicology 48 (2010) S47–S50
Contents lists available at ScienceDirect
Food and Chemical Toxicology
journal homepage: www.elsevier.com/locate/foodchemtox
Review
Fragrance material review on 3,5,5-trimethyl-1-hexanol
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api
Research Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
article
Keywords:
Review
Fragrance
info
abstract
A toxicologic and dermatologic review of 3,5,5-trimethyl-1-hexanol when used as a fragrance ingredient
is presented. 3,5,5-Trimethyl-1-hexanol is a member of the fragrance structural group branched chain
saturated alcohols. The common characteristic structural elements of the alcohols with saturated
branched chain are one hydroxyl group per molecule, and a C 4 to C 12 carbon chain with one or several
methyl side chains. This review contains a detailed summary of all available toxicology and dermatology
papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document.
A safety assessment of the entire branched chain saturated alcohol group will be published simultaneously
with this document; please refer to Belsito et al. (2010) for an overall assessment of the safe
use of this material and all other branched chain saturated alcohols in fragrances.
Ó 2010 Published by Elsevier Ltd.
Contents
Introduction . . . ..................................................................................................... S48
1. Identification . . ..................................................................................................... S48
2. Physical properties . . . . . . . . . . . . . . . . . .................................................................................. S48
3. Usage. . . . . . . . . ..................................................................................................... S48
4. Toxicology data ..................................................................................................... S49
4.1. Acute toxicity (see Table 2). ..................................................................................... S49
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49
4.2. Skin irritation. ................................................................................................ S49
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49
4.2.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49
4.3. Mucous membrane (eye) irritation. ............................................................................... S49
4.4. Skin sensitization. ............................................................................................. S49
4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49
4.5. Phototoxicity and photoallergy. . ................................................................................. S49
4.6. Absorption, distribution and metabolism .......................................................................... S49
4.7. Repeated dose toxicity . . ....................................................................................... S49
4.7.1. Two to fourteen days studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49
4.7.2. Subchronic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49
4.7.3. Chronic (90+ days) studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S50
4.8. Reproductive and developmental toxicity .......................................................................... S50
4.9. Genotoxicity. ................................................................................................. S50
4.9.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S50
4.10. Carcinogenicity . . ............................................................................................. S50
Conflict of interest statement . . . . . . . . .................................................................................. S50
References . . . . ..................................................................................................... S50
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.
E-mail address: dmcginty@RIFM.org (D. McGinty).
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.fct.2010.05.026

S48
D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S47–S50
Introduction
This document provides a summary of the toxicologic review of
3,5,5-trimethyl-1-hexanol when used as a fragrance ingredient
including all human health endpoints. 3,5,5-Trimethyl-1-hexanol
(see Fig. 1; CAS Number 3452-97-9) is a fragrance ingredient used
in cosmetics, fine fragrances, shampoos, toilet soaps and other
toiletries as well as in non-cosmetic products such as household
cleaners and detergents. It is a colorless oily liquid with an oilyherbaceous
odor (Arctander, 1969). This material has been reported
to occur in nature, with quantities observed in black currants, crab,
and strawberry guava (VCF, 2009).
In 2006, a complete literature search was conducted on 3,5,5-
trimethyl-1-hexanol. On-line toxicological databases were
searched including those from the Chemical Abstract Services,
[e.g. ToxCenter (which in itself contains 18 databases including
chemical abstracts)], and the National Library of Medicine [e.g.
Medline, Toxnet (which contains 14 databases)] as well as 26 additional
sources (e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition,
fragrance companies were asked to submit all test data.
The safety data on this material was last reviewed by Letizia et
al. (2000). All relevant references are included in this document.
More details have been provided for unpublished data. The number
of animals, sex and strain are always provided unless they are not
given in the original report or paper. Any papers in which the vehicles
and/or the doses are not given have not been included in this
review. In addition, diagnostic patch test data with fewer than 100
consecutive patients have been omitted.
1. Identification
1.1. Synonyms: 1-hexanol, 3,5,5-trimethyl-; i-nonyl alcohol;
nonylol; trimethylhexanol; 3,5,5-trimethylhexanol; 3,5,5-
trimethylhexan-1-ol; 3,5,5-trimethylhexyl alcohol.
1.2. CAS Registry Number: 3452-97-9.
1.3. EINECS Number: 222-376-7.
1.4. Formula: C 9 H 20 O.
1.5. Molecular weight: 144.26.
1.6. Council of Europe (2000): 3,5,5-trimethyl-1-hexanol was
included by the Council of Europe in the list of substances
HO
Fig. 1. 3,5,5-Trimethyl-1-hexanol.
granted B – information required – 28 days oral study
(COE No. 702).
1.7. JECFA (1998): The Joint FAO/WHP Expert Committee on
Food Additives (JECFA No. 268) concluded that the substance
does not present a safety concern at current levels of intake
when used as a flavouring agent.
1.8. FEMA (1970): Flavor and Extract Manufacturers’ Association
states: generally Recognized as safe as a flavor ingredient –
GRAS 5.
2. Physical properties
2.1. Physical form: a colorless oily liquid.
2.2. Boiling point (calculated; EPA, 2010): 188.53 °C.
2.3. Flash point: 174 °F; CC.
2.4. Henry’s law (calculated; EPA, 2010): 0.0000412 atm m 3 /mol
25 °C.
2.5. Log K ow (calculated; EPA, 2010): 3.11.
2.6. Refractive index: 1.4318.
2.7. Specific gravity: 0.832 (20 °C); 0.8252 (25 °C).
2.8. Vapor pressure (calculated; EPA, 2010): 0.2 mm Hg (20 °C);
0.106 mm Hg (25 °C); 14.1 Pa (25 °C)2.9 water solubility
(calculated; EPA, 2010): 572 mg/l (25 °C).
2.9. UV spectra available. Does not absorb UV light.
3. Usage
3,5,5-Trimethyl-1-hexanol is a fragrance ingredient used in
many fragrance compounds. It may be found in fragrances used
in decorative cosmetics, fine fragrances, shampoos, toilet soaps
and other toiletries as well as in non-cosmetic products such as
household cleaners and detergents. Its use worldwide is in the region
of 1–10 metric tons per annum (IFRA, 2004). The reported volume
of use is for 3,5,5-trimethyl-1-hexanol as used in fragrance
compounds (mixtures) in all finished consumer product categories.
The volume of use is surveyed by IFRA approximately every 4 years
through a comprehensive survey of IFRA and RIFM member companies.
As such the volume of use data from this survey provides
volume of use of fragrance ingredients for the majority of the
fragrance industry.
The dermal systemic exposure in cosmetic products (see Table 1)
is calculated based on the concentrations of the same fragrance
ingredient in ten types of the most frequently used personal care
and cosmetic products (anti-perspirant, bath products, body lotion,
eau de toilette, face cream, fragrance cream, hair spray, shampoo,
shower gel, and toilet soap). The concentration of the fragrance
ingredient in fine fragrances is obtained from examination of several
thousand commercial formulations. The upper 97.5 percentile
concentration is calculated from the data obtained. This upper 97.5
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 3,5,5-trimethyl-1-hexanol.
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient mg/kg/day b
Anti-perspirant 0.5 1 1 0.01 0.14 0.000100
Bath products 17 0.29 0.001 0.02 0.14 0.000001
Body lotion 8 0.71 1 0.004 0.14 0.000500
Eau de toilette 0.75 1 1 0.08 0.14 0.001400
Face cream 0.8 2 1 0.003 0.14 0.000100
Fragrance cream 5 0.29 1 0.04 0.14 0.001400
Hair spray 5 2 0.01 0.005 0.14 0.000010
Shampoo 8 1 0.01 0.005 0.14 0.000010
Shower gel 5 1.07 0.01 0.012 0.14 0.000010
Toilet soap 0.8 6 0.01 0.015 0.14 0.000020
Total 0.0036
a
b
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.
Based on a 60-kg adult.

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S47–S50 S49
percentile concentration is then used for all 10 consumer products.
These concentrations are multiplied by the amount of product applied,
the number of applications per day for each product type,
and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account
for the length of time a product may remain on the skin and/or
likelihood of the fragrance ingredient being removed by washing.
The resultant calculation represents the total consumer exposure
(mg/kg/day) (Cadby et al., 2002; Ford et al., 2000).
This is a conservative calculation of dermal systemic exposure
because it makes the unlikely assumption that a consumer will
use these 10 products containing; which are all perfumed with
the upper 97.5 percentile level of the fragrance ingredient from a
fine fragrance type of product (Cadby et al., 2002; Ford et al.,
2000). The 97.5% percentile use level in formulae for use in cosmetics
in general has been reported to be 0.14 (IFRA, 2007), which
would result in a maximum daily exposure on the skin of
0.0035 mg/kg for high end users.
A maximum skin level is then determined for consideration of
potential sensitization. The exposure is calculated as the percent
concentration of the fragrance ingredient applied to the skin based
on the use of 20% of the fragrance mixture in the fine fragrance
consumer product (IFRA, 2007). The average maximum use level
in formulae that go into fine fragrances has been reported to be
0.68% (IFRA, 2007), assuming use of the fragrance oil at levels up
to 20% the final product.
4. Toxicology data
4.1. Acute toxicity (see Table 2)
4.1.1. Oral studies
The acute oral LD 50 of 3,5,5-trimethyl-1-hexanol in rats (10/
dose) was reported to be 2.3 (95% C.I. 1.7–3.1) g/kg. Mortality was
0, 0, 7, and 10 of 10 rats at 0.67, 1.31, 2.56, and 5.0 g/kg, respectively.
Deaths occurred on days 1, 2, or 3. The observation period
was 14 days. Clinical signs included lethargy, coma, ataxia, diarrhea,
piloerection, ptosis, and chromorhinorrhea. Necropsy observations
included red/yellow oral/nasal exudates, yellow/brown
anogenital exudates, dark areas/orange lungs, dark/mottled liver,
dark/mottled kidneys, red/yellow areas of intestines, stomach
bloated/red–yellow areas/fluid filled, spleen mottled (RIFM, 1977a).
4.1.2. Dermal studies
The acute dermal LD 50 of 3,5,5-trimethyl-1-hexanol in rabbits
(10/dose) was reported to be greater than 5.0 g/kg. Mortality was
3 of 10 rabbits at 5.0 g/kg. Deaths occurred on days 9, 13, and 14.
Observation period was 14 days. Clinical signs included lethargy,
diarrhea, and anorexia. Necropsy observations included mild, moderate,
or severe erythema and mild or moderate edema, yellow/
brown anogenital exudates, dark/mottled liver, dark/mottled/malformed
kidneys, red/yellow areas of intestines, stomach bloated
(RIFM, 1977a).
4.2. Skin irritation
4.2.1. Human studies
In a human maximization test pre-screen, 8% 3,5,5-trimethyl-1-
hexanol was applied to the volar forearms or backs of 25 healthy
Table 2
Summary of acute toxicity studies.
Route Species No. animals/dose group LD 50 (g/kg) References
Oral Rat 10 2.3 RIFM (1977a)
Dermal Rabbit 10 >5.0 RIFM (1977a)
subjects for 48 h under occlusion. No subject had any irritation
(RIFM, 1977b).
4.2.2. Animal studies
Irritation was evaluated during the acute dermal study of 3,5,
5-trimethyl-1-hexanol in 10 rabbits. A single dose of 5.0 g/kg
resulted in mild, moderate, or severe erythema and mild or
moderate edema (RIFM, 1977a).
4.3. Mucous membrane (eye) irritation
No information available.
4.4. Skin sensitization
4.4.1. Human studies
4.4.1.1. Induction studies. In a study involving 25 subjects, a maximization
test (Kligman, 1966; Kligman and Epstein, 1975) was
carried out with 3,5,5-trimethyl-1-hexanol in petrolatum on various
panels of volunteers. Application was under occlusion to the
same site on the forearms or backs of all subjects for five alternate-day
48 h periods. Patch sites were pre-treated for 24 h with
2.5% aqueous sodium lauryl sulfate (SLS) under occlusion. Following
a 10–14 days rest period, challenge patches were applied under
occlusion to fresh sites for 48 h. Challenge applications were preceded
by 60 min SLS treatment. Reactions were read at patch
removal and again at 24 h. There was no evidence of contact
sensitization to 8% 3,5,5-trimethyl-1-hexanol (RIFM, 1977b).
4.4.1.2. Animal studies. No information available.
4.5. Phototoxicity and photoallergy
No information available.
4.6. Absorption, distribution and metabolism
No information available.
4.7. Repeated dose toxicity
4.7.1. Two to fourteen days studies
3,5,5-Trimethyl-1-hexanol was included in a repeat dose oral
gavage study of a series of compounds related to diethylhexl
phthalate and diethylhexyl adipate in male Alderley Park Wistarderived
rats. Animals were dosed for 14 days with 1 mM/kg/d
(144 mg/kg/d) 3,5,5-trimethyl-1-hexanol dissolved in polyethylene
glycol 300. At termination of the study, there was no difference
from controls in body weight, or any clinical or histopathological
signs of hepatotoxicity. At necropsy, relative liver weight was significantly
greater than that of controls, but peroxisome proliferation
and hypocholesterolemia and hypotriglyceridaemia were not
evident (Rhodes et al., 1984).
4.7.2. Subchronic studies
Male SD (CRJ:CD) rats were given 3,5,5-trimethyl-1-hexanol by
gavage for 46 days at doses of 0, 12, 60, or 300 mg/kg body weight/
day in olive oil. Females were dosed 14 days before mating and
through to day 3 of lactation. Renal hyaline droplets and eosinophilic
bodies were observed (slight to moderate) in all dosed male
rats, but these findings were not observed in females. The 60 mg/
kg body weight/day dose group experienced relative liver and kidney
weight increases (males and females), renal epithelial fatty
changes (females), and a decreased implantation index (females).
At 300 mg/kg body weight/day one female died, and three were
put down because of weakness. Body weights increased and food

S50
D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S47–S50
consumption increased in males, but decreased in females. Females
showed a litter loss in two dams. On the basis of these findings
the NOAEL was considered to be 12 mg/kg/day for male and
female rats (MHW, Japan, 1997b as cited in OECD/SIDS (2003)).
4.7.3. Chronic (90+ days) studies
No information available.
4.8. Reproductive and developmental toxicity
No information available.
4.9. Genotoxicity
4.9.1. In vitro studies
4.9.1.1. Bacterial test systems. 3,5,5-Trimethyl-1-hexanol was not
mutagenic in an Ames test (preincubation assay with and without
metabolic activation) in Salmonella typhimurium TA98, TA100,
TA1535, TA1537 and in E. coli WP2 uvrA assays (MHW, Japan
1997c as cited in OECD/SIDS (2003) and Kusakabe et al. (2002)).
4.9.1.2. Studies in mammalian cells. 3,5,5-Trimethyl-1-hexanol up to
100 lg/plate (cytotoxicity occurred at 200 lg/plate) with or without
metabolic activation, did not induce chromosomal aberrations
or polyploidy in an in vitro Chinese hamster lung cell (OECD TG
473) study (MHW, Japan 1997c as cited in OECD/SIDS (2003) and
Kusakabe et al. (2002).
4.9.1.3. In vivo studies. No information available.
4.10. Carcinogenicity
No information available.
This individual fragrance material review is not intended as a
stand-alone document. Please refer to A Safety Assessment of
Branched Chain Saturated Alcohols When Used as Fragrance Ingredients
(Belsito et al., 2010) for an overall assessment of this
material.
Conflict of interest statement
This research was supported by the Research Institute for Fragrance
Materials, an independent research institute that is funded
by the manufacturers of fragrances and consumer products containing
fragrances. The authors are all employees of the Research
Institute for Fragrance Materials.
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Food and Chemical Toxicology 48 (2010) S51–S54
Contents lists available at ScienceDirect
Food and Chemical Toxicology
journal homepage: www.elsevier.com/locate/foodchemtox
Review
Fragrance material review on 3,7-dimethyl-7-methoxyoctan-2-ol
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api
Research Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
article
Keywords:
Review
Fragrance
info
abstract
A toxicologic and dermatologic review of 3,7-dimethyl-7-methoxyoctan-2-ol when used as a fragrance
ingredient is presented. 3,7-Dimethyl-7-methoxyoctan-2-ol is a member of the fragrance structural
group branched chain saturated alcohols. The common characteristic structural elements of the alcohols
with saturated branched chain are one hydroxyl group per molecule, and a C 4 –C 12 carbon chain with one
or several methyl side chains. This review contains a detailed summary of all available toxicology and
dermatology papers that are related to this individual fragrance ingredient and is not intended as a
stand-alone document. A safety assessment of the entire branched chain saturated alcohol group will
be published simultaneously with this document; please refer to Belsito et al. (2010) for an overall assessment
of the safe use of this material and all other branched chain saturated alcohols in fragrances.
Ó 2010 Published by Elsevier Ltd.
Contents
Introduction . . . ..................................................................................................... S52
1. Identification . . ..................................................................................................... S52
2. Physical properties . . . . . . . . . . . . . . . . . .................................................................................. S52
3. Usage. . . . . . . . . ..................................................................................................... S52
4. Toxicology data ..................................................................................................... S53
4.1. Acutetoxicity................................................................................................ S53
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53
4.2. Skinirritation................................................................................................ S53
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53
4.2.2. Animal studies (see Table 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53
4.3. Mucous membrane (eye) irritation. .............................................................................. S53
4.4. Skinsensitization............................................................................................. S53
4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53
4.4.2. Diagnostic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53
4.4.3. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53
4.5. Phototoxicity and photoallergy. . . ............................................................................... S54
4.6. Absorption, distribution and metabolism . . ....................................................................... S54
4.7. Repeated dose toxicity . ....................................................................................... S54
4.8. Reproductive and developmental toxicity . . ....................................................................... S54
4.9. Genotoxicity. . ............................................................................................... S54
4.10. Carcinogenicity.............................................................................................. S54
Conflict of interest statement . . . . . . . . .................................................................................. S54
References . . . . ..................................................................................................... S54
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.
E-mail address: dmcginty@RIFM.org (D. McGinty).
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.fct.2010.05.027

S52
D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S51–S54
Introduction
This document provides a summary of the toxicologic review,
including all human health endpoints, of 3,7-dimethyl-7-methoxyoctan-2-ol
when used as a fragrance ingredient. 3,7-Dimethyl-
7-methoxyoctan-2-ol (see Fig. 1; CAS Number 41890-92-0) is a
fragrance ingredient used in cosmetics, fine fragrances, shampoos,
toilet soaps and other toiletries as well as in non-cosmetic products
such as household cleaners and detergents. It is an almost colorless
liquid and has a sandalwood odor with a flowery, woodsy note.
In 2006, a complete literature search was conducted on 3,7-Dimethyl-7-methoxyoctan-2-ol.
On-line toxicological databases
were searched including those from the Chemical Abstract Services,
[e.g. ToxCenter (which in itself contains 18 databases including
Chemical Abstracts)], and the National Library of Medicine [e.g.
Medline, Toxnet (which contains 14 databases)] as well as 26 additional
sources (e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition,
fragrance companies were asked to submit all test data.
The safety data on this material was last reviewed by Ford et al.,
1992. All relevant references are included in this document. More
details have been provided for unpublished data. The number of
animals, sex and strain are always provided unless they are not given
in the original report or paper. Any papers in which the vehicles
and/or the doses are not given have not been included in this
review. In addition, diagnostic patch test data with fewer than 100
consecutive patients have been omitted.
1. Identification
1.1. Synonyms: 7-Methoxy-3,7-dimethyloctan-2-ol; 2-Octanol,
7-methoxy-3,7-dimethyl; Osirol; Osyrol; 7-Methoxy-3,7-
dimethyloctan-2-ol.
1.2. CAS Registry number: 41890-92-0.
O
HO
Fig. 1. 3,7-Dimethyl-7-methoxyoctan-2-ol.
1.3. EINECS number: 255-574-7.
1.4. Formula: C 11 H 24 O 2.
1.5. Molecular weight: 188.31.
2. Physical properties
2.1. Physical form: An almost colorless liquid.
2.2. Boiling point (calculated; EPA, 2010): 229.67 °C.
2.3. Flash point:>110 °C (230°F).
2.4. Henry’s law (calculated; EPA, 2010): 0.000000404 atm m 3 /
mol 25 °C.
2.5. Log K ow (calculated; EPA, 2010): 2.76.
2.6. Refractive index: 1.446.
2.7. Specific gravity: 0.898.
2.8. Vapor pressure (calculated; EPA, 2010): 0.0119 mm Hg;
1.58 Pa (25 °C).
2.9. Water solubility (calculated; EPA, 2010): 707.1 mg/l (25 °C).
2.10. UV spectra available at RIFM, peaks at 200–210 nm and
returns to baseline at 400 nm. Minor absorption from 290–
400 nm.
3. Usage
3,7-Dimethyl-7-methoxyoctan-2-ol is a fragrance ingredient
used in many fragrance compounds. It may be found in fragrances
used in decorative cosmetics, fine fragrances, shampoos, toilet
soaps and other toiletries as well as in non-cosmetic products such
as household cleaners and detergents. Its use worldwide is in the
region of 1–10 metric tons per annum (IFRA, 2004). The reported
volume of use is for 3,7-dimethyl-7-methoxyoctan-2-ol as used
in fragrance compounds (mixtures) in all finished consumer product
categories. The volume of use is surveyed by IFRA approximately
every 4 years through a comprehensive survey of IFRA
and RIFM member companies. As such the volume of use data from
this survey provides volume of use of fragrance ingredients for the
majority of the fragrance industry.
The dermal systemic exposure in cosmetic products (see Table 1)
is calculated based on the concentrations of the same fragrance
ingredient in ten types of the most frequently used personal care
and cosmetic products (anti-perspirant, bath products, body lotion,
eau de toilette, face cream, fragrance cream, hair spray, shampoo,
shower gel, and toilet soap). The concentration of the fragrance
ingredient in fine fragrances is obtained from examination of several
thousand commercial formulations. The upper 97.5 percentile concentration
is calculated from the data obtained. This upper 97.5 percentile
concentration is then used for all 10 consumer products.
These concentrations are multiplied by the amount of product applied,
the number of applications per day for each product type,
and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account for
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 3,7-dimethyl-7-methoxyoctan-2-ol.
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient mg/kg/day b
Anti-perspirant 0.5 1 1 0.01 3.52 0.0029
Bath products 17 0.29 0.001 0.02 3.52 0.0001
Body lotion 8 0.71 1 0.004 3.52 0.0133
Eau de toilette 0.75 1 1 0.08 3.52 0.0352
Face cream 0.8 2 1 0.003 3.52 0.0028
Fragrance cream 5 0.29 1 0.04 3.52 0.0340
Hair spray 5 2 0.01 0.005 3.52 0.0003
Shampoo 8 1 0.01 0.005 3.52 0.0002
Shower gel 5 1.07 0.01 0.012 3.52 0.0004
Toilet soap 0.8 6 0.01 0.015 3.52 0.0004
Total 0.0897
a
b
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.
Based on a 60-kg adult.

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S51–S54 S53
Table 2
Summary of animal irritation studies.
Method Dose Species Results References
Dermal application 1% Rabbit Slight erythema RIFM (1973a)
Occluded dermal application Induction Guinea pig During the induction, three animals exhibited slight
RIFM (1973b)
5%
2.5%
Challenge
2.5%
erythema and one was moderate
No response to challenge
the length of time a product may remain on the skin and/or likelihood
of the fragrance ingredient being removed by washing. The
resultant calculation represents the total consumer exposure (mg/
kg/day) (Cadby et al., 2002; Ford et al., 2000).
This is a conservative calculation of dermal systemic exposure
because it makes the unlikely assumption that a consumer will
use these 10 products containing; which are all perfumed with
the upper 97.5 percentile level of the fragrance ingredient from a
fine fragrance type of product (Cadby et al., 2002; Ford et al.,
2000). The 97.5% percentile use level in formulae for use in cosmetics
in general has been reported to be 3.52 (IFRA, 2007), which
would result in a maximum daily exposure on the skin of
0.0896 mg/kg for high end users.
A maximum skin level is then determined for consideration of
potential sensitization. The exposure is calculated as the percent
concentration of the fragrance ingredient applied to the skin based
on the use of 20% of the fragrance mixture in the fine fragrance
consumer product (IFRA, 2007). The average maximum use level
in formulae that go into fine fragrances has been reported to be
1.27% (IFRA, 2007), assuming use of the fragrance oil at levels up
to 20% the final product.
4. Toxicology data
4.1. Acute toxicity
4.1.1. Oral studies
The acute oral LD 50 of 3,7-dimethyl-7-methoxyoctan-2-ol in
rats was reported to be approximately 5.0 g/kg. Mortality was 2/
5 males at less than 4 h after dosing and 3/5 females at less than
23 h after dosing. Symptoms included lethargy, piloerection, diuresis,
salivation, and ataxia. Necropsy revealed darkening of the liver
and injection of blood vessels of the abdominal viscera. Recovery of
survivors was apparently complete within 8 days of dosing.
Slightly depressed body weight gains were observed during the
first week after dosing in male rats, but returned to normal during
the second week of observation. Terminal necropsy findings of survivors
were normal (RIFM, 1976).
4.1.2. Dermal studies
No available information.
4.2. Skin irritation
4.2.1. Human studies
In a human maximization test pre-screen, 10% 3,7-Dimethyl-7-
methoxyoctan-2-ol (6900 lg/cm 2 ) was applied under occlusion to
the backs of 27 healthy subjects for 48 h. No significant evidence of
irritation was observed (RIFM, 1982).
4.2.2. Animal studies (see Table 2)
In a rabbit (n = 6) dermal irritation study conducted according
to US FDA Guidelines, 0.5 ml of 1% 3,7-Dimethyl-7-methoxyoctan-2-ol
in propylene glycol on an occlusive 24 h patch was considered
mildly irritating. Very slight erythema was observed in the
intact and abraded sites of 5 animals at 24 h. In one animal there
was no observable response to treatment. At 72 h, the reactions
had ameliorated. One animal showed very slight erythema at the
intact and abraded sites. There was no observable response to
treatment in the remaining 5 animals. The Primary Irritation Index
was calculated to be 0.5 (RIFM, 1973a).
In a guinea pig (n = 10) sensitization study conducted according
to US FDA Guidelines, irritation was not induced by 0.2 ml of 2.5%
or 5% 3,7-Dimethyl-7-methoxyoctan-2-ol in water applied under
occlusion to a 0.5 inch square to the shaved area of the shoulder
24 h per day on alternate days during a 3 week period for a total
of 10 applications. Applications 1 – 7 were at 5% and applications
8 – 10 were at 2.5%. Challenge dose was applied in the same manner
using 2.5% 14 days after the last induction dose. Three animals
exhibited 1 grade 1 response for erythema once each during the
induction period and 1 animal exhibited 2 grade 1 erythema responses
during induction. There were no positive responses following
challenge (RIFM, 1973b).
4.3. Mucous membrane (eye) irritation
In a rabbit (n = 6) eye irritation study conducted according to US
FDA Guidelines, 0.1 ml of 1% 3,7-Dimethyl-7-methoxyoctan-2-ol in
propylene glycol produced only temporary mild conjuctival reactions
in 5 animals. In one animal chemosis of the conjunctiva
was observed. No corneal or iris involvement occurred and all effects
cleared within 3 days (RIFM, 1973c).
4.4. Skin sensitization
4.4.1. Human studies
4.4.1.1. Induction studies. In a human Maximization study involving
27 subjects, there was no evidence of contact sensitization to 10%
3,7-Dimethyl-7-methoxyoctan-2-ol (6900 lg/cm 2 ). Test material
was applied in petrolatum under occlusion to the forearms for a total
of five alternate day, 48 h periods. Each application was preceded
by a 24 h occlusive treatment of the patch sites with 7.5%
aqueous sodium lauryl sulfate. Following a 10–14 day rest period,
challenge patches were applied under occlusion to fresh sites for
48 h. Challenge applications were preceded by 30 min applications
of 7.5% sodium lauryl sulfate under occlusion on the left side and
no pretreatment on the right side. Challenge sites were evaluated
at removal of the patches and 24 h later (RIFM, 1982).
4.4.1.2. Cross-sensitization. No available information.
4.4.2. Diagnostic studies
In a diagnostic patch test study, there were positive responses
to 3,7-dimethyl-7-methoxyoctan-2-ol (concentration not specified)
in 2 of 218 dermatology patients with previous positive reaction
to at least one fragrance material (Larsen et al., 2002).
4.4.3. Animal studies
4.4.3.1. Maximization Test. No available information.
4.4.3.2. Other studies. In a guinea pig (n = 10) sensitization study
conducted according to US FDA Guidelines, sensitization was not

S54
D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S51–S54
induced by 0.2 ml of 2.5% or 5% 3,7-dimethyl-7-methoxyoctan-2-ol
in water applied under occlusion to a 0.5 inch square to the shaved
area of the shoulder 24 h per day on alternate days during a 3 week
period for a total of 10 applications. Applications 1–7 were at 5%
and applications 8–10 were at 2.5%. Challenge dose was applied
in the same manner using 2.5% 14 days after the last induction
dose. Three animals exhibited 1 grade 1 response for erythema
once each during the induction period and 1 animal exhibited
grade 1 erythema responses twice during induction. There were
no positive responses following challenge (RIFM, 1973b).
4.4.3.3. Local Lymph Node Assay (LLNA). No available information.
4.5. Phototoxicity and photoallergy
No available information.
4.6. Absorption, distribution and metabolism
No available information.
4.7. Repeated dose toxicity
No available information.
4.8. Reproductive and developmental toxicity
No available information.
4.9. Genotoxicity
No available information.
4.10. Carcinogenicity
No available information.
This individual Fragrance Material Review is not intended as a
stand-alone document. Please refer to A Safety Assessment of
Branched Chain Saturated Alcohols When Used as Fragrance Ingredients
(Belsito et al., 2010) for an overall assessment of this
material.
Conflict of interest statement
This research was supported by the Research Institute for Fragrance
Materials, an independent research institute that is funded
by the manufacturers of fragrances and consumer products containing
fragrances. The authors are all employees of the Research
Institute for Fragrance Materials.
References
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chain
saturated alcohols when used as fragrance ingredients. Food and Chemical
Toxicology 48 (S4), S1–S46.
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:
providing estimates for safety evaluation. Regulatory Toxicology and
Pharmacology 36, 246–252.
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface
Suite for Microsoft Ò Windows, V 4.00 or Insert Version Used. United States
Environmental Protection Agency, Washington, DC, USA.
Ford, R.A., Api, A.M., Letizia, C.S., 1992. Monograph on 3,7-dimethyl-7-
methoxyoctan-2-ol. Food and Chemical Toxicology 30 (Suppl.), 25S.
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria for
development of a database for safety evaluation of fragrance ingredients.
Regulatory Toxicology and Pharmacology 31, 166–181.
IFRA (International Fragrance Association), 2004. Use Level Survey, August 2004.
IFRA (International Fragrance Association), 2007. Volume of Use Survey, February
2007.
Larsen, W., Nakayama, H., Fischer, T., Elsner, P., Frosch, P., Burrows, D., Jordan, W.,
Shaw, S., Wilkinson, J., Marks, J., Sugawara, M., Nethercott, M., Nethercott, J.,
2002. Fragrance contact dermatitis – a worldwide multicenter investigation
(Part III). Contact Dermatitis 46 (3), 141–144.
RIFM (Research Institute for Fragrance Materials, Inc.), 1973a. Irritant Effects of
3,7-Dimethyl-7-methoxyoctan-2-ol on Rabbit Skin. Unpublished Report from
Bush Boake Allen Ltd., 07 June. Report Number 1765. RIFM, Woodcliff Lake,
NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1973b. Screening Test for
Delayed Dermal Sensitization with 3,7-Dimethyl-7-methoxyoctan-2-ol in the
Albino Guinea Pig. Unpublished Report from Bush Boake Allen Ltd., 03 May.
Report Number 1766. RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1973c. Irritant effects of 3,7-
Dimethyl-7-methoxyoctan-2-ol on Rabbit Eye Mucosa. Unpublished Report
from Bush Boake Allen Ltd., 07 June. Report Number 1767. RIFM, Woodcliff
Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1976. Acute Oral Toxicity of
Valanone B, Cytenol, 3,7-Dimethyl-7-methoxyoctan-2-ol, 8-Methoxy-pmenthene
and Pinocarvyl Acetate in Rats. Unpublished Report from Bush
Boake Allen Ltd., 23 March. Report Number 1764. RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1982. Report on Human
Maximization Studies. RIFM Report Number 1643, October 05. RIFM, Woodcliff
Lake, NJ, USA.

Food and Chemical Toxicology 48 (2010) S55–S59
Contents lists available at ScienceDirect
Food and Chemical Toxicology
journal homepage: www.elsevier.com/locate/foodchemtox
Review
Fragrance material review on 4-methyl-2-pentanol
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api
Research Institute for Fragrance Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
article
Keywords:
Review
Fragrance
info
abstract
A toxicologic and dermatologic review of 4-methyl-2-pentanol when used as a fragrance ingredient is
presented. 4-Methyl-2-pentanol is a member of the fragrance structural group branched chain saturated
alcohols. The common characteristic structural elements of the alcohols with saturated branched chain
are one hydroxyl group per molecule, and a C 4 –C 12 carbon chain with one or several methyl side chains.
This review contains a detailed summary of all available toxicology and dermatology papers that are
related to this individual fragrance ingredient and is not intended as a stand-alone document. A safety
assessment of the entire branched chain saturated alcohol group will be published simultaneously with
this document; please refer to Belsito et al. (2010) for an overall assessment of the safe use of this material
and all other branched chain saturated alcohols in fragrances.
Ó 2010 Published by Elsevier Ltd.
Contents
Introduction . . . ..................................................................................................... S56
1. Identification . . ..................................................................................................... S56
2. Physical properties . . . . . . . . . . . . . . . . . .................................................................................. S56
3. Usage. . . . . . . . . ..................................................................................................... S56
4. Toxicology data ..................................................................................................... S57
4.1. Acute toxicity (see Table 2). ..................................................................................... S57
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57
4.1.3. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57
4.1.4. Miscellaneous studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57
4.2. Skin irritation. ................................................................................................ S57
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57
4.2.2. Animal studies (see Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57
4.3. Mucous membrane (eye) irritation (see Table 4) .................................................................... S57
4.4. Skin sensitization. ............................................................................................. S57
4.5. Phototoxicity and photoallergy. . ................................................................................. S57
4.6. Absorption, distribution and metabolism .......................................................................... S57
4.6.1. Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57
4.6.2. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57
4.6.3. Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57
4.7. Repeated dose toxicity . . ....................................................................................... S58
4.8. Reproductive and developmental toxicity .......................................................................... S58
4.9. Genotoxicity. ................................................................................................. S58
4.9.1. In vitro studies........................................................................................ S58
4.9.2. In vivo studies ........................................................................................ S58
4.10. Carcinogenicity . . ............................................................................................. S58
Conflict of interest statement . . . . . . . . .................................................................................. S58
References . . . . ..................................................................................................... S58
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.
E-mail address: dmcginty@RIFM.org (D. McGinty).
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.fct.2010.05.028

S56
D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S55–S59
Introduction
2. Physical properties
This document provides a comprehensive summary of the
toxicologic review, including all human health endpoints, of
4-Methyl-2-pentanol when used as a fragrance ingredient.
4-Methyl-2-pentanol (see Fig. 1; CAS Number 108-11-2) is a fragrance
ingredient used in cosmetics, fine fragrances, shampoos,
toilet soaps and other toiletries as well as in non-cosmetic products
such as household cleaners and detergents. This material
has been reported to occur in nature, with highest quantities
observed in annatto extract (VCF, 2009).
In 2006, a complete literature search was conducted on 4-
Methyl-2-pentanol. On-line toxicological databases were searched
including those from the Chemical Abstract Services, [e.g., ToxCenter
(which in itself contains 18 databases including Chemical Abstracts)],
and the National Library of Medicine [e.g., Medline,
Toxnet (which contains 14 databases)] as well as 26 additional
sources (e.g., BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance
companies were asked to submit all test data.
The safety data on this material has never been reviewed before
by RIFM (Research Institute for Fragrance Materials, Inc.). All relevant
references are included in this document. More details have
been provided for unpublished data. The number of animals, sex
and strain are always provided unless they are not given in the original
report or paper. Any papers in which the vehicles and/or the
doses are not given have not been included in this review. In addition,
diagnostic patch test data with fewer than 100 consecutive
patients have been omitted.
1. Identification
1.1. Synonyms: Isobutyl methyl carbinol; 4-methylpentan-2-ol;
methyl isobutyl carbinol; MIC; 2-pentanol, 4-methyl-
1.2. CAS registry number: 108-11-2.
1.3. EINECS number: 203-551-7.
1.4. Formula: C 6 H 14 O.
1.5. Molecular weight: 102.18.
HO
Fig. 1. 4-Methyl-2-pentanol.
2.1. Physical form: no information available.
2.2. Boiling point (calculated; EPA, 2010): 124.88 °C.
2.3. Flash point: no information available.
2.4. Henry’s law (calculated; EPA, 2010): 0.0000176 atm m 3 /mol
25 °C.
2.5. Log K ow (calculated; EPA, 2010): 1.68.
2.6. Refractive index: no information available.
2.7. Specific gravity: no information available.
2.8. Vapor pressure (calculated; EPA, 2010): 3.7 mm Hg 20 °C;
3.74 mm Hg (25 °C); 498 Pa (25 °C).
2.9. Water solubility (calculated; EPA, 2010): 13,800 mg/l at
25 °C.
2.10. UV spectra not available at RIFM.
3. Usage
4-Methyl-2-pentanol is a fragrance ingredient used in many fragrance
compounds. It may be found in fragrances used in decorative
cosmetics, fine fragrances, shampoos, toilet soaps and other
toiletries as well as in non-cosmetic products such as household
cleaners and detergents. Its use worldwide is in the region of
0.01–0.1 metric tons per annum (IFRA, 2004). The reported volume
is for the use of 4-methyl-2-pentanol used in fragrance compounds
(mixtures) used in all finished consumer product categories. The
volume of use is surveyed by IFRA approximately every four years
through a comprehensive survey of IFRA and RIFM member companies.
As such the volume of use data from this survey provides
volume of use of fragrance ingredients for the majority of the fragrance
industry.
The dermal systemic exposure in cosmetic products (see Table 1)
is calculated based on the concentrations of the same fragrance
ingredient in ten types of the most frequently used personal care
and cosmetic products (anti-perspirant, bath products, body lotion,
eau de toilette, face cream, fragrance cream, hair spray, shampoo,
shower gel, and toilet soap). The concentration of the fragrance
ingredient in fine fragrances is obtained from examination of several
thousand commercial formulations. The upper 97.5 percentile concentration
is calculated from the data obtained. This upper 97.5 percentile
concentration is then used for all 10 consumer products.
These concentrations are multiplied by the amount of product applied,
the number of applications per day for each product type,
and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account for
the length of time a product may remain on the skin and/or likelihood
of the fragrance ingredient being removed by washing. The
resultant calculation represents the total consumer exposure (mg/
kg/day) (Cadby et al., 2002; Ford et al., 2000).
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 4-methyl-2-pentanol.
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient (mg/kg/day) b
Anti-perspirant 0.5 1 1 0.01 .02 0.000001
Bath products 17 0.29 0.001 0.02 .02 0.000001
Body lotion 8 0.71 1 0.004 .02 0.000100
Eau de toilette 0.75 1 1 0.08 .02 0.000200
Face cream 0.8 2 1 0.003 .02 0.000001
Fragrance cream 5 0.29 1 0.04 .02 0.000200
Hair spray 5 2 0.01 0.005 .02 0.000001
Shampoo 8 1 0.01 0.005 .02 0.000001
Shower gel 5 1.07 0.01 0.012 .02 0.000001
Toilet soap 0.8 6 0.01 0.015 .02 0.000001
Total 0.0005
a
b
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.
Based on a 60-kg adult.

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S55–S59 S57
Table 2
Summary of acute toxicity studies.
Route Species No. animals/
dose group
This is a conservative calculation of dermal systemic exposure
because it makes the unlikely assumption that a consumer will
use these 10 products containing; which are all perfumed with
the upper 97.5 percentile level of the fragrance ingredient from a
fine fragrance type of product (Cadby et al., 2002; Ford et al.,
2000). The 97.5 percentile use level in formulae for use in cosmetics
for 2-ethyl-1-hexanol has been reported to be 0.02% (IFRA,
2007), which would result in a maximum daily exposure on the
skin of 0.0005 mg/kg for high end users (see Table 1).
A maximum skin level is then determined for consideration of
potential sensitization. The exposure is calculated as the percent
concentration of the fragrance ingredient applied to the skin based
on the use of 20% of the fragrance mixture in the fine fragrance
consumer product (IFRA, 2007). The maximum skin level that results
from the use of 4-Methyl-2-pentanol in formulae that go into
fine fragrances has not been reported. A default value of 0.02% is
used assuming use of the fragrance oils at levels up to 20% in the
final product.
4. Toxicology data
4.1. Acute toxicity (see Table 2)
LD 50
(g/kg)
References
Oral Rat 5 2.59 Smyth et al., 1951
Oral Rat N/A 2.95 Bar and Griepentrog, 1967
Oral Rat N/A 2.59 Nishimura et al., 1994
Dermal Rabbit 5 3.56 Smyth et al., 1951
Table 3
Summary of animal irritation studies.
Method
Dose
(%)
Species Reactions References
Dermal irritation 100 Rabbit Trace of capillary
injection
Dermal irritation 100 Rabbit Dry skin with some
sloughing and
cracking
4.1.1. Oral studies
The acute oral LD 50 of 4-methyl-2-pentanol in five rats was reported
to be 2.59 (2.26–2.97) g/kg. No additional details were reported
(Smyth et al., 1951).
The acute oral LD 50 of 4-methyl-2-pentanol in rats was reported
to be 2.95 g/kg. No additional details were reported (Bar and Griepentrog,
1967).
The acute oral LD 50 of 4-methyl-2-pentanol in rats was reported
to be 2.59 g/kg. No additional details were reported (Nishimura
et al., 1994).
4.1.2. Dermal studies
The acute dermal LD 50 of 4-methyl-2-pentanol in rabbits was
reported to be 3.56 (2.72–4.76) ml/kg (3.56 g/kg). No additional
details were reported (Smyth et al., 1951).
Table 4
Summary of eye irritation studies.
Smyth et al.,
1951
McOmie and
Anderson,
1949
Dose (%) Reactions References
100 Irritation observed Smyth et al., 1951
100 Irritation observed McOmie and Anderson, 1949
4.1.3. Inhalation studies
The acute inhalation exposure of six rats to 4-methyl-2-pentanol
at 2000 ppm for 8 h was reported to result in mortality of
5/6. The maximum time for no death was 2 h. No additional details
were reported (Smyth et al., 1951; Carpenter et al., 1949).
When mice were exposed to 4-methyl-2-pentanol vapor saturated
air at 20 °C, mortality was 0, 0, 6, and 8 of 10 animals following
4, 8.5, 10, and 15 h, respectively. The observation period was
7 days. Somnolence was induced in 1 h, anesthesia in 4 h, and
death in 10 h. No additional details were reported (McOmie and
Anderson, 1949).
4.1.4. Miscellaneous studies
No available Information.
4.2. Skin irritation
4.2.1. Human studies
No available information.
4.2.2. Animal studies (see Table 3)
In a rabbit skin irritation study, 4-methyl-2-pentanol induced
grade 2 irritation defined as an average reaction equivalent to a
trace of capillary injection. No additional details were reported
(Smyth et al., 1951, 1949).
In a three rabbit skin irritation study, exposure of rabbits to vapors
of 4-methyl-2-pentanol for 0.25 h resulted in immediate
slight erythema and delayed moderate erythema with drying of
surface. Five direct applications of the 3.0 ml/kg over a 100 cm 2
area material to the skin of rabbits (n = 3) resulted in severe drying
of skin with some sloughing and cracking (McOmie and Anderson,
1949).
4.3. Mucous membrane (eye) irritation (see Table 4)
In a rabbit eye irritation study, 0.005 ml of undiluted 4-methyl-
2-pentanol induced injury of up to 5.0 points. A score of five points
is given for necrosis on 63–87% visible after fluorescein staining,
without corneal opacity. No additional details were reported
(Smyth et al., 1951, 1949).
In a three rabbit eye irritation study conducted according to the
method of Draize, 4-methyl-2-pentanol produced moderate irritation;
some conjunctivitis with some edema and corneal injury but
returned to normal after 7 days (McOmie and Anderson, 1949).
4.4. Skin sensitization
No available information.
4.5. Phototoxicity and photoallergy
No available information.
4.6. Absorption, distribution and metabolism
4.6.1. Absorption
No available information.
4.6.2. Distribution
No available information.
4.6.3. Metabolism
4.6.3.1. In vivo studies in animals. 4-Methyl-2-pentanol (methyl isobutyl
carbinol, MIBC) is an oxygenated solvent that is metabolized
to methylisobutyl ketone (MIBK) and then to 4-hydroxymethyl-2-
pentanone (HMP). Plasma levels of MIBC, MIBK, and HMP were

S58
D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S55–S59
Table 5
Summary of bacterial studies.
Test system Concentration Results References
Ames assay with and without S9 activation Salmonella typhimurium
Up to 5000 lg/plate Not mutagenic Shimizu et al., 1985
TA98, TA100, TA 1535, TA1537 and TA 1538
Escerichia coli WP 2 uvrA
Ames assay with and without S9 activation Salmonella typhimurium
31.25–4000 lg/plate Not mutagenic OECD/SIDS, 2007
TA98, TA100, TA 1535, TA1537 and TA 1538
Escerichia coli WP 2 uvrA pkm 101
Mutation assay Saccharomyces cerevisiae JD1 10–5000 lg/plate Not mutagenic OECD/SIDS, 2007
determined up to 12 h after oral gavage administration of 5 mmol/
kg of MIBC or MIBK (510 and 500 mg/kg, respectively) in corn oil to
male Sprague–Dawley rats (n = at least three blood samples per
sampling time). The major material in the plasma for both test
materials was HMP, with similar areas under the curve (AUCs)
and C-max at 9 h after dosing for both MIBC and MIBK. MIBK plasma
levels and AUC were also comparable after MIBK or MIBC
administration. MIBC AUC was only about 6% of the total material
in the blood following MIBC administration, and insignificant after
MIBK administration. No other metabolites were detected in the
plasma. The extent of metabolism of MIBC to MIBK was at least
73% (Gingell et al., 2003; Granvil et al., 1994).
In an occupational exposure study of workers exposed to mixed
solvents including MIBK or MIBK alone, 4-methyl-2-pentanol was
identified by GCMS in the urine (Hirota, 1991a).
4-Methyl-2-pentanol was identified as a metabolite following
intraperitoneal administration of MIBK to rats (Hirota, 1991b).
Excessive urinary glucuronide excretion, compared to that of
controls, by rabbits (n = 3) following oral gavage administration
of 3 ml/rabbit of 4-methyl-2-pentanol, represented 33.7% of the
administered dose (Kamil et al., 1953).
4.6.3.2. In vitro studies in animals. No available information.
4.7. Repeated dose toxicity
4-Methyl-2-pentanol was exposed to nine mice 12 times for 4 h
at 20 mg/l. No deaths were observed (McOmie and Anderson,
1949).
4-Methyl-2-pentanol was given at doses of 0, 50.5, 198, or
886 ml/m 3 to Wistar rats (12/sex) for 6 h per day, 5 days a week,
over the course of 6 weeks according to OECD guideline TG 407.
At the two lowest doses the concentration of ketone bodies in
the urine increased for males and females. At 886 ml/m 3 the absolute
kidney weight increased (males) and the serum alkaline phosphatase
increased (females). The authors concluded a NOAEC at
198 ml/m 3 (OECD/SIDS 2007).
4.8. Reproductive and developmental toxicity
No available information.
4.9. Genotoxicity
4.9.1. In vitro studies
4.9.1.1. Bacterial test systems (see Table 5). 4-Methyl-2-pentanol up
to 5000 lg/plate was not mutagenic in Salmonella typhimurium
strains TA 98, TA 100, TA1535, TA 1537, and TA 1538 and Escerichia
coli strain WP 2 uvrA, Ames with and without addition of S9 liver
fractions from KC500 induced rats (Shimizu et al., 1985).
An Ames assay with and without metabolic activation found 4-
methyl-2-pentanol as non-mutagenic using Salmonella typhimurium
TA98, TA100, TA1535, TA1537, TA1538, E. coli WP2 uvr A
pkm 101 at 31.25–4000 lg/plate (OECD/SIDS, 2007).
4-Methyl-2-pentanol is not mutagenic according to a gene
mutation study with and without metabolic activation in saccharomyces
cerevisiae JD1 at 10–5000 lg/plate (OECD/SIDS, 2007).
4.9.1.2. Studies in mammalian cells. Rat liver cells (RL4) were tested
in a cytogenetic assay with 0, 0.5, 1, or 2 mg/ml of 4-methyl-2-
pentanol. According to the conditions of this study the results were
negative (OECD/SIDS, 2007).
4.9.2. In vivo studies
No available information.
4.10. Carcinogenicity
No available information.
This individual Fragrance Material Review is not intended as a
stand-alone document. Please refer to A Safety Assessment of
Branched Chain Saturated Alcohols When Used as Fragrance Ingredients
(Belsito et al., 2010) for an overall assessment of this
material.
Conflict of interest statement
This research was supported by the Research Institute for
Fragrance Materials, an independent research institute that is
funded by the manufacturers of fragrances and consumer products
containing fragrances. The authors are all employees of the
Research Institute for Fragrance Materials.
References
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chain
saturated alcohols when used as fragrance ingredients. Food and Chemical
Toxicology 48 (S4), S1–S46.
Bar, V.F., Griepentrog, F., 1967. Die Situation in der gesundheitlichen Beurteilung
der Aromatisierungsmittel fur Lebensmittel (where we stand concerning the
evaluation of flavoring substances from the viewpoint of health). Medizin
Ernahr. 8, 244–251.
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:
providing estimates for safety evaluation. Regulatory Toxicology and
Pharmacology 36, 246–252.
Carpenter, C.P., Smyth, H.F., Pozzani, U.C., 1949. The assay of acute vapor toxicity,
and the grading and interpretation of results on 96 chemical compounds. The
Journal of Industrial Hygiene and Toxicolology 31 (6), 343–346.
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface
Suite for Microsoft Ò Windows, v 4.00 or insert version used. United States
Environmental Protection Agency, Washington, DC, USA.
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria for
development of a database for safety evaluation of fragrance ingredients.
Regulatory Toxicology and Pharmacology 31, 166–181.
Gingell, R., Regnier, J.F., Wilson, D.M., Guillaumat, P.O., Appelqvist, T., 2003.
Comparative metabolism of methyl isobutyl carbinol and methyl isobutyl
ketone in male rats. Toxicology Letters 136 (1–2), 199–204.
Granvil, C.P., Sharkawi, M., Plaa, G.L., 1994. Metabolic fate of methyl n-butyl ketone,
methyl isobutyl ketone and their metabolites in mice. Toxicology Letters 70 (3),
263–267.
Hirota, N., 1991a. The metabolism of methyl isobutyl ketone and biological
monitoring: part 2. Qualitative and quantitative study of 4-methyl-2-pentanol
excreted in the urine of workers exposed to methyl isobutyl ketone. Okayama
Igakkai Zasshi 103 (4), 327–336.

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S55–S59 S59
Hirota, N., 1991b. The metabolism of methyl isobutyl ketone and its biological
monitoring: part 1. Qualitative and quantitative studies of methyl isobutyl
ketone exhaled from the lungs and excreted in the urine, and the metabolites in
the urine of rats inject. Okayama Igakkai Zasshi 103 (4), 315–326.
IFRA (International Fragrance Association), 2004. Use level survey, August 2004.
IFRA (International Fragrance Association), 2007. Volume of use survey, February
2007.
Kamil, I.A., Smith, J.N., Williams, R.T., 1953. Studies in detoxication. 46. The
metabolism of aliphatic alcohols. The glucuronic acid conjugation of acyclic
aliphatic alcohols. Biochemical Journal 53, 129–136.
McOmie, W.A., Anderson, H.H., 1949. Comparative toxicologic effects of some
isobutyl carbinols and ketones. University California Publications Pharmacology
2 (17), 217–230.
Nishimura, H., Saito, S., Kishida, F., Matsuo, M., 1994. Analysis of acute toxicity
(LD50-value) of organic chemicals to mammals by solubility parameter (delta).
1. Acute oral toxicity to rats. Sangyo Igaku 36 (5), 314–323. Japanese Journal
Industrial Health.
OECD and Screening Information Datasets (SIDS), (2007). High production volume
chemicals 4-methylpentan-2-ol (Cas no: 108-11-2). Processed by United
Nations Environmental Program, (UNEP) available online: .
Shimizu, H., Suzuki, Y., Takemura, N., Goto, S., Matsushita, H., 1985. The results of
microbial mutation test for forty-three industrial chemicals. Japanese Journal of
Industrial Health 27 (6), 400–419.
Smyth, H.F., Carpenter, C.P., Weil, C.S., 1949. Range-finding toxicity data, list III. The
Journal of Industrial Hygiene and Toxicolology 31 (1), 60–62.
Smyth, H.F., Carpenter, C.P., Weil, C.S., 1951. Range finding toxicity data: List IV.
Archives of Industrial Hygiene and Occupational Medicine 4, 119–122.
VCF, 2009. (Volatile Compounds in Food): database/Nijssen, L.M., Ingen-Visscher,
C.A. van, Donders, J.J.H. (Eds.). – Version 11.1.1 – TNO Quality of Life, Zeist, The
Netherlands, 1963–2009.

Food and Chemical Toxicology 48 (2010) S60–S62
Contents lists available at ScienceDirect
Food and Chemical Toxicology
journal homepage: www.elsevier.com/locate/foodchemtox
Review
Fragrance material review on 2-methylundecanol
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api
Research Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
article
Keywords:
Review
Fragrance
info
abstract
A toxicologic and dermatologic review of 2-methylundecanol when used as a fragrance ingredient is presented.
2-Methylundecanol is a member of the fragrance structural group branched chain saturated alcohols.
The common characteristic structural elements of the alcohols with saturated branched chain are
one hydroxyl group per molecule, and a C 4 –C 12 carbon chain with one or several methyl side chains. This
review contains the information available on this individual fragrance ingredient and is not intended as a
stand-alone document. A safety assessment of the entire branched chain saturated alcohol group will be
published simultaneously with this document; please refer to Belsito et al. (2010) for an overall assessment
of the safe use of this material and all other branched chain saturated alcohols in fragrances.
Ó 2010 Published by Elsevier Ltd.
Contents
Introduction ........................................................................................................ S60
1. Identification . . . . . . . . . . . . . . . ........................................................................................ S60
2. Physical properties . . . . . . . . . . . ........................................................................................ S60
3. Usage. . . . . . ........................................................................................................ S61
4. Toxicology data . . . . . . . . . . . . . ........................................................................................ S61
Conflict of interest statement . . ........................................................................................ S62
References . ........................................................................................................ S62
Introduction
This document provides a summary of the toxicologic review,
including all human health endpoints, of 2-methylundecanol when
used as a fragrance ingredient. 2-Methylundecanol (see Fig. 1; CAS
Number 10522-26-6) is a fragrance ingredient used in cosmetics,
fine fragrances, shampoos, toilet soaps and other toiletries as well
as in non-cosmetic products such as household cleaners and
detergents.
In 2006, a complete literature search was conducted on 2-Methylundecanol.
On-line toxicological databases were searched
including those from the Chemical Abstract services, [e.g., ToxCenter
(which in itself contains 18 databases including Chemical Abstracts)],
and the National Library of Medicine [e.g., Medline,
Toxnet (which contains 14 databases)] as well as 26 additional
sources (e.g., BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance
companies were asked to submit all test data.
The safety data on this material has never been reviewed before
by RIFM (Research Institute for Fragrance Materials, Inc.). All relevant
references are included in this document. More details have
been provided for unpublished data. The number of animals, sex
and strain are always provided unless they are not given in the original
report or paper. Any papers in which the vehicles and/or the
doses are not given have not been included in this review. In addition,
diagnostic patch test data with fewer than 100 consecutive
patients have been omitted.
1. Identification
1.1 Synonyms: 1-undecanol, 2-methyl-; 2-methylundecan-1-ol
1.2 CAS registry number: 10522-26-6
1.3 EINECS number: 234-067-4
1.4 Formula: C 12 H 26 O
1.5 Molecular weight: 186.39
2. Physical properties
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.
E-mail address: dmcginty@RIFM.org (D. McGinty).
2.1 Physical form: no information available
2.2 Boiling point (calculated; EPA, 2010): 262.99 °C
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.fct.2010.05.029

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S60–S62 S61
2.3 Flash point: no information available
2.4 Henry’s law (calculated; EPA, 2010): 0.0000963 atm m 3 /mol
25 °C
2.5 Log K ow (calculated; EPA, 2010): 4.7
2.6 Refractive index: no information available
2.7 Specific gravity: no information available
2.8 Vapor pressure (calculated; EPA, 2010): 0.0014 mm Hg;
0.186 Pa (25 °C)
2.9 Water solubility (calculated; EPA, 2010): 16.18 mg/l (25 °C)
2.10 UV spectra available at RIFM, peaks at 200–205 nm and
returns to baseline at 270–280 nm
3. Usage
Fig. 1. 2-Methylundecanol.
2-Methylundecanol is a fragrance ingredient used in many fragrance
compounds. It may be found in fragrances used in decorative
cosmetics, fine fragrances, shampoos, toilet soaps and other
toiletries as well as in non-cosmetic products such as household
cleaners and detergents. Its use worldwide is in the region of

S62
D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S60–S62
Conflict of interest statement
This research was supported by the Research Institute for Fragrance
Materials, an independent research institute that is funded
by the manufacturers of fragrances and consumer products containing
fragrances. The authors are all employees of the Research
Institute for Fragrance Materials.
References
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A toxicologic and dermatologic
assessment of alcohols branched chain saturated when used as fragrance
ingredients. Food and Chemical Toxicology, this issue 48 (S4), S1–S46.
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:
providing estimates for safety evaluation. Regulatory Toxicology and
Pharmacology 36, 246–252.
EPA (Environmental Protection Agency), 2010. Estimation programs interface
suite for Microsoft Ò Windows, v 4.00 or insert version used]. United States
Environmental Protection Agency, Washington, DC, USA.
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria for
development of a database for safety evaluation of fragrance ingredients.
Regulatory Toxicology and Pharmacology 31, 166–181.
IFRA (International Fragrance Association), 2004. Use level survey, August 2004.
IFRA (International Fragrance Association), 2007. Volume of use survey, February
2007.

Food and Chemical Toxicology 48 (2010) S63–S66
Contents lists available at ScienceDirect
Food and Chemical Toxicology
journal homepage: www.elsevier.com/locate/foodchemtox
Review
Fragrance material review on 3,4,5,6,6-pentamethylheptan-2-ol
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api
Research Institute for Fragrance Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
article
Keywords:
Review
Fragrance
info
abstract
A toxicologic and dermatologic review of 3,4,5,6,6-pentamethylheptan-2-ol when used as a fragrance
ingredient is presented. 3,4,5,6,6-Pentamethylheptan-2-ol is a member of the fragrance structural group
branched chain saturated alcohols. The common characteristic structural elements of the alcohols with
saturated branched chain are one hydroxyl group per molecule, and a C 4 –C 12 carbon chain with one or
several methyl side chains. This review contains a detailed summary of all available toxicology and dermatology
papers that are related to this individual fragrance ingredient and is not intended as a standalone
document. A safety assessment of the entire branched chain saturated alcohol group will be published
simultaneously with this document; please refer to Belsito et al. (2010) for an overall assessment
of the safe use of this material and all other branched chain saturated alcohols in fragrances.
Ó 2010 Published by Elsevier Ltd.
Contents
Introduction . . . ...................................................................................................... S64
1. Identification . . ...................................................................................................... S64
2. Physical properties . . . . . . . . . . . . . . . . . ................................................................................... S64
3. Usage. . . . . . . . . ...................................................................................................... S64
4. Toxicology data ...................................................................................................... S65
4.1. Acute toxicity (see Table 2) . . . . . . . . . . . . . . ......................................................................... S65
4.1.1. Oral studies. . . . . . . . . . . . . . . .............................................................................. S65
4.1.2. Dermal studies . . . . . . . . . . . . .............................................................................. S65
4.1.3. Intraperitoneal studies . . . . . . .............................................................................. S65
4.2. Skin irritation . . . . . . . . . ......................................................................................... S65
4.2.1. Human studies . . . . . . . . . . . . .............................................................................. S65
4.2.2. Animal studies . . . . . . . . . . . . .............................................................................. S65
4.3. Mucous membrane (eye) irritation . . . . . . . . ......................................................................... S65
4.4. Skin sensitization . . . . . . ......................................................................................... S65
4.4.1. Human studies . . . . . . . . . . . . .............................................................................. S65
4.4.2. Animal studies . . . . . . . . . . . . .............................................................................. S65
4.5. Phototoxicity and photoallergy . . . . . . . . . . . ......................................................................... S65
4.6. Absorption, distribution and metabolism . . . ......................................................................... S66
4.7. Repeated dose toxicity . . ......................................................................................... S66
4.7.1. Two to fourteen day studies . .............................................................................. S66
4.7.2. Subchronic studies (see Table 3) . . . . . . . . . . . . . . . . . ........................................................... S66
4.7.3. Chronic studies . . . . . . . . . . . . .............................................................................. S66
4.8. Reproductive and developmental toxicity . . . ......................................................................... S66
4.9. Genotoxicity . . . . . . . . . . ......................................................................................... S66
4.9.1. In vitro studies . . . . . . . . . . . . .............................................................................. S66
4.9.2. In vivo studies. . . . . . . . . . . . . .............................................................................. S66
4.10. Carcinogenicity . . . . . . . ......................................................................................... S66
Conflict of interest statement . . . . . . . . ................................................................................... S66
References . . . . ...................................................................................................... S66
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.
E-mail address: dmcginty@RIFM.org (D. McGinty).
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.fct.2010.05.030

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D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S63–S66
Introduction
This document provides a summary of the toxicologic review,
including all human health endpoints, of 3,4,5,6,6-pentamethylheptan-2-ol
when used as a fragrance ingredient. 3,4,5,6,6-Pentamethylheptan-2-ol
(see Fig. 1; CAS Number 87118-95-4) is a
fragrance ingredient used in cosmetics, fine fragrances, shampoos,
toilet soaps and other toiletries as well as in non-cosmetic products
such as household cleaners and detergents.
In 2006, a complete literature search was conducted on
3,4,5,6,6-pentamethylheptan-2-ol. On-line toxicological databases
were searched including those from the Chemical Abstract Services
[e.g. ToxCenter (which in itself contains 18 databases including
Chemical Abstracts)], and the National Library of Medicine [e.g.
Medline, Toxnet (which contains 14 databases)] as well as 26 additional
sources (e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition,
fragrance companies were asked to submit all test data.
The safety data on this material has never been reviewed before
by RIFM (Research Institute for Fragrance Materials, Inc.). All relevant
references are included in this document. More details have
been provided for unpublished data. The number of animals, sex
and strain are always provided unless they are not given in the original
report or paper. Any papers in which the vehicles and/or the
doses are not given have not been included in this review. In addition,
diagnostic patch test data with fewer than 100 consecutive
patients have been omitted.
1. Identification
1.1. Synonyms: 2-heptanol, 3,4,5,6,6-pentamethyl-; Koavol DH.
1.2. CAS Registry Number: 87118-95-4.
1.3. EINECS Number: 401-030-0.
1.4. Formula: C 12 H 26 O.
1.5. Molecular weight: 186.39.
2. Physical properties
2.1. Physical form: no information available.
2.2. Boiling point: 220.2–231.7 °C.
2.3. Flash point: 365.5 K (92.5 °C).
Fig. 1. 3,4,5,6,6-Pentamethylheptan-2-ol.
2.4. Henry’s law (calculated; EPA, 2010): 0.0000963 atm m 3 /mole.
2.5. Log K ow : 4.0587 at 19 °C.
2.6. Refractive index: no information available.
2.7. Specific gravity: no information available.
2.8. Vapor pressure: 2.088 Pa at 298 K.
2.9. Water solubility: 0.066 g/l at 19 °C.
2.10. UV spectra available at RIFM, peaks at 200–205 nm and
returns to baseline 264–271 nm.
3. Usage
3,4,5,6,6-Pentamethylheptan-2-ol is a fragrance ingredient used
in many fragrance compounds. It may be found in fragrances used
in decorative cosmetics, fine fragrances, shampoos, toilet soaps and
other toiletries as well as in non-cosmetic products such as household
cleaners and detergents. Its use worldwide is in the range of
10–100 metric tons per annum (IFRA, 2004). The reported volume
of use is for 3,4,5,6,6-pentamethylheptan-2-ol as used in fragrance
compounds (mixtures) in all finished consumer product categories.
The volume of use is surveyed by IFRA approximately every four
years through a comprehensive survey of IFRA and RIFM member
companies. As such the volume of use data from this survey provides
volume of use of fragrance ingredients for the majority of
the fragrance industry.
The dermal systemic exposure in cosmetic products (see Table 1)
is calculated based on the concentrations of the same fragrance
ingredient in 10 types of the most frequently used personal care
and cosmetic products (anti-perspirant, bath products, body lotion,
eau de toilette, face cream, fragrance cream, hair spray, shampoo,
shower gel, and toilet soap). The concentration of the fragrance
ingredient in fine fragrances is obtained from examination of several
thousand commercial formulations. The upper 97.5 percentile
concentration is calculated from the data obtained. This upper
97.5 percentile concentration is then used for all 10 consumer products.
These concentrations are multiplied by the amount of product
applied, the number of applications per day for each product type,
and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account for
the length of time a product may remain on the skin and/or likelihood
of the fragrance ingredient being removed by washing. The
resultant calculation represents the total consumer exposure (mg/
kg/day) (Cadby et al., 2002; Ford et al., 2000).
This is a conservative calculation of dermal systemic exposure
because it makes the unlikely assumption that a consumer will
use these 10 products containing; which are all perfumed with
the upper 97.5 percentile level of the fragrance ingredient from a
fine fragrance type of product (Cadby et al., 2002; Ford et al.,
2000). The 97.5 percentile use level in formulae for use in cosmetics
in general has been reported to be 5.5% (IFRA, 2007), which
would result in a maximum daily exposure on the skin of
0.1403 mg/kg for high end users.
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 3,4,5,6,6-pentamethylheptan-2-ol.
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient (mg/kg/day) b
Anti-perspirant 0.5 1 1 0.01 5.5 0.0046
Bath products 17 0.29 0.001 0.02 5.5 0.0001
Body lotion 8 0.71 1 0.004 5.5 0.0208
Eau de toilette 0.75 1 1 0.08 5.5 0.0550
Face cream 0.8 2 1 0.003 5.5 0.0044
Fragrance cream 5 0.29 1 0.04 5.5 0.0532
Hair spray 5 2 0.01 0.005 5.5 0.0005
Shampoo 8 1 0.01 0.005 5.5 0.0004
Shower gel 5 1.07 0.01 0.012 5.5 0.0006
Toilet soap 0.8 6 0.01 0.015 5.5 0.0007
Total 0.1401
a
b
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.
Based on a 60-kg adult.

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S63–S66 S65
A maximum skin level is then determined for consideration of
potential sensitization. The exposure is calculated as the percent
concentration of the fragrance ingredient applied to the skin based
on the use of 20% of the fragrance mixture in the fine fragrance
consumer product (IFRA, 2007). The average maximum use level
in formulae that go into fine fragrances has been reported to be
1.73% (IFRA, 2007), assuming use of the fragrance oil at levels up
to 20% in the final product.
4. Toxicology data
4.1. Acute toxicity (see Table 2)
4.1.1. Oral studies
Sprague–Dawley albino rats were divided into three groups of
10 animals, consisting of five males and five females per group.
The three dose levels of undiluted 3,4,5,6,6-pentamethylheptan-
2-ol was orally administered (via gavage) at 7.81, 6.25, or 5.0 g/
kg bodyweight. Animals were observed immediately after dosing,
at 1 and 4 h, and twice daily thereafter for 14 days. At 5.0 g/kg 1
of 10 died, and clinical signs included moderate salivation, piloerection,
lethargy, lacrimation, hunched posture, and epistaxis. At
6.25 g/kg, 8 of 10 died with clinical signs including diarrhea,
hunched posture, lethargy, piloerection, ataxia, moderate tremors,
lacrimation, and epistaxis. In the highest dosage group (7.81 g/kg)
9 of 10 died, and clinical signs were the same as above. No controls
were used and the LD 50 was calculated to be 5.845 (5.36–6.375) g/
kg bodyweight (RIFM, 1984a).
4.1.2. Dermal studies
A group of 10 (5/sex) HC/CFY (remote Sprague–Dawley) rats
were treated with the 3,4,5,6,6-pentamethylheptan-2-ol at 2.0 g/
kg bodyweight. A dermal application was made to the dorso-lumbar
region (which had been previously clipped free of fur), covered
with a gauze patch, and held in place with an impermeable dressing.
All animals were observed soon after dosing, frequently on day
1, and at least twice per day for 14 days after dosing. There were no
mortalities, clinical signs of toxicity, or skin reactions at the site of
application. The acute LD 50 was determined to be greater than
2.0 g/kg bodyweight (RIFM, 1985c).
4.1.3. Intraperitoneal studies
In a preliminary dose range finding study, 3,4,5,6,6-pentamethylheptan-2-ol
was administered intraperitoneally to eight groups
(2/sex/group) of CD-1 mice at doses of 50, 166, 500, 750, 1000,
1250, 1666 and 3000 mg/kg bodyweight. Signs were observed at
all levels of 1000 mg/kg and higher. One animal died at 1250 mg/
kg and all animals at the two highest dosage levels. Due to the
severity of the signs and mortality, 900 mg/kg was selected as
the maximum tolerated dose (RIFM, 1985a).
4.2. Skin irritation
4.2.1. Human studies
Irritation was evaluated during the induction phase in a human
repeated insult patch test (HRIPT). A 0.2 ml aliquot of a 15% solution
in alcohol SDA-39C was applied to clear plastic patches,
1.5 1.5 in. (Parke–Davis Readi–Bandages). The patches were
Table 2
Summary of acute toxicity studies.
Route Species Number of
animals/dose group
LD 50 (g/kg)
References
Oral Rat 10 5.8 RIFM (1984a)
Dermal Rat 10 >2.0 RIFM (1985a)
placed on the subjects’ skin between the left scapula and spinal
mid-line for 24 h under occlusion. After a 24–48 h rest period, subjects
were again patched at the same site. Nine applications were
made in a three week period. Slight irritation was observed in 5
of the 51 male and female volunteers (RIFM, 1983).
4.2.2. Animal studies
A group of six male albino New Zealand rabbits were given
0.5 ml of the undiluted 3,4,5,6,6-pentamethylheptan-2-ol and observed
for up to 72 h. Erythema and edema were not observed in
any of the six rabbits tested (RIFM, 1984b).
4.3. Mucous membrane (eye) irritation
3,4,5,6,6-Pentamethylheptan-2-ol was evaluated for eye irritation
in nine healthy albino rabbits. Undiluted aliquots of 0.1 ml
were instilled into one eye. The untreated eye of each animal
served as a control. Observations were made at 1 h, and daily
thereafter for a week. Irritation was observed in the cornea and
conjunctiva, but cleared by the seventh day (RIFM, 1984c).
4.4. Skin sensitization
4.4.1. Human studies
4.4.1.1. Induction studies. A repeated insult patch tests was conducted
to determine if 15% 3,4,5,6,6-pentamethylheptan-2-ol in
alcohol SDA-39C would induce dermal sensitization in 51 human
volunteers. During the induction phase 0.2 ml was applied onto
Parke–Davis Readi–Bandages and applied to the backs of each volunteer
for 24 h. Induction applications were made for a total of
nine applications during three week period. Following a one week
rest period, a challenge patch was applied to a site previously unexposed
on the upper back. Patches were applied as in the induction
phase and kept in place for 24 h after which time they were
removed. Reactions to the challenge were scored at 24, 48, and
72 h after application. There were no sensitization reactions during
the challenge phase (RIFM, 1983).
4.4.2. Animal studies
No information available.
4.5. Phototoxicity and photoallergy
No information available.
4.6. Absorption, distribution and metabolism
No information available.
4.7. Repeated dose toxicity
4.7.1. Two to fourteen day studies
No information available.
4.7.2. Subchronic studies (see Table 3)
3,4,5,6,6-Pentamethylheptan-2-ol was assessed for its toxicity
to 10 New Zealand white rabbits (5/sex) when administered to
the occluded skin. Applications of 1000 mg/kg were made for 6 h
each day for 28 consecutive days. Irritation progressed rapidly in
all rabbits and within two weeks severe erythema and edema were
observed. Histopathological examination revealed the treated skin
to have acanthotic and focal ulcerative changes in the epidermis,
along with associated inflammation, hyperkeratosis, and scab formation.
A systemic NOAEL of 1000 mg/kg bodyweight/day was
decided for 3,4,5,6,6-pentamethylheptan-2-ol although severe irritation
was observed (RIFM, 1985d).
At concentrations of 1.5%, 5.0%, 15%, and 50% 3,4,5,6,6-pentamethylheptan-2-ol
in 1% aqueous methylcellulose (equivalent to 30,
100, 300, and 1000 mg/kg/day) was applied to the intact skin of

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D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S63–S66
Table 3
Summary of subchronic studies.
Method
Dose
(mg/kg/day)
Species Results References
Dermal application under occlusion 1000 Rabbits NOAEL: 1000 mg/kg bodyweight/day RIFM (1985d)
Severe irritation; associated inflammation,
hyperkeratosis, and scabbing
Dermal application under occlusion Up to 1000 Rabbits NOAEL: 1000 mg/kg bodyweight/day RIFM (1986)
Slight to moderate dermal irritation; severe
irritation at high doses; reversible after 8 days
New Zealand white rabbits (10/sex). The two lowest dosages (30
and 100 mg/kg/day) were allowed to run for 6 h per day, and 28
consecutive days under an occlusive patch. Slight to moderate dermal
irritation developed for both dosages but ameliorated by day
16 for 30 mg/kg/day, and persisted to termination for 100 mg/kg/
day. Treatment of the two highest dosages (300 and 1000 mg/kg/
day) was terminated after nine applications because of the severity
of the dermal reactions. However, after 8 days irritation subsided
and the data suggests the dermal reactions are reversible. A systemic
NOAEL of 1000 mg/kg bodyweight/day was decided for
3,4,5,6,6-pentamethylheptan-2-ol although severe irritation was
observed (RIFM, 1986).
4.7.3. Chronic studies
No information available.
4.8. Reproductive and developmental toxicity
No information available.
4.9. Genotoxicity
4.9.1. In vitro studies
4.9.1.1. Bacterial test systems. An Ames test using 0.1 ml of
3,4,5,6,6-pentamethylheptan-2-ol was added to Escherichia coli
WP2 uvrA, Salmonella typhimurium TA 98, 100, 1535, 1537, and
1538 cultures at concentrations up to 1000 lg/plate with and
without S9 activation. Toxicity was observed with tester strains
TA 98, 100, and 1535 at the higher dose levels. A second round
of tests, up to 100 lg/plate, did not show any substantial increases
in revertant colony numbers. It was concluded that the test material
showed no evidence of mutagenic activity in these bacterial
systems (RIFM, 1985b).
4.9.1.2. Studies in mammalian cells. No information available.
4.9.2. In vivo studies
In a CD-1 mouse micronucleus test, three groups of 10 animals
(5 males and 5 females per group) were given single doses of
3,4,5,6,6-pentamethylheptan-2-ol in corn oil by intraperitoneal
injection at 900 mg/kg and sacrificed at 30, 48, and 72 h. All groups
showed significantly lower ratios of polychromatic erythrocytes to
normochromatic erythrocytes (PCE/NCE) suggesting the bioavailability
of the test article. Statistically significant increases in the
incidence of micronuclei of experimental animals were not observed.
Based upon the inability of the test article to produce a significant
increase in the incidence of micronuclei per 1000
polychromatic erythrocytes in the treated versus the negative control
groups, 3,4,5,6,6-pentamethylheptan-2-ol was determined to
be negative in the micronucleus test (RIFM, 1985c).
4.10. Carcinogenicity
No available information.
This individual Fragrance Material Review is not intended as a
stand-alone document. Please refer to A Safety Assessment of
Branched Chain Saturated Alcohols When Used as Fragrance Ingredients
(Belsito et al., 2010) for an overall assessment of this
material.
Conflict of interest statement
This research was supported by the Research Institute for Fragrance
Materials, an independent research institute that is funded
by the manufacturers of fragrances and consumer products containing
fragrances. The authors are all employees of the Research
Institute for Fragrance Materials.
References
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chain
saturated alcohols when used as fragrance ingredients. Food and Chemical
Toxicology 48 (S4), S1–S46.
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:
providing estimates for safety evaluation. Regulatory Toxicology and
Pharmacology 36, 246–252.
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface
Suite for Microsoft Ò Windows, v 4.00 or Insert Version Used. United States
Environmental Protection Agency, Washington, DC, USA.
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria for
development of a database for safety evaluation of fragrance ingredients.
Regulatory Toxicology and Pharmacology 31, 166–181.
IFRA (International Fragrance Association), 2004. Use Level Survey, August 2004.
IFRA (International Fragrance Association), 2007. Volume of Use Survey, February
2007.
RIFM (Research Institute for Fragrance Materials, Inc.), 1983. Evaluation of Potential
Irritation and Sensitization Hazards by Dermal Contact: Repeated Insult Patch
Test with 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished Report from
International Flavors and Fragrances, 27 October. Report Number 48462,
RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1984a. Acute Oral LD50
Determination in the Rat on 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished
Report from International Flavors and Fragrances, Report Number 47552, RIFM,
Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1984b. Primary Dermal
Irritation Test of 3,4,5,6,6-Pentamethylheptan-2-ol on the Rabbit. Unpublished
Report from International Flavors and Fragrances, Report Number 47792, RIFM,
Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1984c. Acute Eye Irritation/
Corrosion Test to the Rabbit of 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished
Report from International Flavors and Fragrances, Report Number 47677, RIFM,
Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1985a. Acute Dermal
Toxicity to the Rat of 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished Report
from International Flavors and Fragrances, Report Number 47587, RIFM,
Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1985b. Microbial Metabolic
Activation Test to Assess the Potential Mutagenic Effect of 3,4,5,6,6-
Pentamethylheptan-2-ol. Unpublished Report from International Flavors and
Fragrances, Report Number 48164, RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1985c. Micronucleus Test
(MNT) OECD on 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished Report from
International Flavors and Fragrances, Report Number 48252, RIFM, Woodcliff
Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1985d. Twenty-eight Day
Dermal Irritation Study in Rabbits with 3,4,5,6,6-Pentamethylheptan-2-ol.
Unpublished Report from International Flavors and Fragrances, Report
Number 47793, RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1986. Twenty-eight Day
Dermal Irritation Study in Rabbits with 3,4,5,6,6-Pentamethylheptan-2-ol.
Unpublished Report from International Flavors and Fragrances, Report
Number 48027, RIFM, Woodcliff Lake, NJ, USA.

Food and Chemical Toxicology 48 (2010) S67–S69
Contents lists available at ScienceDirect
Food and Chemical Toxicology
journal homepage: www.elsevier.com/locate/foodchemtox
Review
Fragrance material review on isodecyl alcohol
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api
Research Institute for Fragrance Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
article
Keywords:
Review
Fragrance
info
abstract
A toxicologic and dermatologic review of isodecyl alcohol when used as a fragrance ingredient is presented.
Isodecyl alcohol is a member of the fragrance structural group branched chain saturated alcohols.
The common characteristic structural elements of the alcohols with saturated branched chain are one
hydroxyl group per molecule, and a C 4 –C 12 carbon chain with one or several methyl side chains. This
review contains a detailed summary of all available toxicology and dermatology papers that are related
to this individual fragrance ingredient and is not intended as a stand-alone document. A safety assessment
of the entire branched chain saturated alcohol group will be published simultaneously with this
document; please refer to Belsito et al. (2010) for an overall assessment of the safe use of this material
and all other branched chain saturated alcohols in fragrances.
Ó 2010 Published by Elsevier Ltd.
Contents
Introduction . . . ..................................................................................................... S67
1. Identification . . ..................................................................................................... S68
2. Physical properties . . . . . . . . . . . . . . . . . .................................................................................. S68
3. Usage. . . . . . . . . ..................................................................................................... S68
4. Toxicology data ..................................................................................................... S69
4.1. Acute toxicity. ................................................................................................ S69
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S69
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S69
4.2. Skin irritation. ................................................................................................ S69
4.3. Mucous membrane (eye) irritation. ............................................................................... S69
4.4. Skin sensitization. ............................................................................................. S69
4.5. Phototoxicity and photoallergy. . ................................................................................. S69
4.6. Absorption, distribution and metabolism .......................................................................... S69
4.7. Repeated dose toxicity . . ....................................................................................... S69
4.8. Reproductive and developmental toxicity .......................................................................... S69
4.9. Genotoxicity. ................................................................................................. S69
4.10. Carcinogenicity . . ............................................................................................. S69
Conflict of interest statement . . . . . . . . .................................................................................. S69
References . . . . ..................................................................................................... S69
Introduction
This document provides a summary of the toxicologic review,
including all human health endpoints, of isodecyl alcohol when
used as a fragrance ingredient. Isodecyl alcohol (see Fig. 1; CAS
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.
E-mail address: dmcginty@RIFM.org (D. McGinty).
Number 25339-17-7) is a fragrance ingredient used in cosmetics,
fine fragrances, shampoos, toilet soaps and other toiletries as well
as in non-cosmetic products such as household cleaners and
detergents.
In 2006, a complete literature search was conducted on isodecyl
alcohol. On-line toxicological databases were searched including
those from the Chemical Abstract Services [e.g. ToxCenter (which
in itself contains 18 databases including Chemical Abstracts)],
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.fct.2010.05.031

S68
D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S67–S69
2. Physical properties
2.1. Physical form: no information available.
2.2. Boiling point (calculated; EPA, 2010): 227.56 °C.
2.3. Flash point: no information available.
2.4. Henry’s law (calculated; EPA, 2010): 0.0000547 atm m 3 /mol
(25 °C).
2.5. Log K ow (calculated; EPA, 2010): 3.71.
2.6. Refractive index: no information available.
2.7. Specific gravity: no information available.
2.8. Vapor pressure (calculated; EPA, 2010): 0.0204 mm Hg;
2.72 Pa (25 °C).
2.9. Water solubility (calculated; EPA, 2010): 151.8 mg/l (25 °C).
2.10. UV spectra not available at RIFM.
3. Usage
and the National Library of Medicine [e.g. Medline, Toxnet
(which contains 14 databases)] as well as 26 additional sources
(e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance
companies were asked to submit all test data.
The safety data on this material has never been reviewed before
by RIFM (Research Institute for Fragrance Materials, Inc.). All relevant
references are included in this document. More details have
been provided for unpublished data. The number of animals, sex
and strain are always provided unless they are not given in the original
report or paper. Any papers in which the vehicles and/or the
doses are not given have not been included in this review. In addition,
diagnostic patch test data with fewer than 100 consecutive
patients have been omitted.
1. Identification
Fig. 1. Isodecyl alcohol.
1.1. Synonyms: isodecanol; 8-methylnonan-1-ol.
1.2. CAS Registry Number: 25339-17-7.
1.3. EINECS Number: 246-869-1.
1.4. Formula: C 10 H 22 O.
1.5. Molecular weight: 158.85.
Isodecyl alcohol is a fragrance ingredient used in many fragrance
compounds. It may be found in fragrances used in decorative
cosmetics, fine fragrances, shampoos, toilet soaps and other
toiletries as well as in non-cosmetic products such as household
cleaners and detergents. Its use worldwide is in the region of
0.1–1.0 metric tons per annum (IFRA, 2004). The reported volume
of use is for isodecyl alcohol as used in fragrance compounds (mixtures)
in all finished consumer product categories. The volume of
use is surveyed by IFRA approximately every four years through
a comprehensive survey of IFRA and RIFM member companies.
As such the volume of use data from this survey provides volume
of use of fragrance ingredients for the majority of the fragrance
industry.
The dermal systemic exposure in cosmetic products (see
Table 1) is calculated based on the concentrations of the same fragrance
ingredient in 10 types of the most frequently used personal
care and cosmetic products (anti-perspirant, bath products, body
lotion, eau de toilette, face cream, fragrance cream, hair spray,
shampoo, shower gel, and toilet soap). The concentration of the
fragrance ingredient in fine fragrances is obtained from examination
of several thousand commercial formulations. The upper
97.5 percentile concentration is calculated from the data obtained.
This upper 97.5 percentile concentration is then used for all 10
consumer products. These concentrations are multiplied by the
amount of product applied, the number of applications per day
for each product type, and a ‘‘retention factor” (ranging from
0.001 to 1.0) to account for the length of time a product may remain
on the skin and/or likelihood of the fragrance ingredient
being removed by washing. The resultant calculation represents
the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford
et al., 2000).
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing isodecyl alcohol.
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient (mg/kg/day) b
Anti-perspirant 0.5 1 1 0.01 0.0009 0.0000001
Bath products 17 0.29 0.001 0.02 0.0009 0.0000001
Body lotion 8 0.71 1 0.004 0.0009 0.0000001
Eau de toilette 0.75 1 1 0.08 0.0009 0.0000100
Face cream 0.8 2 1 0.003 0.0009 0.0000001
Fragrance cream 5 0.29 1 0.04 0.0009 0.0000100
Hair spray 5 2 0.01 0.005 0.0009 0.0000001
Shampoo 8 1 0.01 0.005 0.0009 0.0000001
Shower gel 5 1.07 0.01 0.012 0.0009 0.0000001
Toilet soap 0.8 6 0.01 0.015 0.0009 0.0000001
Total 0.00002
a
b
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.
Based on a 60-kg adult.

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S67–S69 S69
This is a conservative calculation of dermal systemic exposure
because it makes the unlikely assumption that a consumer will
use these 10 products containing; which are all perfumed with
the upper 97.5 percentile level of the fragrance ingredient from a
fine fragrance type of product (Cadby et al., 2002; Ford et al.,
2000). The 97.5 percentile use level in formulae for use in cosmetics
in general has been not been reported. As such the default value
of 0.02% is used to calculate the maximum daily exposure on the
skin of 0.00002 mg/kg for high end users.
A maximum skin level is then determined for consideration of
potential sensitization. The exposure is calculated as the percent
concentration of the fragrance ingredient applied to the skin based
on the use of 20% of the fragrance mixture in the fine fragrance
consumer product (IFRA, 2007). The average maximum use level
in formulae that go into fine fragrances has not been reported. A
default value of 0.02% is used, assuming use of the fragrance oil
levels up to 20% in the final product.
4. Toxicology data
4.1. Acute toxicity
4.1.1. Oral studies
The acute oral LD 50 of isodecyl alcohol in rats was reported to be
6.5 g/kg. No additional details available (Article in Japanese)
(Nishimura et al., 1994).
4.1.2. Dermal studies
No information available.
4.2. Skin irritation
No information available.
4.3. Mucous membrane (eye) irritation
No information available.
4.4. Skin sensitization
No information available.
4.5. Phototoxicity and photoallergy
No information available.
4.6. Absorption, distribution and metabolism
No information available.
4.7. Repeated dose toxicity
No information available.
4.8. Reproductive and developmental toxicity
In a comparative developmental toxicity study, isodecyl alcohol
was administered by gavage to Wistar rats (10/group) at 0, 1, 5,
and 10 mmol/kg (0, 158, 790, and 1580 mg/kg/day) on gestation
days 6–15. Maternal toxicity and incidences of fetal retardations
and rare malformations were observed at 10 mmol/kg. Maternal
mortality was 4/10 in this dose group. Body weight on days 15
and 20, uterus weight, and fetal weights were all significantly lower
than controls in the 10 mmol/kg group. Post-implantation loss,
resorptions, and number of fetuses with malformations were all
higher than controls at 10 mmol/kg. There was no maternal mortality
in any of the other groups. Some maternal signs, but no fetal
signs were observed at 5 mmol/kg. The clinical signs included nasal
discharge, salivation, and signs of CNS depression. None of the
measured maternal or fetal parameters were significantly different
than controls at this dose. The NOEL for maternal effects was
1 mmol/kg and for fetal effects 5 mmol/kg (Hellwig and Jackh,
1997).
4.9. Genotoxicity
No information available.
4.10. Carcinogenicity
No information available.
This individual Fragrance Material Review is not intended as a
stand-alone document. Please refer to A Safety Assessment of
Branched Chain Saturated Alcohols When Used as Fragrance Ingredients
(Belsito et al., 2010) for an overall assessment of this
material.
Conflict of interest statement
This research was supported by the Research Institute for Fragrance
Materials, an independent research institute that is funded
by the manufacturers of fragrances and consumer products containing
fragrances. The authors are all employees of the Research
Institute for Fragrance Materials.
References
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chain
saturated alcohols when used as fragrance ingredients. Food and Chemical
Toxicology 48 (S4), S1–S46.
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:
providing estimates for safety evaluation. Regulatory Toxicology and
Pharmacology 36, 246–252.
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface
Suite for Microsoft Ò Windows v 4.00 or Insert Version Used. United States
Environmental Protection Agency, Washington, DC, USA.
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria for
development of a database for safety evaluation of fragrance ingredients.
Regulatory Toxicology and Pharmacology 31, 166–181.
Hellwig, J., Jackh, R., 1997. Differential prenatal toxicity of one straight-chain and
five branched-chain primary alcohols in rats. Food and Chemical Toxicology 35
(5), 489–500.
IFRA (International Fragrance Association), 2004. Use Level Survey, August 2004.
IFRA (International Fragrance Association), 2007. Volume of Use Survey, February
2007.
Nishimura, H., Saito, S., Kishida, F., Matsuo, M., 1994. Analysis of acute toxicity
(LD50-value) of organic chemicals to mammals by solubility parameter (delta).
1. Acute oral toxicity to rats. Sangyo Igaku 36 (5), 314–323 (Japanese Journal
Industrial Health).

Food and Chemical Toxicology 48 (2010) S70–S72
Contents lists available at ScienceDirect
Food and Chemical Toxicology
journal homepage: www.elsevier.com/locate/foodchemtox
Review
Fragrance material review on isooctan-1-ol
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api
Research Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
article
Keywords:
Review
Fragrance
info
abstract
A toxicologic and dermatologic review of isooctan-1-ol when used as a fragrance ingredient is presented.
Isooctan-1-ol is a member of the fragrance structural group branched chain saturated alcohols. The common
characteristic structural elements of the alcohols with saturated branched chain are one hydroxyl
group per molecule, and a C 4 –C 12 carbon chain with one or several methyl side chains. This review contains
a detailed summary of all available toxicology and dermatology papers that are related to this individual
fragrance ingredient and is not intended as a stand-alone document. A safety assessment of the
entire branched chain saturated alcohol group will be published simultaneously with this document;
please refer to Belsito et al. (2010) for an overall assessment of the safe use of this material and all other
branched chain saturated alcohols in fragrances.
Ó 2010 Published by Elsevier Ltd.
Contents
Introduction ........................................................................................................ S70
1. Identification . . . . . . . . . . . . . . . ........................................................................................ S71
2. Physical properties . . . . . . . . . . . ........................................................................................ S71
3. Usage. . . . . . ........................................................................................................ S71
4. Toxicology data . . . . . . . . . . . . . ........................................................................................ S72
4.1. Acute toxicity. ................................................................................................ S72
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S72
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S72
4.1.3. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S72
4.2. Skin irritation. ................................................................................................ S72
4.3. Mucous membrane (eye) irritation. ............................................................................... S72
4.4. Skin sensitization. ............................................................................................. S72
4.5. Phototoxicity and photoallergy. . ................................................................................. S72
4.6. Absorption, distribution and metabolism .......................................................................... S72
4.7. Repeated dose toxicity . . ....................................................................................... S72
4.8. Reproductive and developmental toxicity .......................................................................... S72
4.9. Genotoxicity. ................................................................................................. S72
4.10. Carcinogenicity . . ............................................................................................. S72
Conflict of interest statement . . ........................................................................................ S72
References . ........................................................................................................ S72
Introduction
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.
E-mail address: dmcginty@RIFM.org (D. McGinty).
This document provides a summary of the toxicologic review,
including all human health endpoints, of isooctan-1-ol when used
as a fragrance ingredient. Isooctan-1-ol (see Fig. 1; CAS Number
26952-21-6) is a fragrance ingredient used in cosmetics, fine fragrances,
shampoos, toilet soaps and other toiletries as well as in
non-cosmetic products such as household cleaners and detergents.
In 2006, a complete literature search was conducted on isooctan-1-ol.
On-line toxicological databases were searched including
those from the Chemical Abstract Services [e.g. ToxCenter (which
in itself contains 18 databases including Chemical Abstracts)],
and the National Library of Medicine [e.g. Medline, Toxnet (which
contains 14 databases)] as well as 26 additional sources (e.g. BIO-
SIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance companies
were asked to submit all test data.
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.fct.2010.05.032

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S70–S72 S71
2.9. Water solubility (calculated; EPA, 2010): 1379 mg/l (25 °C).
2.10. UV spectra are not available at RIFM.
3. Usage
The safety data on this material has never been reviewed before
by RIFM (Research Institute for Fragrance Materials, Inc.). All relevant
references are included in this document. More details have
been provided for unpublished data. The number of animals, sex
and strain are always provided unless they are not given in the original
report or paper. Any papers in which the vehicles and/or the
doses are not given have not been included in this review. In addition,
diagnostic patch test data with fewer than 100 consecutive
patients have been omitted.
1. Identification
1.1. Synonyms: isooctanol; 6-methylheptan-1-ol.
1.2. CAS Registry Number: 26952-21-6.
1.3. EINECS Number: 248-133-5.
1.4. Formula: C 8 H 18 O.
1.5. Molecular weight: 130.31.
2. Physical properties
Fig. 1. Isooctan-1-ol.
2.1. Physical form: no information available.
2.2. Boiling point (calculated; EPA, 2010): 188.52 °C.
2.3. Flash point: no information available.
2.4. Henry’s law (calculated; EPA, 2010): 0.000031 m 3 /mol
(25 °C).
2.5. Log K ow (calculated; EPA, 2010): 2.73.
2.6. Refractive index: no information available.
2.7. Specific gravity: no information available.
2.8. Vapor pressure (calculated; EPA, 2010): 0.151 mm Hg;
20.1 Pa (25 °C).
Isooctan-1-ol is a fragrance ingredient used in many fragrance
compounds. It may be found in fragrances used in decorative cosmetics,
fine fragrances, shampoos, toilet soaps and other toiletries
as well as in non-cosmetic products such as household cleaners
and detergents. Its use worldwide is in the region of less than
0.01 metric tons per annum (IFRA, 2004). The reported volume of
use is for isooctan-1-ol as used in fragrance compounds (mixtures)
in all finished consumer product categories. The volume of use is
surveyed by IFRA approximately every four years through a comprehensive
survey of IFRA and RIFM member companies. As such
the volume of use data from this survey provides volume of use
of fragrance ingredients for the majority of the fragrance industry.
The dermal systemic exposure in cosmetic products (see Table
1) is calculated based on the concentrations of the same fragrance
ingredient in ten types of the most frequently used
personal care and cosmetic products (anti-perspirant, bath products,
body lotion, eau de toilette, face cream, fragrance cream, hair
spray, shampoo, shower gel, and toilet soap). The concentration of
the fragrance ingredient in fine fragrances is obtained from examination
of several thousand commercial formulations. The upper
97.5 percentile concentration is calculated from the data obtained.
This upper 97.5 percentile concentration is then used for all 10
consumer products. These concentrations are multiplied by the
amount of product applied, the number of applications per day
for each product type, and a ‘‘retention factor” (ranging from
0.001 to 1.0) to account for the length of time a product may remain
on the skin and/or likelihood of the fragrance ingredient
being removed by washing. The resultant calculation represents
the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford
et al., 2000).
This is a conservative calculation of dermal systemic exposure
because it makes the unlikely assumption that a consumer will
use these 10 products containing; which are all perfumed with
the upper 97.5 percentile level of the fragrance ingredient from a
fine fragrance type of product (Cadby et al., 2002; Ford et al.,
2000). The 97.5 percentile use level in formulae for use in cosmetics
in general has not been reported. As such the default value of
0.02% is used to calculate the maximum daily exposure on the skin
of 0.0005 mg/kg for high end users of these products (see Table 1).
A maximum skin level is then determined for consideration of
potential sensitization. The exposure is calculated as the percent
concentration of the fragrance ingredient applied to the skin based
on the use of 20% of the fragrance mixture in the fine fragrance
consumer product (IFRA, 2007). The maximum skin level that
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing isooctan-1-ol.
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient (mg/kg/day) b
Anti-perspirant 0.5 1 1 0.01 .02 0.000001
Bath products 17 0.29 0.001 0.02 .02 0.000001
Body lotion 8 0.71 1 0.004 .02 0.000100
Eau de toilette 0.75 1 1 0.08 .02 0.000200
Face cream 0.8 2 1 0.003 .02 0.000001
Fragrance cream 5 0.29 1 0.04 .02 0.000200
Hair spray 5 2 0.01 0.005 .02 0.000001
Shampoo 8 1 0.01 0.005 .02 0.000001
Shower gel 5 1.07 0.01 0.012 .02 0.000001
Toilet soap 0.8 6 0.01 0.015 .02 0.000001
Total 0.0005
a
b
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.
Based on a 60-kg adult.

S72
D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S70–S72
results from the use of isooctan-1-ol in formulae that go into fine
fragrances has been not been reported. A default value of 0.02%
is used assuming use of the fragrance oils at levels up to 20% in
the final product.
4. Toxicology data
4.1. Acute toxicity
4.1.1. Oral studies
No information available.
4.1.2. Dermal studies
No information available.
4.1.3. Inhalation studies
There was no mortality, clinical signs, or autopsy findings when
three female Alderly-Park rats were exposed in whole body exposure
chambers. Animals were exposed for up to 6 h a day, 5 days a
weeks (a total of 13 over 4 weeks) to saturated vapor of a mixture
of branched chain alcohols designated isooctan-1-ol, with a boiling
point of 185–189 °C. Concentration was 1 mg/l or 188 ppm (Gage,
1970).
4.2. Skin irritation
No information available.
4.3. Mucous membrane (eye) irritation
No information available.
4.4. Skin sensitization
No information available.
4.5. Phototoxicity and photoallergy
No information available.
4.6. Absorption, distribution and metabolism
No information available.
4.7. Repeated dose toxicity
No information available.
4.8. Reproductive and developmental toxicity
No information available.
4.9. Genotoxicity
No information available.
4.10. Carcinogenicity
No information available.
This individual Fragrance Material Review is not intended as a
stand-alone document. Please refer to A Safety Assessment of
Branched Chain Saturated Alcohols When Used as Fragrance Ingredients
(Belsito et al., 2010) for an overall assessment of this
material.
Conflict of interest statement
This research was supported by the Research Institute for Fragrance
Materials, an independent research institute that is funded
by the manufacturers of fragrances and consumer products containing
fragrances. The authors are all employees of the Research
Institute for Fragrance Materials.
References
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chain
saturated alcohols when used as fragrance ingredients. Food and Chemical
Toxicology 48 (S4), S1–S46.
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:
providing estimates for safety evaluation. Regulatory Toxicology and
Pharmacology 36, 246–252.
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface
Suite for Microsoft Ò Windows, v 4.00 or Insert Version Used. United States
Environmental Protection Agency, Washington, DC, USA.
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria for
development of a database for safety evaluation of fragrance ingredients.
Regulatory Toxicology and Pharmacology 31, 166–181.
Gage, J.C., 1970. The subacute inhalation toxicity of 109 industrial chemicals. British
Journal of Industrial Medicine 27, 1–18.
IFRA (International Fragrance Association), 2004. Use Level Survey, August 2004.
IFRA (International Fragrance Association), 2007. Volume of Use Survey, February
2007.

Food and Chemical Toxicology 48 (2010) S73–S78
Contents lists available at ScienceDirect
Food and Chemical Toxicology
journal homepage: www.elsevier.com/locate/foodchemtox
Review
Fragrance material review on isotridecan-1-ol (isomeric mixture)
D. McGinty * , S.P. Bhatia, J. Scognamiglio, C.S. Letizia, A.M. Api
Research Institute for Fragrance Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
article
Keywords:
Review
Fragrance
info
abstract
A toxicologic and dermatologic review of isotridecan-1-ol (isomeric mixture) when used as a fragrance
ingredient is presented. Isotridecan-1-ol (isomeric mixture) is a member of the fragrance structural group
branched chain saturated alcohols. The common characteristic structural elements of the alcohols with
saturated branched chain are one hydroxyl group per molecule, and a C 4 –C 12 carbon chain with one or
several methyl side chains. This review contains a detailed summary of all available toxicology and dermatology
papers that are related to this individual fragrance ingredient and is not intended as a standalone
document. A safety assessment of the entire branched chain saturated alcohol group will be published
simultaneously with this document; please refer to Belsito et al. (2010) for an overall assessment
of the safe use of this material and all other branched chain saturated alcohols in fragrances.
Ó 2010 Published by Elsevier Ltd.
Contents
Introduction . . . ..................................................................................................... S73
1. Identification . . ..................................................................................................... S74
2. Physical properties . . . . . . . . . . . . . . . . . .................................................................................. S74
3. Usage. . . . . . . . . ..................................................................................................... S74
4. Toxicology data ..................................................................................................... S75
4.1. Acute toxicity (see Table 2). ..................................................................................... S75
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S75
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S75
4.1.3. Intraperitoneal studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S75
4.1.4. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S75
4.2. Skin irritation. ................................................................................................ S76
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S76
4.2.2. Animal studies (see Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S76
4.3. Mucous membrane (eye) irritation (see Table 4) .................................................................... S76
4.4. Skin sensitization. ............................................................................................. S76
4.5. Phototoxicity and photoallergy. . ................................................................................. S76
4.6. Absorption, distribution and metabolism .......................................................................... S76
4.7. Repeated dose toxicity . . ....................................................................................... S76
4.8. Reproductive and developmental toxicity .......................................................................... S77
4.9. Genotoxicity. ................................................................................................. S77
4.9.1. In vitro studies........................................................................................ S77
4.9.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S77
4.10. Carcinogenicity . . ............................................................................................. S77
Conflict of interest statement . . . . . . . . .................................................................................. S77
References . . . . ..................................................................................................... S77
Introduction
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.
E-mail address: dmcginty@RIFM.org (D. McGinty).
This document provides a summary of the toxicologic review,
including all human health endpoints, of isotridecan-1-ol (isomeric
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.fct.2010.05.033

S74
D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S73–S78
mixture) when used as a fragrance ingredient. Isotridecan-1-ol (see
Fig. 1; CAS Number 27458-92-0) is a fragrance ingredient used in
cosmetics, fine fragrances, shampoos, toilet soaps and other toiletries
as well as in non-cosmetic products such as household cleaners
and detergents. This material has been reported to occur in
nature within beef (VCF, 2009).
In 2006, a complete literature search was conducted on Isotridecan-1-ol.
On-line toxicological databases were searched including
those from the Chemical Abstract Services, [e.g., ToxCenter (which
in itself contains 18 databases including Chemical Abstracts)], and
the National Library of Medicine [e.g., Medline, Toxnet (which contains
14 databases)] as well as 26 additional sources (e.g., BIOSIS,
Embase, RTECS, OSHA, ESIS). In addition, fragrance companies were
asked to submit all test data.
The safety data on this material has never been reviewed before
by RIFM (Research Institute for Fragrance Materials, Inc.). All relevant
references are included in this document. More details have
been provided for unpublished data. The number of animals, sex
and strain are always provided unless they are not given in the original
report or paper. Any papers in which the vehicles and/or the
doses are not given have not been included in this review. In addition,
diagnostic patch test data with fewer than 100 consecutive
patients have been omitted.
1. Identification
1.1 Synonyms: Isotridecanol; 11-methyldodecan-1-ol
1.2 CAS registry number: 27458-92-0
1.3 EINECS number: 248-469-2
1.4 Formula: C 13 H 28 O
1.5 Molecular weight: 200.66
2. Physical properties
2.1 Physical form: no information available
2.2 Boiling point (calculated; EPA, 2010): 279.35 °C
2.3 Flash point: no information available
2.4 Henry’s law (calculated; EPA, 2010): 0.000128 atm m 3 /mol
25 °C
2.5 Log K ow (calculated; EPA, 2010): 5.19
2.6 Refractive index: no information available
2.7 Specific gravity: no information available
2.8 Vapor pressure (calculated; EPA, 2010): 0.000462 mm Hg;
0.0615 Pa (25 °C)
2.9 Water solubility (calculated; EPA, 2010): 5.237 mg/l at 25°
2.10 UV spectra available at RIFM. Does not absorb UV light.
3. Usage
Fig. 1. Isotridecan-1-ol (isomeric mixture).
Isotridecan-1-ol (isomeric mixture) is a fragrance ingredient
used in many fragrance compounds. It may be found in fragrances
used in decorative cosmetics, fine fragrances, shampoos, toilet
soaps and other toiletries as well as in non-cosmetic products such
as household cleaners and detergents. Its use worldwide is in the
region of 10–100 metric tons per annum (IFRA, 2004). The reported
volume of use is for isotridecan-1-ol as used in fragrance compounds
(mixtures) in all finished consumer product categories.
The volume of use is surveyed by IFRA approximately every four
years through a comprehensive survey of IFRA and RIFM member
companies. As such the volume of use data from this survey provides
volume of use of fragrance ingredients for the majority of
the fragrance industry.
The dermal systemic exposure in cosmetic products (see
Table 1) is calculated based on the concentrations of the same fragrance
ingredient in ten types of the most frequently used personal
care and cosmetic products (anti-perspirant, bath products, body
lotion, eau de toilette, face cream, fragrance cream, hair spray,
shampoo, shower gel, and toilet soap). The concentration of the
fragrance ingredient in fine fragrances is obtained from examination
of several thousand commercial formulations. The upper
97.5 percentile concentration is calculated from the data obtained.
This upper 97.5 percentile concentration is then used for all 10
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing isotridecan-1-ol (isomeric mixture).
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient (mg/kg/day) b
Anti-perspirant 0.5 1 1 0.01 1.4 0.0012
Bath products 17 0.29 0.001 0.02 1.4 0.00002
Body lotion 8 0.71 1 0.004 1.4 0.0053
Eau de toilette 0.75 1 1 0.08 1.4 0.0140
Face cream 0.8 2 1 0.003 1.4 0.0011
Fragrance cream 5 0.29 1 0.04 1.4 0.0135
Hair spray 5 2 0.01 0.005 1.4 0.0001
Shampoo 8 1 0.01 0.005 1.4 0.0001
Shower gel 5 1.07 0.01 0.012 1.4 0.0001
Toilet soap 0.8 6 0.01 0.015 1.4 0.0002
Total 0.0357
a
b
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.
Based on a 60-kg adult.

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S73–S78 S75
consumer products. These concentrations are multiplied by the
amount of product applied, the number of applications per day
for each product type, and a ‘‘retention factor” (ranging from
0.001 to 1.0) to account for the length of time a product may remain
on the skin and/or likelihood of the fragrance ingredient
being removed by washing. The resultant calculation represents
the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford
et al., 2000).
This is a conservative calculation of dermal systemic exposure
because it makes the unlikely assumption that a consumer will
use these 10 products containing; which are all perfumed with
the upper 97.5 percentile level of the fragrance ingredient from a
fine fragrance type of product (Cadby et al., 2002; Ford et al.,
2000). The 97.5% percentile use level in formulae for use in cosmetics
in general has been reported to be 1.4 (IFRA, 2007), which
would result in a maximum daily exposure on the skin of
0.0356 mg/kg for high end users.
A maximum skin level is then determined for consideration of
potential sensitization. The exposure is calculated as the percent
concentration of the fragrance ingredient applied to the skin based
on the use of 20% of the fragrance mixture in the fine fragrance
consumer product (IFRA, 2007). The average maximum use level
in formulae that go into fine fragrances has been reported to be
0.69% (IFRA, 2007), assuming use of the fragrance oil at levels up
to 20% the final product.
4. Toxicology data
4.1. Acute toxicity (see Table 2)
4.1.1. Oral studies
The acute oral LD 50 of isotridecan-1-ol (1-tridecanol: mixed primary
isomers) in male rats (n = 5) was reported to be 17.2 (12.3–
23.9) ml/kg (17.2; 12.3–23.6 g/kg). No additional details were reported
(Smyth et al., 1962; Nishimura et al., 1994).
Scala and Burtis (1973) reported an LD 50 for isotridecan-1-ol (1-
tridecanol: mixed primary isomers) of 4.75 g/kg in Sprague–Dawley
rats (five/dose). The principal clinical signs were central nervous
system depression and labored respiration. The depression
included inactivity, ataxia, limb sprawling, depressed righting
and placement reflexes, prostration, and coma. The intensity of
the signs was related to dose. The signs of effect had an early onset,
and recovery was complete by the second or third day. Where
deaths occurred, they were seen as late as 4 days.
The LD 50 of isotridecan-1-ol in Wistar rats was found to be
greater than 2 g/kg body weight for male and female rats. Single
gavage doses of 2.0 g/kg body weight of isotridecan-1-ol in olive
oil were given to six (three/sex/group) fasted animals. No mortality
occurred in the 2 g/kg groups. Piloerection was the only clinical
sign observed, in males, 5 h after administration. No clinical signs
and findings were observed in the females of the 2 g/kg administration
group. The mean body weights of the administration groups
increased throughout the study period. No macroscopic pathologic
abnormalities were observed. This study was based on the OECD,
EU and US EPA OPPTS guidelines (RIFM, 2002a).
Greim (2000) reported acute oral an LD 50 value of isotridecan-1-
ol (isomeric mixture: 50% branched, 50% linear form) as greater
than 2.0 g/kg in rats (further information not obtained, ECB, 1995).
The acute oral LD 50 in mice with 30% isotridecan-1-ol (isomeric
mixture) as an aqueous emulsion with tragacanth gum was reported
to be >6.5 ml (6.5 g/kg) body weight. Observations were
made for 7 days. The clinical signs noted were staggering, accelerated
respiration, tremors, and slow recovery. The mortalities were
sporadic and late (RIFM, 1963a).
Greim (2000) reported acute oral an LD 50 value of isotridecan-1-
ol (isomeric mixture) as 7.257 g/kg in mice (further information
not obtained, ECB, 1995; Hoechst, 1961a).
4.1.2. Dermal studies
The acute dermal LD 50 of isotridecan-1-ol (Tridecanol: mixed
primary isomers) in male rabbits (n = 4) was reported to be 7.07
(2.33–21.4) ml/kg (7.07; 2.33–24.4 g/kg). Contact time was 24 h
and observation time was 14 days. No additional details were reported
(Smyth et al., 1962).
The dermal LD 50 for isotridecan-1-ol (Tridecanol: mixed primary
isomers) applied occlusively for 24 h to rabbits (four/dose)
was reported to be >2.6 g/kg. There were no clinical signs indicative
of systemic effects at the highest level tested. Dermal irritation
was dose dependent (Scala and Burtis, 1973).
4.1.3. Intraperitoneal studies
The intraperitoneal LD 50 of mice with 8% isotridecan-1-ol
(mixed isomers) as an aqueous emulsion with tragacanth gum
was reported to be about 0.6 ml/kg body weight (0.6 g/kg).
Observations included staggering, accelerated respiration, tremors,
and slow recovery. Mortalities were sporadic and late. Necropsy
findings included adhesions in the abdominal cavity (RIFM, 1963b).
4.1.4. Inhalation studies
The study of the acute inhalation hazard of isotridecan-1-ol
(isomeric mixture) in rats resulted in no deaths (0/12) and no
abnormalities. Animals were exposed for 8 h to atmosphere saturated
with vapor at 20 °C (room temperature). For saturation, air
was conducted through a layer of about 5 cm of the product (RIFM,
1963c; Smyth et al., 1962).
No deaths were reported when 10 rats, mice, and guinea pigs
were exposed by whole body inhalation for 6 h to air bubbled
through isotridecan-1-ol (mixed isomers) to yield a nominal chamber
concentration of 12 ppm (12 ml/m 3 ) at 30°C. Clinical signs
indicated moderate local irritation and slight to moderate systemic
effects. Local irritation involved the mucous membranes of the
eyes, nose, throat, and respiratory passages and was manifest as
blinking, lacrimation, preening, nasal discharge, salivation, gasping,
and chewing movements. Responses were temporary and all
animals had recovered within 1 h after termination of exposure.
Table 2
Summary of acute toxicity studies.
Route Species No. animals/dose group LD 50 (g/kg) References
Oral Rat 5 17.2 Smyth et al., 1962; Nishimura, 1994
Oral Rat 5 4.75 Scala and Burtis, 1973
Oral Rat 3 >2.0 RIFM, 2002a
Oral Rat N/A >2.0 ECB, 1995 as cited in Greim, 2000
Oral Mouse N/A 6.5 RIFM, 1963a
Oral Mouse N/A 7.257 ECB, 1995; Hoechst, 1961a; as cited in Greim, 2000
Dermal Rabbit 4 7.07 Smyth et al., 1962
Dermal Rabbit 4 >2.6 Scala and Burtis, 1973
Intraperitoneal Mouse N/A 0.6 RIFM, 1963b

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D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S73–S78
Gross necropsy findings were normal in appearance (Scala and
Burtis, 1973).
4.2. Skin irritation
4.2.1. Human studies
In an in vitro human study it was concluded that isotridecan-1-
ol (mixed isomers) does not show a corrosive potential in the Epi-
Derm skin corrosivity test (RIFM, 2003a).
Table 4
Summary of eye irritation studies.
Dose
(%)
Reactions
References
100 Irritation was observed. In one animal slight RIFM, 2002b
corneal opacity and loss of corneal tissue
100 Slight irritation RIFM, 1963f
100 Small area of necrosis on the eye Smyth et al., 1962
100 Moderately irritating Scala and
Burtis, 1973
4.2.2. Animal studies (see Table 3)
Isotridecan-1-ol (mixed isomers) was applied ‘‘at full-strength”
to the closely clipped, intact abdominal skin of albino rabbits (four/
group). The exposed area was then covered with an occlusive patch
for 24 h. Doses of 0.10, 0.316, 1.0, or 3.16 ml/kg were administered
volumetrically and observations for signs of toxicity were made
once daily for 7 days. Moderate irritation was observed (Scala
and Burtis, 1973).
A primary skin irritation evaluation was done on the clipped
skin (uncovered) of five albino rabbits with undiluted isotridecan-1-ol
(mixed isomers) and resulted in grade 4 (moderate) irritation
(Smyth et al., 1962).
Undiluted isotridecan-1-ol (mixed isomers) produced irritation
when administered percutaneously to the intact dorsal and ear
skin of rabbits. The time of exposure on the dorsal skin was 1, 5,
15, and 20 h, and 20 h for the ears. The skin was checked after
24 h and after 8 days. After 20 h of exposure, the dorsal skin resulted
in severe erythema and distinct edema when observed at
24 h, then distinct scarring and severe scaling at 8 days. When
the dorsal skin was exposed for 1, 5, or 15 h severe erythema
was observed at 24 h, then scaling at 8 days. Exposure of 20 h to
the ear resulted in severe erythema at 24 h and severe erythema
and scaring at 8 days (RIFM, 1963d,e).
In order to assess the acute skin irritation potential of isotridecanol-1-ol
in White New Zealand rabbits a dermal irritation/corrosion
test was performed according to the method described in
OECD guideline 404. A 0.5 ml sample of the isotridecanol-1-ol
was applied for 4 h to the intact skin of three rabbits, using a patch
of 2.5 cm 2.5 cm, covered with semi-occlusive dressing. After removal
of the patch the application area was washed off. The skin
reactions were assessed immediately after removal of the patch,
approximately 1, 24, 48 and 72 h after removal and then win
weekly intervals until day 14. Slight to marked erythema, slight
or moderate edema and scaling were observed in almost all animals
during the course of the study. Additionally the described
findings above were partly extended beyond the area of exposure.
Moreover severe scaling and petechiae, both extending beyond the
area of exposure and thickening of the skin in the regions of the
application area were noted in a single animal. The cutaneous reactions
(such as slight erythema) were not reversible in all animals
within study termination of day 14. The average score (24 to
72 h) for irritation was calculated to be 3.0 for erythema and 0.3
for edema (RIFM, 2003b).
4.3. Mucous membrane (eye) irritation (see Table 4)
An eye irritation test was conducted in three White New Zealand
rabbits subjected to a single dose ocular application of
0.1 ml of undiluted isotridecan-1-ol (mixed isomers). The ocular
reactions were assessed approximately 1, 24, 48, 72 h and 7 days
after application. Slight to moderate conjunctival redness, slight
conjunctival chemosis and moderate to severe discharge were observed
during the course of the study. In addition in one animal
slight corneal opacity and loss of corneal tissue was noted during
the observation period (RIFM, 2002b).
An eye irritation test was conducted in rabbits. Undiluted isotridecan-1-ol
(mixed isomers) was applied (1 50 mm 3 or
50 mg) to the conjunctival sac of the eyelid. The findings after
1 h included slight redness. The findings after 24 h and 8 days were
nonirritating. No further information (RIFM, 1963d; RIFM, 1963f).
Application of to the eyes isotridecan-1-ol (mixed isomers) of
rabbits produced irritation grade 2 on a ten-grade scale with Grade
1 a very small area of necrosis from 0.5 ml of an undiluted chemical
in the eye and Grade 5 representing a severe burn from
0.005 ml (Smyth et al., 1962).
Six rabbits were given single 0.1 ml application of isotridecan-
1-ol (mixed isomers) undiluted. Observations were made after 1,
4, and 24 h, 2, 3, 4, and 7 days. Moderate irritation was observed
(Scala and Burtis, 1973).
4.4. Skin sensitization
No data available.
4.5. Phototoxicity and photoallergy
No data available.
4.6. Absorption, distribution and metabolism
No data available.
4.7. Repeated dose toxicity
Isotridecan-1-ol (isomeric mixture) in polyethylene glycol was
given to Alderley Park Wistar-derived rats, five rats treated and
10 controls, by gavage for 14 days. At 1 mmol/kg body weight/
Table 3
Summary of animal irritation studies.
Method
Dose
(%)
Species Reactions References
Single occlusive patch for 24 h to intact skin of
four rabbits
100 Rabbits Moderately irritating Scala and Burtis,
1973
Single uncovered application of 0.01 ml for 24 h 100 Rabbits Moderately irritating Smyth et al., 1962
Percutaneously to the intact dorsal skin for 20 h 100 Rabbits Severe erythema and distinct edema at 24 h. Distinct scarring and severe RIFM, 1963e
scaling at 8 days
4-h semi-occlusive irritation 100 Rabbits Slight to marked erythema, slight or moderate edema and scaling RIFM, 2003b

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S73–S78 S77
day (200 mg/kg body weight/day) the liver weight was unaffected,
no hepatomegaly, peroxisome proliferation, hypolipidemia, or testicular
atrophy was observed (Rhodes et al., 1984).
4.8. Reproductive and developmental toxicity
Isotridecan-1-ol (isomeric mixture) was tested for its prenatal
developmental toxicity in 25 mated female Wistar rats as a solution
in olive oil. Gavage administration of 0, 60, 250, or 750 mg/
kg body weight were given on days 6 through day 19 post coitum
(p.c.). A standard dose volume of 5 ml/kg body weight was used for
each group. Food consumption and body weights of the animals
were recorded regularly throughout the study period. On day 20
p.c., blood was taken from all females, then sacrificed and assessed
by gross pathology (including weight determinations of the unopened
uterus, the liver, the kidneys, the spleen and the placentae).
For each dam, corpora lutea were counted and number and distribution
of implantation sites (differentiated as resorptions, live and
dead fetuses) were determined. The fetuses were removed from
the uterus, sexed, weighed and further investigated for any external
findings soft tissue and skeletal findings. In the 750 mg/kg body
weight/day dose: transient salivation was noted in all rats between
treatment days 7–19 p.c.; urine-smeared fur in 4 females on gestation
days 10–13 and 17–20 p.c.; statistically significant reduction
of food consumption on days 6–10 p.c. (up to about 11% below
the corresponding control value); statistically significant increased
alanine aminotransferase values; statistically significant increased
triglycerides and relative liver weights (about 14% or 18%, respectively
above control values) were noted; statistically significant decreased
total protein and globulin concentrations; no substancerelated
effects on gestational parameters or fetuses. Substance related
findings in the 250 mg/kg body weight/day group included:
transient salivation in 17/25 rats immediately after gavaging between
treatment days 12–19 p.c.; no substance-related effects on
gestational parameters or fetuses were noted. No substance-related
effects on dams, gestational parameters or fetuses were
noted the 60 mg/kg body weight/day group.
Under the conditions of this prenatal developmental toxicity
study, the oral administration of isotridecan-1-ol (isomeric mixture)
to pregnant Wistar rats from implantation to one day prior
to the expected day of parturition (days 6–19 p.c.) elicited some
signs of maternal toxicity at 750 mg/kg body weight/day. Placental
and fetal body weights, the external, soft tissue and/or skeletal
(including cartilage) examinations of the fetuses revealed no biologically
relevant differences between the control and the substance-treated
groups. Based on these results, the no observed
adverse effect level (NOAEL) for maternal toxicity is 250 mg/kg
body weight/day, while it is 750 mg/kg body weight/day for prenatal
developmental toxicity (RIFM, 2003c).
4.9. Genotoxicity
4.9.1. In vitro studies
4.9.1.1. Bacterial test systems. Isotridecan-1-ol (isomeric mixture)
in DMSO was tested for mutagenicity in the Ames test (Ames
et al., 1975) (standard plate test and preincubation test) at doses
up to 5000 lg/plate both in the presence and absence of a metabolizing
system obtained from rat liver (S-9 mix) using Salmonella
typhimurium strains TA1537, TA 1535, TA100, and TA98. No mutagenicity
was observed (RIFM, 1989).
4.9.1.2. Studies in mammalian cells. No data available.
4.9.2. In vivo studies
No data available.
4.10. Carcinogenicity
No data available.
This individual Fragrance Material Review is not intended as a
stand-alone document. Please refer to A Safety Assessment of
Branched Chain Saturated Alcohols When Used as Fragrance Ingredients
(Belsito et al., 2010) for an overall assessment of this
material.
Conflict of interest statement
This research was supported by the Research Institute for Fragrance
Materials, an independent research institute that is funded
by the manufacturers of fragrances and consumer products containing
fragrances. The authors are all employees of the Research
Institute for Fragrance Materials.
References
Ames, B.N., McCann, J., Yamasaki, E., 1975. Methods for detecting carcinogens and
mutagens with the salmonella/mammalian-mincrosome mutagenicity test.
Mutation Research 31, 347–363.
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A toxicologic and dermatologic
assessment of Alcohols Branched Chain Saturated when used as fragrance
ingredients. Food and Chemical Toxicology 48 (S4), S1–S46.
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:
providing estimates for safety evaluation. Regulatory Toxicology and
Pharmacology 36, 246–252.
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface
Suite for Microsoft Ò Windows, v 4.00 or insert version used. United States
Environmental Protection Agency, Washington, DC, USA.
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria for
development of a database for safety evaluation of fragrance ingredients.
Regulatory Toxicology and Pharmacology 31, 166–181.
Greim, H. (ed.), 2000. iso-Tridecanol (Isomerengemisch verzweigter primärer C10-
C14-Alkohole). Toxikologisch-arbeitsmedizinische Begründungen von MAK-
Werten, 30. Lieferung, Wiley-VCH, Weinheim.
IFRA (International Fragrance Association), 2004. Use level survey, August 2004.
IFRA (International Fragrance Association), 2007. Volume of use survey, February
2007.
Nishimura, H., Saito, S., Kishida, F.,Matsuo, M., 1994. Analysis of acute toxicity
(LD50-value) of organic chemicals to mammals by solubility parameter (delta).
1. Acute oral toxicity to rats. Sangyo Igaku, 36(5), 314–323 (Japanese Journal
Industrial Health).
Rhodes, C., Soames, T., Stonard, M.D., Simpson, M.G., Vernall, A.J., Elcombe, C.R.,
1984. The absence of testicular atrophy & in vivo & in vitro effects on
hepatocyte morphology and peroxisomal enzyme activities in male rats
following the administration of several alkanols. Toxicology Letters 21, 103–
109.
RIFM (Research Institute for Fragrance Materials, Inc.), 1963a. Report on the study
of the acute oral toxicity of isotridecan-1-ol in mice. Unpublished report from
BASF, Report number 55417, RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1963b. Report on the study
of the acute intraperitoneal toxicity of isotridecan-1-ol in mice. Unpublished
report from BASF, Report number 55414, RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1963c. Report on the study
of the acute inhalation hazard of isotridecan-1-ol in rats (inhalation hazard
test). Unpublished report from BASF, Report number 55415, RIFM, Woodcliff
Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1963d. Results of the
analytical toxicology tests with isotridecan-1-ol. Unpublished report from BASF,
Report number 55424, RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1963e. Report on the study
of the primary irritation/corrosion of isotridecan-1-ol to the intact skin of
rabbits. Unpublished report from BASF, Report number 55426, RIFM, Woodcliff
Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1963f. Report on the study of
the primary irritation of isotridecan-1-ol to the eye of rabbits. Unpublished
report from BASF, Report number 55431, RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1989. Report on the study of
Isotridecan-1-ol in the AMES test. Unpublished report from BASF, Report
number 55420, RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 2002a. Isotridecan-1-ol:
Acute oral toxicity study in Wistar rats. Unpublished report from BASF, Report
number 55416, RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 2002b. Isotridecan-1-ol:
Acute eye irritation in rabbits. Unpublished report from BASF, Report number
55430, RIFM, Woodcliff Lake, NJ, USA.

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RIFM (Research Institute for Fragrance Materials, Inc.), 2003a Isotridecan-1-ol:
EpiDerm skin corrosivity test. Unpublished report from BASF, Report number
55423, RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 2003b. Isotridecan-1-ol:
Acute dermal irritation/corrosion in rabbits. Unpublished report from BASF,
Report number 55427, RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 2003c. Isotridecan-1-ol:
prenatal developmental toxicity study in Wistar rats by oral administration
(gavage). Unpublished report from BASF, Report number 55432, RIFM,
Woodcliff Lake, NJ, USA.
Scala, R.A., Burtis, E.G., 1973. Acute toxicity of a homologous series of branchedchain
primary alcohols. American Industrial Hygiene Association Journal
(AIHAJ) 34 (11), 493–499.
Smyth, F., Carpenter, C.P., Weil, M.A., Pozzani, U.C., Striegel, J.A., 1962. Range-finding
toxicity data: List VI. Industrial Hygiene Association Journal 23, 95–107.
VCF (Volatile Compounds in Food): database. In: Nijssen, L.M.; Ingen-Visscher, C.A.
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Netherlands, 1963–2009.

Food and Chemical Toxicology 48 (2010) S79–S81
Contents lists available at ScienceDirect
Food and Chemical Toxicology
journal homepage: www.elsevier.com/locate/foodchemtox
Review
Fragrance material review on isononyl alcohol
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api
Research Institute for Fragrance Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
article
Keywords:
Review
Fragrance
info
abstract
A toxicologic and dermatologic review of isononyl alcohol when used as a fragrance ingredient is presented.
Isononyl alcohol is a member of the fragrance structural group branched chain saturated alcohols.
The common characteristic structural elements of the alcohols with saturated branched chain are one
hydroxyl group per molecule, and a C 4 –C 12 carbon chain with one or several methyl side chains. This
review contains a detailed summary of all available toxicology and dermatology papers that are related
to this individual fragrance ingredient and is not intended as a stand-alone document. A safety assessment
of the entire branched chain saturated alcohol group will be published simultaneously with this
document; please refer to Belsito et al. (2010) for an overall assessment of the safe use of this material
and all other branched chain saturated alcohols in fragrances.
Ó 2010 Published by Elsevier Ltd.
Contents
Introduction . . . ..................................................................................................... S79
1. Identification . . ..................................................................................................... S80
2. Physical properties . . . . . . . . . . . . . . . . . .................................................................................. S80
3. Usage. . . . . . . . . ..................................................................................................... S80
4. Toxicology data ..................................................................................................... S81
4.1. Acute toxicity. ................................................................................................ S81
4.2. Skin irritation. ................................................................................................ S81
4.3. Mucous membrane (eye) irritation. ............................................................................... S81
4.4. Skin sensitization. ............................................................................................. S81
4.5. Phototoxicity and photoallergy. . ................................................................................. S81
4.6. Absorption, distribution, and metabolism .......................................................................... S81
4.7. Repeated dose toxicity . . ....................................................................................... S81
4.8. Reproductive and developmental toxicity .......................................................................... S81
4.9. Genotoxicity. ................................................................................................. S81
4.10. Carcinogenicity . . ............................................................................................. S81
Conflict of interest statement . . . . . . . . .................................................................................. S81
References . . . . ..................................................................................................... S81
Introduction
This document provides a summary of the toxicologic review,
including all human health endpoints, of isononyl alcohol when used
as a fragrance ingredient. Isononyl alcohol (see Fig. 1; CAS Number
27458-94-2) is a fragrance ingredient used in cosmetics, fine fragrances,
shampoos, toilet soaps and other toiletries as well as in
non-cosmetic products such as household cleaners and detergents.
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.
E-mail address: dmcginty@RIFM.org (D. McGinty).
In 2006, a complete literature search was conducted on isononyl
alcohol. On-line toxicological databases were searched including
those from the Chemical Abstract Services [e.g., ToxCenter
(which in itself contains 18 databases including Chemical Abstracts)],
and the National Library of Medicine [e.g., Medline, Toxnet
(which contains 14 databases)] as well as 26 additional sources
(e.g., BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance
companies were asked to submit all test data.
The safety data on this material has never been reviewed before
by RIFM (Research Institute for Fragrance Materials, Inc.). All relevant
references are included in this document. More details have
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.fct.2010.05.034

S80
D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S79–S81
3. Usage
been provided for unpublished data. The number of animals, sex
and strain are always provided unless they are not given in the original
report or paper. Any papers in which the vehicles and/or the
doses are not given have not been included in this review. In addition,
diagnostic patch test data with fewer than 100 consecutive
patients have been omitted.
1. Identification
1.1 Synonyms: isononanol; 7-methyloctan-1-ol
1.2 CAS registry number: 27458-94-2
1.3 EINECS number: 248-471-3
1.4 Formula: C 9 H 20 O
1.5 Molecular weight: 144.58
2. Physical properties
Fig. 1. Isononyl alcohol.
2.1 Physical form: no information available
2.2 Boiling point (calculated; EPA, 2010): 208.49
2.3 Flash point: no information available
2.4 Henry’s law (calculated; EPA, 2010): 0.0000412 atm m 3 /mol
25 °C
2.5 Log K ow (calculated; EPA, 2010): 3.22
2.6 Refractive index: no information available
2.7 Specific gravity: no information available
2.8 Vapor pressure (calculated; EPA, 2010): 0.0198 mm Hg;
2.63 Pa (25 °C)
2.9 Water solubility (calculated; EPA, 2010): 459.7 mg/l (25 °C)
2.10 UV spectra not available at RIFM
Isononyl alcohol is a fragrance ingredient used in many fragrance
compounds. It may be found in fragrances used in decorative
cosmetics, fine fragrances, shampoos, toilet soaps and other
toiletries as well as in non-cosmetic products such as household
cleaners and detergents. Its use worldwide is in the region of 1–
10 metric tons per annum (IFRA, 2004). The reported volume of
use is for isononyl alcohol as used in fragrance compounds (mixtures)
in all finished consumer product categories. The volume of
use is surveyed by IFRA approximately every four years through
a comprehensive survey of IFRA and RIFM member companies.
As such the volume of use data from this survey provides volume
of use of fragrance ingredients for the majority of the fragrance
industry.
The dermal systemic exposure in cosmetic products (see
Table 1) is calculated based on the concentrations of the same fragrance
ingredient in ten types of the most frequently used personal
care and cosmetic products (anti-perspirant, bath products, body
lotion, eau de toilette, face cream, fragrance cream, hair spray,
shampoo, shower gel, and toilet soap). The concentration of the
fragrance ingredient in fine fragrances is obtained from examination
of several thousand commercial formulations. The upper
97.5 percentile concentration is calculated from the data obtained.
This upper 97.5 percentile concentration is then used for all 10
consumer products. These concentrations are multiplied by the
amount of product applied, the number of applications per day
for each product type, and a ‘‘retention factor” (ranging from
0.001 to 1.0) to account for the length of time a product may remain
on the skin and/or likelihood of the fragrance ingredient
being removed by washing. The resultant calculation represents
the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford
et al., 2000).
This is a conservative calculation of dermal systemic exposure
because it makes the unlikely assumption that a consumer will
use these 10 products containing; which are all perfumed with
the upper 97.5 percentile level of the fragrance ingredient from a
fine fragrance type of product (Cadby et al., 2002; Ford et al.,
2000). The 97.5 percentile use level in formulae for use in cosmetics
in general has been reported to be 4.46% (IFRA, 2007), which
would result in a maximum daily exposure on the skin of
0.1137 mg/kg for high end users.
A maximum skin level is then determined for consideration of
potential sensitization. The exposure is calculated as the percent
concentration of the fragrance ingredient applied to the skin based
on the use of 20% of the fragrance mixture in the fine fragrance
consumer product (IFRA, 2007). The average maximum use level
in formulae that go into fine fragrances has been reported to be
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing isononyl alcohol.
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient (mg/kg/day) b
Anti-perspirant 0.5 1 1 0.01 4.46 0.0037
Bath products 17 0.29 0.001 0.02 4.46 0.0001
Body lotion 8 0.71 1 0.004 4.46 0.0169
Eau de toilette 0.75 1 1 0.08 4.46 0.0446
Face cream 0.8 2 1 0.003 4.46 0.0036
Fragrance cream 5 0.29 1 0.04 4.46 0.0431
Hair spray 5 2 0.01 0.005 4.46 0.0004
Shampoo 8 1 0.01 0.005 4.46 0.0003
shower gel 5 1.07 0.01 0.012 4.46 0.0005
Toilet soap 0.8 6 0.01 0.015 4.46 0.0005
Total 0.1136
a
b
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.
Based on a 60-kg adult.

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S79–S81 S81
0.30% (IFRA, 2007), assuming use of the fragrance oil at levels up to
20% of the final product.
4. Toxicology data
4.1. Acute toxicity
No available information.
4.2. Skin irritation
No available information.
4.3. Mucous membrane (eye) irritation
No available information.
4.4. Skin sensitization
No available information.
4.5. Phototoxicity and photoallergy
No available information.
4.6. Absorption, distribution, and metabolism
No available information.
4.7. Repeated dose toxicity
No available information.
4.8. Reproductive and developmental toxicity
In a comparative developmental toxicity (OECD TG 414) two
different isomeric mixes of isononyl alcohol were administered
by gavage to Wistar rats (10 per group) at 144, 720, 1080, and
1440 mg/kg/d (0, 1, 5, 7.5, and 10 mmol/kg/d) on gestation days
6–15. The 1080 mg/kg group was a supplemental group with supplemental
control due to high maternal mortality at 1440 mg/kg/d
in the original study. Both types of isononyl alcohols exhibited a
marked degree of maternal and fetal toxicity at 1080, and
1440 mg/kg/d and slight effects at 720 mg/kg. Maternal mortality
was 10/10 for mixture 1 and 3/10 for mixture 2 at 1440 mg/kg/d.
Fetal observations for the 1080 mg/kg groups showed increases
in resorptions, post-implantation loss, and the number/percent of
fetuses/litters with malformations or retardations. At 720 mg/kg,
the maternal clinical signs included reduced body weight gain,
apathy, and nasal discharge. Fetal observations included an increased
number of skeletal variations and delayed ossifications.
There were no significant differences from control at 144 mg/kg
in either maternal or fetal parameters (Hellwig and Jackh, 1997,
and EPA, 1991).
4.9. Genotoxicity
No available information.
4.10. Carcinogenicity
No available information.
This individual Fragrance Material Review is not intended as a
stand-alone document. Please refer to A Toxicologic and Dermatologic
Assessment of Alcohols Branched Chain Saturated When Used
as Fragrance Ingredients (Belsito et al., 2010) for an overall assessment
of this material.
Conflict of interest statement
This research was supported by the Research Institute for
Fragrance Materials, an independent research institute that is
funded by the manufacturers of fragrances and consumer products
containing fragrances. The authors are all employees of the
Research Institute for Fragrance Materials.
References
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A toxicologic and dermatologic
assessment of alcohols branched chain saturated when used as fragrance
ingredients. Food and Chemical Toxicology 48 (S4), S1–S46.
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:
providing estimates for safety evaluation. Regulatory Toxicology and
Pharmacology 36, 246–252.
EPA (Environmental Protection Agency), 1991. Study of the prenatal toxicity of
isononylalcohol 1 and isononylalcohol 2 in rats after oral administration
(gavage). Unpublished report. Report number 34403 (RIFM, Woodcliff Lake, NJ,
USA).
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface
Suite for Microsoft Ò Windows, v 4.00 or insert version used]. United States
Environmental Protection Agency, Washington, DC, USA.
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria for
development of a database for safety evaluation of fragrance ingredients.
Regulatory Toxicology and Pharmacology 31, 166–181.
Hellwig, J., Jackh, R., 1997. Differential prenatal toxicity of one straight-chain and
five branched-chain primary alcohols in rats. Food and Chemical Toxicology 35
(5), 489–500.
IFRA (International Fragrance Association), 2004. Use level survey, August 2004.
IFRA (International Fragrance Association), 2007. Volume of use survey, February
2007.

Food and Chemical Toxicology 48 (2010) S82–S84
Contents lists available at ScienceDirect
Food and Chemical Toxicology
journal homepage: www.elsevier.com/locate/foodchemtox
Review
Fragrance material review on 6,8-dimethylnonan-2-ol
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api
Research Institute for Fragrance Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
article
Keywords:
Review
Fragrance
info
abstract
A toxicologic and dermatologic review of 6,8-dimethylnonan-2-ol when used as a fragrance ingredient is
presented. 6,8-Dimethylnonan-2-ol is a member of the fragrance structural group branched chain saturated
alcohols. The common characteristic structural elements of the alcohols with saturated branched
chain are one hydroxyl group per molecule, and a C 4 –C 12 carbon chain with one or several methyl side
chains. This review contains the information available on this individual fragrance ingredient and is
not intended as a stand-alone document. A safety assessment of the entire branched chain saturated alcohol
group will be published simultaneously with this document; please refer to Belsito et al. (2010) for an
overall assessment of the safe use of this material and all other branched chain saturated alcohols in
fragrances.
Ó 2010 Published by Elsevier Ltd.
Contents
Introduction ........................................................................................................ S82
1. Identification . . . . . . . . . . . . . . . ........................................................................................ S82
2. Physical properties . . . . . . . . . . . ........................................................................................ S83
3. Usage. . . . . . ........................................................................................................ S83
4. Toxicology data . . . . . . . . . . . . . ........................................................................................ S83
Conflict of interest statement . . ........................................................................................ S83
References . ........................................................................................................ S84
Introduction
* Corresponding author. Tel.: +1 201 689 8089; fax: +1 201 689 8088.
E-mail address: dmcginty@RIFM.org (D. McGinty).
This document provides a summary of the toxicologic review,
all human health endpoints, of 6,8-dimethylnonan-2-ol when used
as a fragrance ingredient. 6,8-Dimethylnonan-2-ol (see Fig. 1; CAS
Number 70214-77-6) is a fragrance ingredient used in cosmetics,
fine fragrances, shampoos, toilet soaps and other toiletries as well
as in non-cosmetic products such as household cleaners and
detergents.
In 2006, a complete literature search was conducted on 6,8-
dimethylnonan-2-ol. On-line toxicological databases were
searched including those from the Chemical Abstract Services
[e.g. ToxCenter (which in itself contains 18 databases including
Chemical Abstracts], and the National Library of Medicine [e.g.
Medline, Toxnet (which contains 14 databases)] as well as 26 additional
sources (e.g. BIOSIS, Embase, RTECS, OSHA and ESIS). In addition,
fragrance companies were asked to submit all test data.
The safety data on this material has never been reviewed before
by RIFM (Research Institute for Fragrance Materials Inc.). All relevant
references are included in this document. More details have
been provided for unpublished data. The number of animals, sex
and strain are always provided unless they are not given in the original
report or paper. Any papers in which the vehicles and/or the
doses are not given have not been included in this review. In addition,
diagnostic patch test data with fewer than 100 consecutive
patients have been omitted.
1. Identification
1.1. Synonyms: 2-Nonanol, 6,8-dimethyl-; Nonadyl.
1.2. CAS Registry number: 70214-77-6.
1.3. EINECS number: 274-447-7.
1.4. Formula: C 11 H 24 O.
1.5. Molecular weight: 172.12.
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.fct.2010.05.035

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S82–S84 S83
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 6,8-dimethylnonan-2-ol.
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient mg/kg/day b
Anti-perspirant 0.5 1 1 0.01 0.05 0.000001
Bath products 17 0.29 0.001 0.02 0.05 0.000001
Body lotion 8 0.71 1 0.004 0.05 0.000200
Eau de toilette 0.75 1 1 0.08 0.05 0.000500
Face cream 0.8 2 1 0.003 0.05 0.000001
Fragrance cream 5 0.29 1 0.04 0.05 0.000500
Hair spray 5 2 0.01 0.005 0.05 0.000001
Shampoo 8 1 0.01 0.005 0.05 0.000001
Shower gel 5 1.07 0.01 0.012 0.05 0.000001
Toilet soap 0.8 6 0.01 0.015 0.05 0.000001
Total 0.0012
a
b
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.
Based on a 60-kg adult.
2. Physical properties
2.1. Physical form: no information available.
2.2. Boiling point (calculated; EPA, 2010): 217.59.
2.3. Flash point: no information available.
2.4. Henry’s law (calculated; EPA, 2010): 0.0000726 atm m 3 /
mole.
2.5. Log K ow (calculated; EPA, 2010): 4.06.
2.6. Refractive index: no information available.
2.7. Specific gravity: 0.827 g/ml at 20 °C.
2.8. Vapor pressure (calculated; EPA, 2010): 0.0252 mm Hg;
3.36 Pa (25 °C).
2.9. Water solubility (calculated; EPA, 2010): no information
available.
2.10. UV spectra available at RIFM, peaks at 200–210 nm and
returns to baseline 230–240 nm. Minor absorption from
260 to 320 nm.
3. Usage
Fig. 1. 6,8-Dimethylnonan-2-ol.
OH
6,8-Dimethylnonan-2-ol is a fragrance ingredient used in many
fragrance compounds. It may be found in fragrances used in decorative
cosmetics, fine fragrances, shampoos, toilet soaps and other
toiletries as well as in non-cosmetic products such as household
cleaners and detergents. Its use worldwide is in the region of 1–
10 metric tons per annum (IFRA, 2004). The reported volume of
use is for 6,8-dimethylnonan-2-ol as used in fragrance compounds
(mixtures) in all finished consumer product categories. The volume
of use is surveyed by IFRA approximately every 4 years through a
comprehensive survey of IFRA and RIFM member companies. As
such the volume of use data from this survey provides volume of
use of fragrance ingredients for the majority of the fragrance
industry.
The dermal systemic exposure in cosmetic products (see
Table 1) is calculated based on the concentrations of the same
fragrance ingredient in 10 types of the most frequently used
personal care and cosmetic products (anti-perspirant, bath products,
body lotion, eau de toilette, face cream, fragrance cream, hair
spray, shampoo, shower gel and toilet soap). The concentration of
the fragrance ingredient in fine fragrances is obtained from examination
of several thousand commercial formulations. The upper
97.5 percentile concentration is calculated from the data obtained.
This upper 97.5 percentile concentration is then used for all 10
consumer products. These concentrations are multiplied by the
amount of product applied, the number of applications per day
for each product type, and a ‘‘retention factor” (ranging from
0.001 to 1.0) to account for the length of time a product may remain
on the skin and/or likelihood of the fragrance ingredient
being removed by washing. The resultant calculation represents
the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford
et al., 2000).
This is a conservative calculation of dermal systemic exposure
because it makes the unlikely assumption that a consumer will
use these 10 products containing; which are all perfumed with
the upper 97.5 percentile level of the fragrance ingredient from a
fine fragrance type of product (Cadby et al. 2002, Ford et al.
2000). The 97.5% percentile use level in formulae for use in cosmetics
in general has been reported to be 0.5% (IFRA, 2007), which
would result in a maximum daily exposure on the skin of
0.0012 mg/kg for high end users (see Table 1).
A maximum skin level is then determined for consideration of
potential sensitization. The exposure is calculated as the percent
concentration of the fragrance ingredient applied to the skin based
on the use of 20% of the fragrance mixture in the fine fragrance
consumer product (IFRA, 2007). The average maximum use level
in formulae that go into fine fragrances has been reported to be
0.009% (IFRA, 2007), assuming use of the fragrance oil at levels
up to 20% in the final product.
4. Toxicology data
No available information.
This individual Fragrance Material Review is not intended as a
stand-alone document. Please refer to A Safety Assessment of
Branched Chain Saturated Alcohols When Used as Fragrance Ingredients
Belsito et al. (2010) for an overall assessment of this
material.
Conflict of interest statement
This research was supported by the Research Institute for
Fragrance Materials, an independent research institute that is
funded by the manufacturers of fragrances and consumer products
containing fragrances. The authors are all employees of the
Research Institute for Fragrance Materials.

S84
D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S82–S84
References
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A toxicologic and dermatologic
assessment of Alcohols Branched Chain Saturated when used as fragrance
ingredients. Food and Chemical Toxicology 48 (S4), S1–S46.
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:
providing estimates for safety evaluation. Regulatory Toxicology and
Pharmacology 36, 246–252.
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface
Suite for Microsoft Ò Windows, v 4.00 or Insert Version Used. United States
Environmental Protection Agency, Washington, DC, USA.
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria for
development of a database for safety evaluation of fragrance ingredients.
Regulatory Toxicology and Pharmacology 31, 166–181.
IFRA (International Fragrance Association), 2004. Use Level Survey, August 2004.
IFRA (International Fragrance Association), 2007. Volume of Use Survey, February
2007.

Food and Chemical Toxicology 48 (2010) S85–S88
Contents lists available at ScienceDirect
Food and Chemical Toxicology
journal homepage: www.elsevier.com/locate/foodchemtox
Review
Fragrance material review on 2-ethyl-1-butanol
D. McGinty * , C.S. Letizia, A.M. Api
Research Institute for Fragrance Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
article
Keywords:
Review
Fragrance
info
abstract
A toxicologic and dermatologic review of 2-ethyl-1-butanol when used as a fragrance ingredient is presented.
2-Ethyl-1-butanol is a member of the fragrance structural group branched chain saturated alcohols.
The common characteristic structural elements of the alcohols with saturated branched chain are
one hydroxyl group per molecule, and a C 4 –C 12 carbon chain with one or several methyl side chains. This
review contains a detailed summary of all available toxicology and dermatology papers that are related to
this individual fragrance ingredient and is not intended as a stand-alone document. A safety assessment
of the entire branched chain saturated alcohol group will be published simultaneously with this document;
please refer to Belsito et al. (2010) for an overall assessment of the safe use of this material and
all other branched chain saturated alcohols in fragrances.
Ó 2010 Published by Elsevier Ltd.
Contents
Introduction . . . ..................................................................................................... S86
1. Identification . . ..................................................................................................... S86
2. Physical properties . . . . . . . . . . . . . . . . . .................................................................................. S86
3. Usage. . . . . . . . . ..................................................................................................... S86
4. Toxicology data ..................................................................................................... S87
4.1. Acute toxicity. ................................................................................................ S87
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87
4.1.3. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87
4.1.4. Other studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87
4.2. Skin irritation. ................................................................................................ S87
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87
4.2.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87
4.3. Mucous membrane (eye) irritation. ............................................................................... S87
4.4. Skin densitization ............................................................................................. S87
4.5. Phototoxicity and photoallergy. . ................................................................................. S87
4.6. Absorption, distribution and metabolism .......................................................................... S87
4.6.1. Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87
4.6.2. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87
4.6.3. Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87
4.7. Repeated dose toxicity . . ....................................................................................... S87
4.8. Reproductive and developmental toxicity .......................................................................... S87
4.9. Genotoxicity. ................................................................................................. S87
4.10. Carcinogenicity . . ............................................................................................. S88
Conflict of interest statement . . . . . . . . .................................................................................. S88
References . . . . ..................................................................................................... S88
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.
E-mail address: dmcginty@RIFM.org (D. McGinty).
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.fct.2010.05.036

S86
D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S85–S88
Introduction
This document provides a comprehensive summary of the toxicologic
review of 2-ethyl-1-butanol when used as a fragrance
ingredient including all human health endpoints. 2-Ethyl-1-butanol
(see Fig. 1; CAS Number 97-95-0) is a fragrance ingredient used
in cosmetics, fine fragrances, shampoos, toilet soaps and other toiletries
as well as in non-cosmetic products such as household
cleaners and detergents. This material has been reported to occur
in nature, with highest quantities observed in mushrooms (VCF,
2009).
In 2006, a complete literature search was conducted on isoamyl
alcohol. On-line toxicological databases were searched including
those from the Chemical Abstract Services [e.g. ToxCenter [which
in itself contains 18 databases including Chemical Abstracts)] and
the National Library of Medicine [e.g. Medline, Toxnet (which contains
14 databases)] as well as 26 additional sources (e.g. BIOSIS,
Embase, RTECS, OSHA, ESIS). In addition, fragrance companies were
asked to submit all test data.
The safety data on this material has never been reviewed before
by RIFM (Research Institute for Fragrance Materials, Inc.). All relevant
references are included in this document. More details have
been provided for unpublished data. The number of animals, sex
and strain are always provided unless they are not given in the original
report or paper. Any papers in which the vehicles and/or the
doses are not given have not been included in this review. In addition,
diagnostic patch test data with fewer than 100 consecutive
patients have been omitted.
1. Identification
1.1. Synonyms: 1-butanol, 2-ethyl-, 2-ethylbutyl alcohol, 2-ethylbutan-1-ol.
1.2. CAS Registry Number: 97-95-0.
1.3. EINECS Number: 202-621-4.
Fig. 1. 2-Ethyl-1-butanol.
1.4. Formula: C 6 H 14 O.
1.5. Molecular weight: 102.18.
1.6. Council of Europe (2000): 2-ethyl-1-butanol was included
by the Council of Europe in the list of substances granted B
– information required – 28 day oral study (COE No. 543).
2. Physical properties
2.1. Physical form: no information available.
2.2. Boiling point (calculated; EPA, 2010): 145.86 °C.
2.3. Flash point: no information available.
2.4. Henry’s law (calculated; EPA, 2010): 0.0000176 atm m 3 /mol
25 °C.
2.5. Log K ow (calculated; EPA, 2010): 1.75.
2.6. Refractive index: no information available.
2.7. Specific gravity: no information available.
2.8. Vapor pressure (calculated; EPA, 2010): 1.0 mm Hg (20 °C);
1.6 mm Hg (25 °C); 213 Pa (25 °C).
2.9. Water solubility (calculated; EPA, 2010): 11950 mg/l (25 °C).
2.10. UV spectra not available at RIFM.
3. Usage
2-Ethyl-1-butanol is a fragrance ingredient used in many fragrance
compounds. It may be found in fragrances used in decorative
cosmetics, fine fragrances, shampoos, toilet soaps and other
toiletries as well as in non-cosmetic products such as household
cleaners and detergents. Its use worldwide is in the region of less
than 0.01 metric tons per annum (IFRA, 2004). The reported volume
of use is for 2-ethyl-1-butanol as used in fragrance compounds
(mixtures) in all finished consumer product categories.
The volume of use is surveyed by IFRA approximately every four
years through a comprehensive survey of IFRA and RIFM member
companies. As such the volume of use data from this survey provides
volume of use of fragrance ingredients for the majority of
the fragrance industry.
The dermal systemic exposure in cosmetic products (see Table
1) is calculated based on the concentrations of the same fragrance
ingredient in 10 types of the most frequently used
personal care and cosmetic products (anti-perspirant, bath products,
body lotion, eau de toilette, face cream, fragrance cream, hair
spray, shampoo, shower gel, and toilet soap). The concentration of
the fragrance ingredient in fine fragrances is obtained from examination
of several thousand commercial formulations. The upper
97.5 percentile concentration is calculated from the data obtained.
This upper 97.5 percentile concentration is then used for all 10
consumer products. These concentrations are multiplied by the
amount of product applied, the number of applications per day
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2-ethyl-1-butanol.
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient b (mg/kg/day)
Anti-perspirant 0.5 1 1 0.01 0.0003 0.000001
Bath products 17 0.29 0.001 0.02 0.0003 0.000001
Body lotion 8 0.71 1 0.004 0.0003 0.000100
Eau de toilette 0.75 1 1 0.08 0.0003 0.000200
Face cream 0.8 2 1 0.003 0.0003 0.000001
Fragrance cream 5 0.29 1 0.04 0.0003 0.000200
Hair spray 5 2 0.01 0.005 0.0003 0.000001
Shampoo 8 1 0.01 0.005 0.0003 0.000001
Shower gel 5 1.07 0.01 0.012 0.0003 0.000001
Toilet soap 0.8 6 0.01 0.015 0.0003 0.000001
Total 0.0005
a
b
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.
Based on a 60-kg adult.

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S85–S88 S87
for each product type, and a ‘‘retention factor” (ranging from 0.001
to 1.0) to account for the length of time a product may remain on
the skin and/or likelihood of the fragrance ingredient being removed
by washing. The resultant calculation represents the total
consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford et al.,
2000).
This is a conservative calculation of dermal systemic exposure
because it makes the unlikely assumption that a consumer will
use these 10 products containing; which are all perfumed with
the upper 97.5 percentile level of the fragrance ingredient from a
fine fragrance type of product (Cadby et al. 2002; Ford et al.,
2000). The 97.5 percentile use level in formulae for use in cosmetics
for 2-ethyl-1-hexanol has been reported to be 0.02% (IFRA,
2007), which would result in a maximum daily exposure on the
skin of 0.0005 mg/kg for high end users (see Table 1).
A maximum skin level is then determined for consideration of
potential sensitization. The exposure is calculated as the percent
concentration of the fragrance ingredient applied to the skin based
on the use of 20% of the fragrance mixture in the fine fragrance
consumer product (IFRA, 2007). The maximum skin level that results
from the use of 2-ethyl-1-butanol in formulae that go into
fine fragrances has been not been reported.
4. Toxicology data
4.1. Acute toxicity
Summary of acute toxicity studies is given in Table 2.
4.1.1. Oral studies
The acute oral LD 50 of 2-ethyl-1-butanol in Carworth-Wistar
male or female rats (5/group) was reported to be 1.85 (1.52–
2.24) g/kg. Observations were made for 14 days. No additional details
were reported (Smyth et al., 1954).
The acute oral LD 50 of 2-ethyl-1-butanol in rats was reported to
be 1.85 g/kg. No additional details were reported (Bar and Griepentrog,
1967; Nishimura et al., 1994).
The acute oral LD 50 of 2-ethyl-1-butanol in rabbits was reported
to be 1.2 ml/kg (1.2 g/kg). No additional details were reported
(Draize et al., 1944).
4.1.2. Dermal studies
The acute dermal LD 50 of 2-ethyl-1-butanol in rabbits (4/group)
was reported to be 1.26 (0.85–1.87) g/kg. Observations were made
for 14 days. No additional details were reported (Smyth et al.,
1954).
The acute dermal LD 50 of 2-ethyl-1-butanol in rabbits was reported
to be 2.0 ml/kg (2.0 g/kg). No additional details were reported
(Draize et al., 1944).
4.1.3. Inhalation studies
In an acute inhalation study of 2-ethyl-1-butanol in male rats
(6/group), the maximum time to death of exposure to concentrated
Table 2
Summary of acute toxicity studies.
Route Species No. animals/
dose group
LD 50
(g/kg)
References
Oral Rat 5 1.85 Smyth et al. (1954)
Oral Rat N/A 1.85 Nishimura et al. (1994)
Bar and Griepentrog (1967)
Oral Rabbit N/A 1.2 Draize et al. (1944)
Dermal Rabbit 4 1.26 Smyth et al. (1954)
Dermal Rabbit N/A 2.0 Draize et al. (1944)
vapors was reported to be 8 h. No additional details were reported
(Smyth et al., 1954).
4.1.4. Other studies
The acute intraperitoneal ED3 for induction of pronounced
ataxia in rats was reported to be 2.3 mmol/kg (0.24 g/kg) (McCreery
and Hunt, 1978).
4.2. Skin irritation
4.2.1. Human studies
No available information.
4.2.2. Animal studies
In a group of 5 rabbits (giant albino, New Zealand rabbits) dermal
irritation study for 24 h uncovered neat 2-ethyl-1-butanol was
applied at 0.1 ml to clipped skin. Slight to moderate irritation
(grade 2) was reported (Smyth et al., 1954).
4.3. Mucous membrane (eye) irritation
In a rabbit eye irritation study, a 1% of 2-ethyl-1-butanol solution
was reported to produce necrosis of the eye (Smyth et al.,
1954).
4.4. Skin densitization
No available information.
4.5. Phototoxicity and photoallergy
No available information.
4.6. Absorption, distribution and metabolism
4.6.1. Absorption
No available information.
4.6.2. Distribution
No available information.
4.6.3. Metabolism
4.6.3.1. In vivo studies in animals. Kamil et al. (1953a) reported that
when 25 mmol (2.55 g) of 2-ethyl-1-butanol was administered by
oral gavage to 3.0 kg rabbits (n = 3), 40% of the administered dose
was excreted in the urine as the glucuronide within 24 h.
Furthermore, Kamil et al. (1953b) reported that 2-ethyl-1-butanol,
2.55 g (3.1 ml), administered by oral gavage to a rabbit was excreted
in the urine (24 h) as diethylacetylglucuronide. A small
amount of methyl-n-propyl ketone was also excreted.
4.6.3.2. In vitro studies in animals. No available information.
4.7. Repeated dose toxicity
No available information.
4.8. Reproductive and developmental toxicity
No available information.
4.9. Genotoxicity
No available information.

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D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S85–S88
4.10. Carcinogenicity
No available information.
This individual Fragrance Material Review is not intended as a
stand-alone document. Please refer to A Safety Assessment of
Branched Chain Saturated Alcohols When Used as Fragrance Ingredients
(Belsito et al., 2010) for an overall assessment of this
material.
Conflict of interest statement
This research was supported by the Research Institute for Fragrance
Materials, an independent research institute that is funded
by the manufacturers of fragrances and consumer products containing
fragrances. The authors are all employees of the Research
Institute for Fragrance Materials.
References
Bar, V.F., Griepentrog, F., 1967. Die Situation in der gesundheitlichen Beurteilung
der Aromatisierungsmittel fur Lebensmittel (where we stand concerning the
evaluation of flavoring substances from the viewpoint of health). Medizin
Ernährung 8, 244–251.
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chain
saturated alcohols when used as fragrance ingredients. Food and Chemical
Toxicology 48 (S4), S1–S46.
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:
providing estimates for safety evaluation. Regulatory Toxicology and
Pharmacology 36, 246–252.
Council of Europe, 2000. Partial Agreement in the Social and Public Health Field.
Chemically-defined flavouring substances. Group 2.1.3 Aliphatic Alcohols,
branched chain. p. 59, number 543. Council of Europe Publishing, Strasbourg.
Draize, J.H., Woodard, G., Calvery, H.O., 1944. Methods for the study of irritation and
toxicity of substances applied topically to the skin and mucous membranes.
Journal of Pharmacology and Experimental Therapeutics 82 (2), 377–390.
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface
Suite for Microsoft Ò Windows, v 4.00 or Insert Version used. United States
Environmental Protection Agency, Washington, DC, USA.
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria for
development of a database for safety evaluation of fragrance ingredients.
Regulatory Toxicology and Pharmacology 31, 166–181.
IFRA (International Fragrance Association), 2004. Use Level Survey, August 2004.
IFRA (International Fragrance Association), 2007. Volume of Use Survey, February
2007.
Kamil, I.A., Smith, J.N., Williams, R.T., 1953a. Studies in detoxication. 46. The
metabolism of aliphatic alcohols. The glucuronic acid conjugation of acyclic
aliphatic alcohols. Biochemical Journal 53, 129–136.
Kamil, I.A., Smith, J.N., Williams, R.T., 1953b. Studies in detoxication. 47. The
formation of ester glucuronides of aliphatic acids during the metabolism of 2-
ethylbutanol and 2-ethylhexanol. Biochemical Journal 53 (1), 137–140.
McCreery, M.J., Hunt, W.A., 1978. Physico-chemical correlates of alcohol
intoxication. Neuropharmacology 17, 451–461.
Nishimura, H., Saito, S., Kishida, F., Matsuo, M., 1994. Analysis of acute toxicity
(LD 50 -value) of organic chemicals to mammals by solubility parameter (delta).
1. Acute oral toxicity to rats. Sangyo Igaku 36 (5), 314–323 (Japanese Journal
Industrial Health).
Smyth, H.F., Carpenter, C.P., Weil, C.S., Pozzani, U.C., 1954. Range-finding toxicity
data. List V. Archives of Industrial Hygiene 10, 61–68.
VCF, 2009. Volatile Compounds in Food: Database/Nijssen, L.M., van Ingen-Visscher,
C.A., Donders, J.J.H. (Eds.) – Version 11.1.1. TNO Quality of Life, Zeist, The
Netherlands, 1963–2009.

Food and Chemical Toxicology 48 (2010) S89–S92
Contents lists available at ScienceDirect
Food and Chemical Toxicology
journal homepage: www.elsevier.com/locate/foodchemtox
Review
Fragrance material review on 2,6-dimethyl-4-heptanol
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api
Research Institute for Fragrance Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
article
Keywords:
Review
Fragrance
info
abstract
A toxicologic and dermatologic review of 2,6-dimethyl-4-heptanol when used as a fragrance ingredient is
presented. 2,6-Dimethyl-4-heptanol is a member of the fragrance structural group branched chain saturated
alcohols. The common characteristic structural elements of the alcohols with saturated branched
chain are one hydroxyl group per molecule, and a C 4 –C 12 carbon chain with one or several methyl side
chains. This review contains a detailed summary of all available toxicology and dermatology papers that
are related to this individual fragrance ingredient and is not intended as a stand-alone document. A safety
assessment of the entire branched chain saturated alcohol group will be published simultaneously with
this document; please refer to Belsito et al. (2010) for an overall assessment of the safe use of this material
and all other branched chain saturated alcohols in fragrances.
Ó 2010 Published by Elsevier Ltd.
Contents
Introduction . . . ..................................................................................................... S90
1. Identification . . ..................................................................................................... S90
2. Physical properties . . . . . . . . . . . . . . . . . .................................................................................. S90
3. Usage. . . . . . . . . ..................................................................................................... S90
4. Toxicology data ..................................................................................................... S91
4.1. Acute toxicity (see Table 2). ..................................................................................... S91
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S91
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S91
4.1.3. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S91
4.2. Skin irritation. ................................................................................................ S91
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S91
4.2.2. Animal studies (see Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S91
4.3. Mucous membrane (eye) irritation (see Table 4) .................................................................... S92
4.4. Skin sensitization. ............................................................................................. S92
4.5. Phototoxicity and photoallergy. . ................................................................................. S92
4.6. Absorption, distribution and metabolism .......................................................................... S92
4.7. Repeated dose toxicity . . ....................................................................................... S92
4.7.1. Two to 30-day studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S92
4.7.2. Subchronic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S92
4.7.3. Chronic (90+ days) studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S92
4.8. Reproductive and developmental toxicity .......................................................................... S92
4.9. Genotoxicity. ................................................................................................. S92
4.10. Carcinogenicity . . ............................................................................................. S92
Conflict of interest statement . . . . . . . . .................................................................................. S92
References . . . . ..................................................................................................... S92
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.
E-mail address: dmcginty@RIFM.org (D. McGinty).
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.fct.2010.05.037

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D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S89–S92
1. Identification
1.1. Synonyms: diisobutylcarbinol; 4-heptanol, 2,6-dimethyl-;
2,6-dimethylheptan-4-ol.
1.2. CAS registry number: 108-82-7.
1.3. EINECS number: 203-619-6.
1.4. Formula: C 9 H 20 O.
1.5. Molecular weight: 144.26.
1.6. JECFA (2003): The Joint FAO/WHP Expert Committee on
Food Additives (JECFA No. 303) concluded that the substance
does not present a safety concern at current levels of intake
when used as a flavouring agent.
1.7. FEMA (1970): Flavor and Extract Manufacturers’ Association
states: generally Recognized as Safe as a flavor ingredient –
GRAS 4. (3140) Hall, 1970.
Introduction
Fig. 1. 2,6,-Dimethyl-4-heptanol.
This document provides a summary of the toxicologic review,
including all human health endpoints, of 2,6-dimethyl-4-heptanol
when used as a fragrance ingredient. 2,6-Dimethyl-4-heptanol (see
Fig. 1; CAS No. 108-82-7) is a fragrance ingredient used in cosmetics,
fine fragrances, shampoos, toilet soaps and other toiletries as
well as in non-cosmetic products such as household cleaners and
detergents.
In 2006, a complete literature search was conducted on 2,6-dimethyl-4-heptanol.
On-line toxicological databases were searched
including those from the Chemical Abstract Services, e.g. ToxCenter
[which in itself contains 18 databases including Chemical Abstracts)],
and the National Library of Medicine [e.g. Medline, Toxnet
(which contains 14 databases)] as well as 26 additional sources
(e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance
companies were asked to submit all test data.
The safety data on this material has never been reviewed before
by RIFM (Research Institute for Fragrance Materials, Inc.). All relevant
references are included in this document. More details have
been provided for unpublished data. The number of animals, sex
and strain are always provided unless they are not given in the original
report or paper. Any papers in which the vehicles and/or the
doses are not given have not been included in this review. In addition,
diagnostic patch test data with fewer than 100 consecutive
patients have been omitted.
2. Physical properties
2.1. Physical form: no information available.
2.2. Boiling point (calculated; EPA, 2010): 177.59 °C.
2.3. Flash point: no information available.
2.4. Henry’s law (calculated; EPA, 2010): 0.0000412 atm m 3 /mol
25 °C.
2.5. Log K ow (calculated; EPA, 2010): 3.08.
2.6. Refractive index: no information available.
2.7. Specific gravity: no information available.
2.8. Vapor pressure: (calculated; EPA, 2010): 0.334 mm Hg;
44.5 Pa (25 °C).
2.9. Water solubility (calculated; EPA, 2010): 613.8 mg/l @ 25 °C.
2.10. UV spectra available at RIFM, does not absorb UV light.
3. Usage
2,6-Dimethyl-4-heptanol is a fragrance ingredient used in many
fragrance compounds. It may be found in fragrances used in decorative
cosmetics, fine fragrances, shampoos, toilet soaps and other
toiletries as well as in non-cosmetic products such as household
cleaners and detergents. Its use worldwide is in the region of 10–
100 metric tons per annum (IFRA, 2004). The reported volume of
use is for 2,6-dimethyl-4-heptanol as used in fragrance compounds
(mixtures) in all finished consumer product categories. The volume
of use is surveyed by IFRA approximately every four years through
a comprehensive survey of IFRA and RIFM member companies. As
such the volume of use data from this survey provides volume of
use of fragrance ingredients for the majority of the fragrance
industry.
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2,6-dimethyl-4-heptanol.
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient (mg/kg/day) b
Anti-perspirant 0.5 1 1 0.01 .02 0.000001
Bath products 17 0.29 0.001 0.02 .02 0.000001
Body lotion 8 0.71 1 0.004 .02 0.000100
Eau de toilette 0.75 1 1 0.08 .02 0.000200
Face cream 0.8 2 1 0.003 .02 0.000001
Fragrance cream 5 0.29 1 0.04 .02 0.000200
Hair spray 5 2 0.01 0.005 .02 0.000001
Shampoo 8 1 0.01 0.005 .02 0.000001
Shower gel 5 1.07 0.01 0.012 .02 0.000001
Toilet soap 0.8 6 0.01 0.015 .02 0.000001
Total 0.0005
a
b
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.
Based on a 60 kg adult.

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S89–S92 S91
Table 2
Summary of acute toxicity studies.
Route Species No. animals/
dose group
The dermal systemic exposure in cosmetic products (see Table
1) is calculated based on the concentrations of the same fragrance
ingredient in ten types of the most frequently used
personal care and cosmetic products (anti-perspirant, bath products,
body lotion, eau de toilette, face cream, fragrance cream, hair
spray, shampoo, shower gel, and toilet soap). The concentration of
the fragrance ingredient in fine fragrances is obtained from examination
of several thousand commercial formulations. The upper
97.5 percentile concentration is calculated from the data obtained.
This upper 97.5 percentile concentration is then used for all 10
consumer products. These concentrations are multiplied by the
amount of product applied, the number of applications per day
for each product type, and a ‘‘retention factor” (ranging from
0.001 to 1.0) to account for the length of time a product may remain
on the skin and/or likelihood of the fragrance ingredient
being removed by washing. The resultant calculation represents
the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford
et al., 2000).
This is a conservative calculation of dermal systemic exposure
because it makes the unlikely assumption that a consumer will
use these 10 products containing; which are all perfumed with
the upper 97.5 percentile level of the fragrance ingredient from a
fine fragrance type of product (Cadby et al., 2002; Ford et al.,
2000). The 97.5% percentile use level in formulae for use in cosmetics
in general has not been reported. As such the default value of
0.02% is used to calculate the maximum daily exposure on the skin
of 0.0005 mg/kg for high end users of these products.
A maximum skin level is then determined for consideration of
potential sensitization. The exposure is calculated as the percent
concentration of the fragrance ingredient applied to the skin based
on the use of 20% of the fragrance mixture in the fine fragrance
consumer product (IFRA, 2007). The maximum skin level that results
from the use of 2,6-dimethyl-4-heptanol in formulae that
go into fine fragrances has not been reported. A default value of
0.02% is used, assuming use of the fragrance oil at levels up to
20% in the final product.
4. Toxicology data
4.1. Acute toxicity (see Table 2)
LD 50
(g/kg)
References
Oral Rats 5 3.56 Smyth et al. (1949)
Oral Rats 32 4.35 Posternak and Vodoz (1975)
Oral Rats 5,6 or 11 6.5 McOmie and Anderson (1949)
Oral Mice 6 or 14 5 McOmie and Anderson (1949)
Dermal Rabbit 5 5.66 Smyth et al. (1949)
4.1.1. Oral studies
Five rats per dose were given a single dose of 2,6-dimethyl-4-
heptanol at 1, 2, 4, and 8 g/kg. Observations for mortality and or
systemic effects were made for 14 days. The acute oral LD 50 in rats
was calculated to be 3.56 g/kg (95% CI 1.43–8.86) (Smyth et al.,
1949).
Sixteen male and sixteen female rats of the Wistar CF/Gif Carworth
strain were given 2,6-dimethyl-4-heptanol with food.
Observations for mortality and or systemic effects were made.
The acute oral LD 50 in rats was calculated to be 4.35 g/kg. Necropsy
results done at week 12 showed organ weights and organ histopathology
to be within normal limits (Posternak and Vodoz, 1975).
Rats (5, 6, or 11/dose) were dosed intra-gastrically with 2.5, 3.7,
5.0, 7.5, 10, and 12.5 g/kg in 1% aqueous Tergitol. Observations for
mortality and or systemic effects were made. The acute oral LD 50 in
rats was calculated to be 6.5 ml/kg (6.5 g/kg) (McOmie and Anderson,
1949).
In the same study as above, mice (6 or 14/dose) were dosed intra-gastrically
with 2.5, 5.0, and 10 g/kg in 1% Tergitol. Observations
for mortality and systemic effects were made. The LD 50 in
mice was calculated to be 5.0 g/kg (95% CI 2.5–7.5) (McOmie and
Anderson, 1949).
4.1.2. Dermal studies
Five rabbits received a single dermal application of 1, 2, 4 or 8 g/
kg 2,6-dimethyl-4-heptanol. Observations for mortality and/or systemic
effects were made for 14 days. The acute dermal LD 50 in rabbits
was calculated to be 5.66 g/kg (95% CI 2.51–12.80) (Smyth
et al., 1949).
4.1.3. Inhalation studies
A group of male and female subjects (n = 12) were exposed by
inhalation to 2,6-dimethyl-4-heptanol for 15 min. The sensory response
limit and the concentration that produced irritation of the
mucus membranes of the eyes, nose, or throat were determined.
Less than 5 ppm produced eye irritation in the majority of subjects.
At 10 ppm nose and throat were irritated as well (Silverman et al.,
1946).
Groups of an unspecified number of rats were exposed to a saturated
vapor of two samples of 2,6-dimethyl-4-heptanol. The maximum
period of exposure to both samples one and two that did not
result in any deaths was 8 h (Smyth et al., 1949).
Ten mice were exposed by inhalation to 2 mg/l of 2,6-dimethyl-
4-heptanol as a saturated vapor-air mixture. No deaths were reported
after the 12-h exposure (McOmie and Anderson, 1949).
4.2. Skin irritation
4.2.1. Human studies
No available information.
4.2.2. Animal studies (see Table 3)
The primary skin irritation of neat 2,6-dimethyl-4-heptanol was
evaluated on groups of five rabbits. Scoring similar to the Draize
method was used, with grades ranging from 1 to 10. A grade of 1
was observed; this indicates there was no irritation from the undiluted
material (Smyth et al., 1949).
Seven 5 h applications of neat 2,6-dimethyl-4-heptanol were
made to the intact skin of two rabbits over a period of 21 days.
Observations included definite erythema after the 2nd exposure,
areas of flaking after the 4th exposure, and cracking of the skin
with bleeding fissures after the 7th exposure (McOmie and
Anderson, 1949).
Table 3
Summary of animal irritation studies.
Method Dose (%) Species Reactions References
Dermal application 100% Rabbit 0/5 No irritation Smyth et al. (1949)
Dermal application 100% Rabbit Definite erythema, flaking, and bleeding fissures McOmie and Anderson (1949)
Dermal application 100% Rabbit 2/5 erythema and slight edema McOmie and Anderson (1949)

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D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S89–S92
Table 4
Summary of eye irritation studies.
Dose (%) Vehicle Reactions References
100% NA Irritation observed Smyth et al. (1949)
NA NA Irritation observed McOmie and Anderson (1949)
The cuff method was used for acute dermal exposure in five rabbits.
Animals were given 4 h semi-occlusive applications of neat
2,6-dimethyl-4-heptanol from 3.9–9.4 ml/kg. Two of the five rabbits
showed some erythema and slight edema (McOmie and
Anderson, 1949).
4.3. Mucous membrane (eye) irritation (see Table 4)
An ocular irritation study was conducted with two samples of
neat 2,6-dimethyl-4-heptanol. Groups of five rabbits per dose were
used, and the test material was applied to the corneas. The retracted
eyelids were released approximately 1 min after the instillation,
and the eyes were stained with fluorescein 18–24 h later.
The eyes were examined and scored according to a 10-point scale.
Both samples of 2,6-dimethyl-4-heptanol were assigned a score of
2, which was equivalent to 0.5 ml of the neat material producing
injury of 1–5 points. Prior to the fluorescein staining, an injury of
one point was equivalent to iritis and five points was equivalent
to corneal opacity. After fluorescein staining, one point was equivalent
to necrosis on less than 5% of the cornea and five points was
equivalent to necrosis on 63–87% of the cornea (Smyth et al.,
1949).
2,6-Dimethyl-4-heptanol was tested in one rabbit. Moderate
Irritation was observed within the first 24 h, but returned to normal
by the 72nd hour (McOmie and Anderson, 1949).
4.4. Skin sensitization
No available information.
4.5. Phototoxicity and photoallergy
No available information.
4.6. Absorption, distribution and metabolism
No available information.
4.7. Repeated dose toxicity
4.7.1. Two to 30-day studies
No available information.
4.7.2. Subchronic studies
No available information.
4.7.3. Chronic (90+ days) studies
A 12-week oral study was conducted on groups of 32 Wistar CF/
Gif Carworth strain rats (16 per sex), and the treated animals were
fed a diet containing 2,6-dimethyl-4-heptanol mixed with microcrystalline
cellulose. The controls were only fed the basic diet,
but both the test and control animals were allowed access to food
ad libitum. The daily intake of the test material was estimated to
be 11 mg/kg bodyweight per day. Individual body weights were recorded
prior to the test and weekly thereafter. Observations of
physical appearance and behavior were made daily. Food consumption
was measured on a weekly basis, and efficiency of food
utilization (EFU) was calculated for pairs of rats (as housed). Hematological
examinations and blood urea determinations were carried
out on 50% of the animals at week seven, and on all the
animals at the end of the treatment period. All animals were sacrificed
at the end of the study, and a gross necropsy was conducted
at that time. The liver and kidneys were weighed, and a histological
examination was conducted. No adverse effects were observed,
and no changes of any biological significance were observed (Posternak
and Vodoz, 1975).
4.8. Reproductive and developmental toxicity
No available information.
4.9. Genotoxicity
No available information.
4.10. Carcinogenicity
No available information.
This individual Fragrance Material Review is not intended as a
stand-alone document. Please refer to A Safety Assessment of Alcohols
Branched Chain Saturated when used as fragrance ingredients
(Belsito et al., 2010) for an overall assessment of this material.
Conflict of interest statement
This research was supported by the Research Institute for Fragrance
Materials, an independent research institute that is funded
by the manufacturers of fragrances and consumer products containing
fragrances. The authors are all employees of the Research
Institute for Fragrance Materials.
References
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chain
saturated alcohols when used as fragrance ingredients. Food and Chemistry
Toxicology 48 (S4), S1–46.
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:
providing estimates for safety evaluation. Regulatory Toxicology and
Pharmacology 36, 246–252.
EPA (Environmental Protection Agency), 2010. Estimation programs interface
suite for Microsoft Ò Windows, v 4.00 or insert version used. United States
Environmental Protection Agency, Washington, DC, USA.
FEMA (Flavor and Extract Manufacturers Association), 1970. Recent progress in the
consideration of flavoring ingredients under the food additives amendment 4.
GRAS substances. Food Technology, 24(5), 25–34.
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria for
development of a database for safety evaluation of fragrance ingredients.
Regulatory Toxicology and Pharmacology 31, 166–181.
IFRA (International Fragrance Association), 2004. Use level survey, August 2004.
IFRA (International Fragrance Association), 2007. Volume of use survey, February
2007.
JECFA (Joint Expert Committee on Food Additives), 2003. Safety evaluation of
certain food additives. Who Food Additives Series:42. Prepared by the Fifty-First
Meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA).
World Health Organization, Geneva 1999.
McOmie, W.A., Anderson, H.H., 1949. Comparative toxicologic effects of some
isobutyl carbinols and ketones. University California Publications Pharmacology
2 (17), 217–230.
Posternak, J.M., Vodoz, C.A., 1975. Toxicology tests on flavouring matters. II.
Pyrazines and other compounds. Food and Cosmetics Toxicology 13, 487–490.
Silverman, L., Schultz, H.F., First, M.W., 1946. Further studies on sensory response to
certain industrial solvent vapors. The Journal of Industrial Hygiene and
Toxicolology 28, 262–266.
Smyth, H.F., Carpenter, C.P., Weil, C.S., 1949. Range-finding toxicity data, list III. The
Journal of Industrial Hygiene and Toxicolology 31 (1), 60–62.

Food and Chemical Toxicology 48 (2010) S93–S96
Contents lists available at ScienceDirect
Food and Chemical Toxicology
journal homepage: www.elsevier.com/locate/foodchemtox
Review
Fragrance material review on 3-methyl-1-pentanol
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api
Research Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
article
Keywords:
Review
Fragrance
info
abstract
A toxicologic and dermatologic review of 3-methyl-1-pentanol when used as a fragrance ingredient is
presented. 3-Methyl-1-pentanol is a member of the fragrance structural group branched chain saturated
alcohols. The common characteristic structural elements of the alcohols with saturated branched chain
are one hydroxyl group per molecule, and a C 4 to C 12 carbon chain with one or several methyl side chains.
This review contains a detailed summary of all available toxicology and dermatology papers that are
related to this individual fragrance ingredient and is not intended as a stand-alone document. A safety
assessment of the entire branched chain saturated alcohol group will be published simultaneously with
this document; please refer to Belsito et al. (2010) for an overall assessment of the safe use of this material
and all other branched chain saturated alcohols in fragrances.
Ó 2010 Published by Elsevier Ltd.
Contents
Introduction . . . ..................................................................................................... S94
1. Identification . . ..................................................................................................... S94
2. Physical properties . . . . . . . . . . . . . . . . . .................................................................................. S94
3. Usage. . . . . . . . . ..................................................................................................... S94
4. Toxicology data ..................................................................................................... S95
4.1. Acute toxicity (see Table 2). ..................................................................................... S95
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95
4.1.3. Other studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95
4.2. Skin irritation. ................................................................................................ S95
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95
4.2.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95
4.3. Mucous membrane (eye) irritation. ............................................................................... S95
4.4. Skin sensitization. ............................................................................................. S95
4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95
4.4.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95
4.5. Phototoxicity and photoallergy. . ................................................................................. S95
4.6. Absorption, distribution and metabolism .......................................................................... S95
4.7. Repeated dose toxicity . . ....................................................................................... S95
4.8. Reproductive and developmental toxicity .......................................................................... S95
4.9. Genotoxicity. ................................................................................................. S95
4.10. Carcinogenicity . . ............................................................................................. S95
Conflict of interest statement . . . . . . . . .................................................................................. S96
References . . . . ..................................................................................................... S96
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.
E-mail address: dmcginty@RIFM.org (D. McGinty).
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.fct.2010.05.038

S94
D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S93–S96
1.6. JECFA (1998): The Joint FAO/WHP Expert Committee on
Food Additives (JECFA No. 263) concluded that the substance
does not present a safety concern at current levels of intake
when used as a flavoring agent.
1.7. FEMA (1990): Flavor and Extract Manufacturers’ Association
states: Generally Recognized as Safe as a flavor ingredient –
GRAS 15 (3762).
Introduction
This document provides a summary of the toxicologic review,
including all human health endpoints, of 3-methyl-1-pentanol
when used as a fragrance ingredient. 3-Methyl-1-pentanol (see
Fig. 1; CAS Number 589-35-5) is a fragrance ingredient used in cosmetics,
fine fragrances, shampoos, toilet soaps and other toiletries
as well as in non-cosmetic products such as household cleaners
and detergents. This material has been reported to occur in nature,
with quantities observed in the mangifera species of mango (VCF,
2009).
In 2006, a complete literature search was conducted on 3-
methyl-1-pentanol. On-line toxicological databases were searched
including those from the Chemical Abstract Services [e.g. ToxCenter
[which in itself contains 18 databases including Chemical Abstracts)]
and the National Library of Medicine [e.g. Medline,
Toxnet (which contains 14 databases)] as well as 26 additional
sources (e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance
companies were asked to submit all test data.
The safety data on this material has never been reviewed before
by RIFM (Research Institute for Fragrance Materials, Inc.). All relevant
references are included in this document. More details have
been provided for unpublished data. The number of animals, sex
and strain are always provided unless they are not given in the original
report or paper. Any papers in which the vehicles and/or the
doses are not given have not been included in this review. In addition,
diagnostic patch test data with fewer than 100 consecutive
patients have been omitted.
1. Identification
Fig. 1. 3-Methyl-1-pentanol.
1.1. Synonyms: 2-ethyl-4-butanol; 1-pentanol, 3-methyl;
methyl pentanol-3.
1.2. CAS Registry Number: 589-35-5.
1.3. EINECS Number: 209-644-9.
1.4. Formula: C 6 H 14 O.
1.5. Molecular weight: 102.18.
2. Physical properties
2.1. Physical form: no information available.
2.2. Boiling point (calculated; EPA, 2010): 145.86 °C.
2.3. Flash point: no information available.
2.4. Henry’s law (calculated; EPA, 2010): 0.0000176 atm m 3 /mol
25 °C.
2.5. Log K ow (calculated; EPA, 2010): 1.75.
2.6. Refractive index: no information available.
2.7. Specific gravity: no information available.
2.8. Vapor pressure (calculated; EPA, 2010): 0.7 mm Hg (20 °C);
1.7 mm Hg (25 °C); 227 Pa (25 °C).
2.9. Water solubility (calculated; EPA, 2010): 11950 mg/l (25 °C).
2.10. UV spectra available at RIFM, peaks at 200–210 nm and
returns to baseline at 280–290 nm.
3. Usage
3-Methyl-1-pentanol is a fragrance ingredient used in many fragrance
compounds. It may be found in fragrances used in decorative
cosmetics, fine fragrances, shampoos, toilet soaps and other
toiletries as well as in non-cosmetic products such as household
cleaners and detergents. Its use worldwide is in the region of less
than 0.01 metric tons per annum (IFRA, 2004). The reported volume
of use is for 3-methyl-1-pentanol as used in fragrance compounds
(mixtures) in all finished consumer product categories.
The volume of use is surveyed by IFRA approximately every four
years through a comprehensive survey of IFRA and RIFM member
companies. As such the volume of use data from this survey provides
volume of use of fragrance ingredients for the majority of
the fragrance industry.
The dermal systemic exposure in cosmetic products (see Table 1)
is calculated based on the concentrations of the same fragrance
ingredient in 10 types of the most frequently used personal care
and cosmetic products (anti-perspirant, bath products, body lotion,
eau de toilette, face cream, fragrance cream, hair spray, shampoo,
shower gel, and toilet soap). The concentration of the fragrance
ingredient in fine fragrances is obtained from examination of several
thousand commercial formulations. The upper 97.5 percentile
concentration is calculated from the data obtained. This upper 97.5
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 3-methyl-1-pentanol.
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient b (mg/kg/day)
Anti-perspirant 0.5 1 1 0.01 0.0006 0.000001
Bath products 17 0.29 0.001 0.02 0.0006 0.000001
Body lotion 8 0.71 1 0.004 0.0006 0.000001
Eau de toilette 0.75 1 1 0.08 0.0006 0.000010
Face cream 0.8 2 1 0.003 0.0006 0.000001
Fragrance cream 5 0.29 1 0.04 0.0006 0.000010
Hair spray 5 2 0.01 0.005 0.0006 0.000001
Shampoo 8 1 0.01 0.005 0.0006 0.000001
Shower gel 5 1.07 0.01 0.012 0.0006 0.000001
Toilet soap 0.8 6 0.01 0.015 0.0006 0.000001
Total 0.00002
a
b
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.
Based on a 60-kg adult.

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S93–S96 S95
percentile concentration is then used for all 10 consumer products.
These concentrations are multiplied by the amount of product applied,
the number of applications per day for each product type,
and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account for
the length of time a product may remain on the skin and/or likelihood
of the fragrance ingredient being removed by washing. The
resultant calculation represents the total consumer exposure (mg/
kg/day) (Cadby et al., 2002; Ford et al., 2000).
This is a conservative calculation of dermal systemic exposure
because it makes the unlikely assumption that a consumer will
use these 10 products containing; which are all perfumed with
the upper 97.5 percentile level of the fragrance ingredient from a
fine fragrance type of product (Cadby et al., 2002; Ford et al.,
2000). The 97.5 percentile use level in formulae for use in cosmetics
in general has been reported to be 0.0006 (IFRA, 2007), which
would result in a maximum daily exposure on the skin of
0.00002 mg/kg for high end users of these products (Table 1).
A maximum skin level is then determined for consideration of
potential sensitization. The exposure is calculated as the percent
concentration of the fragrance ingredient applied to the skin based
on the use of 20% of the fragrance mixture in the fine fragrance
consumer product (IFRA, 2007). The maximum skin level in formulae
that go into fine fragrances has been reported to be 0.0002%
(IFRA, 2007), assuming use of the fragrance oil at levels up to
20% in the final product.
4. Toxicology data
4.1. Acute toxicity (see Table 2)
4.1.1. Oral studies
The acute oral LD 50 of 3-methyl-1-pentanol in mice was reported
to be >2 g/kg. Mortality was 0, 0, 1, and 10 of 10 mice at
0.5, 1.0, 2.0, and 4.0 g/kg. At the top dose 8/10 animals died within
24 h. Surviving animals were observed for 14 days post-dosing
(RIFM, 1982).
4.1.2. Dermal studies
No information available.
4.1.3. Other studies
The acute intraperitoneal LD 50 of 3-methyl-1-pentanol in mice
was reported to be >0.25 g/kg. Mortality was 0, 0, 8, 9, 10, and 10
of 10 mice at 0.125, 0.25, 0.5, 1.0, 2.0, and 4.0 g/kg. At the 0.5,
1.0, 2.0, and 4.0 g/kg, 7, 9, 10, and 10 animals, respectively, died
within 24 h. Surviving animals were observed for 14 days postdosing
(RIFM, 1982).
4.2. Skin irritation
4.2.1. Human studies
Irritation was evaluated during the induction phase in a human
repeated insult patch test (HRIPT). An application of 0.5 ml with
0.5% 3-methyl-1-pentanol in 99.5% alcohol SDA 39C on a 1 1-
inch Webril patch was administered to the upper arms of the
panelists and removed after 24 h. Irritation was scored 48 h after
initial application and a new patch reapplied at that time. Nine
Table 2
Summary of acute toxicity studies.
Route Species No. animals/
dose group
LD 50 (g/kg)
References
Oral Mice 10 >2.0 RIFM (1982)
Intraperitoneal Mice 10 >0.25 RIFM (1982)
applications were made in a three week period. Little or no irritation
was found in all 41 male and female volunteers (RIFM, 1973).
4.2.2. Animal studies
A group of three albino rabbits were given 0.5 ml of 0.5% 3-
methyl-1-pentanol in 99.5% Alcohol SDA 39C and observed at the
end of the 24 h contact period and again 48 h later. Erythema
and edema were not observed in any of the three rabbits tested
and therefore 3-methyl-1-pentanol cannot be considered a primary
irritant (RIFM, 1972).
4.3. Mucous membrane (eye) irritation
No information available.
4.4. Skin sensitization
4.4.1. Human studies
4.4.1.1. Induction studies. A repeated insult patch test was conducted
to determine if 3-methyl-1-pentanol would induce dermal
sensitization in human volunteers. During the induction phase
0.5 ml was applied onto a Webril swatch and applied to the upper
arms of each volunteer for 24 h. Induction applications were made
for a total of 9 applications during 3 week period. Following a two
week rest period, a challenge patch was applied to the original site
as well as a fresh site. Patches were applied as in the induction
phase and kept in place for 24 h after which time they were removed.
Reactions to the challenge were scored at 48 and 72 h after
application. There was no sensitization reactions observed during
the challenge phase (RIFM, 1973).
4.4.1.2. Cross-sensitization. No information available.
4.4.1.3. Diagnostic studies. No information available.
4.4.2. Animal studies
No information available.
4.5. Phototoxicity and photoallergy
No information available.
4.6. Absorption, distribution and metabolism
No information available.
4.7. Repeated dose toxicity
No information available.
4.8. Reproductive and developmental toxicity
No information available.
4.9. Genotoxicity
No information available.
4.10. Carcinogenicity
No information available.
This individual Fragrance Material Review is not intended as a
stand-alone document. Please refer to A Safety Assessment of
Branched Chain Saturated Alcohols When Used as Fragrance

S96
D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S93–S96
Ingredients (Belsito et al., 2010) for an overall assessment of this
material.
Conflict of interest statement
This research was supported by the Research Institute for Fragrance
Materials, an independent research institute that is funded
by the manufacturers of fragrances and consumer products containing
fragrances. The authors are all employees of the Research
Institute for Fragrance Materials.
References
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chain
saturated alcohols when used as fragrance ingredients. Food Chem. Toxicol. 48
(S4), S1–S46.
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:
providing estimates for safety evaluation. Regul. Toxicol. Pharma. 36, 246–252.
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface
Suite for Microsoft Ò Windows, v 4.00 or Insert Version used. United States
Environmental Protection Agency, Washington, DC, USA.
FEMA (Flavor and Extract Manufacturers Association), 1990. Recent progress in the
consideration of flavoring ingredients under the food additives amendment. 15.
GRAS substances. Food Technol. 44 (2). 78, 80, 82, 84, 86.
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria for
Development of a database for safety evaluation of fragrance ingredients. Regul.
Toxicol. Pharm. 31, 166–181.
IFRA (International Fragrance Association), 2004. Use Level Survey, August 2004.
IFRA (International Fragrance Association), 2007. Volume of Use Survey, February
2007.
JECFA (Joint Expert Committee on Food Additives), 1998. Safety Evaluation of
Certain Food Additives. Who Food Additives Series: 40. Prepared by the Fortyninth
Meeting of the Joint FAO/WHO Expert Committee on Food Additives
(JECFA). World Health Organization, Geneva.
RIFM (Research Institute for Fragrance Materials, Inc.), 1972. Skin Irritation Study
with 3-Methyl-1-pentanol in Rabbits. Unpublished Report from International
Flavors and Fragrances. Report Number 53594. RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1973. Repeated Insult Patch
Test with 3-Methyl-1-pentanol. Unpublished Report from International Flavors
and Fragrances. Report Number 53593 RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1982. 14-Day LD50 Study on
3-Methyl-1-pentanolin Mice. Private Communication to FEMA. Unpublished
Report from H.W. Engler B. Bahler. Report Number 9019. RIFM, Woodcliff Lake,
NJ, USA.
VCF, 2009. (Volatile Compounds in Food): Database/Nijssen, L.M., van Ingen-
Visscher, C.A., Donders, J.J.H. (Eds.), – Version 11.1.1. TNO Quality of Life, Zeist,
The Netherlands, 1963–2009.

Food and Chemical Toxicology 48 (2010) S97–S101
Contents lists available at ScienceDirect
Food and Chemical Toxicology
journal homepage: www.elsevier.com/locate/foodchemtox
Review
Fragrance material review on 2-methylbutanol
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api
Research Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
article
Keywords:
Review
Fragrance
info
abstract
A toxicologic and dermatologic review of 2-methylbutanol when used as a fragrance ingredient is presented.
2-Methylbutanol is a member of the fragrance structural group branched chain saturated alcohols.
The common characteristic structural elements of the alcohols with saturated branched chain are
one hydroxyl group per molecule, and a C 4 –C 12 carbon chain with one or several methyl side chains. This
review contains a detailed summary of all available toxicology and dermatology papers that are related to
this individual fragrance ingredient and is not intended as a stand-alone document. A safety assessment
of the entire branched chain saturated alcohol group will be published simultaneously with this document;
please refer to Belsito et al., 2010 for an overall assessment of the safe use of this material and
all other branched chain saturated alcohols in fragrances.
Ó 2010 Published by Elsevier Ltd.
Contents
Introduction . . . ..................................................................................................... S98
1. Identification . . ..................................................................................................... S98
2. Physical properties . . . . . . . . . . . . . . . . . .................................................................................. S98
3. Usage. . . . . . . . . ..................................................................................................... S99
4. Toxicology data ..................................................................................................... S99
4.1. Acute toxicity (see Table 2). ..................................................................................... S99
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S99
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S99
4.1.3. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S99
4.1.4. Intraperitoneal studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S99
4.1.5. Other studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S99
4.2. Skin irritation. ................................................................................................ S99
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S99
4.2.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S100
4.3. Mucous membrane (eye) irritation. ............................................................................... S100
4.4. Skin sensitization. ............................................................................................. S100
4.5. Phototoxicity and photoallergy. . ................................................................................. S100
4.6. Absorption, distribution and metabolism .......................................................................... S100
4.6.1. Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S100
4.6.2. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S100
4.6.3. Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S100
4.7. Repeated dose toxicity . . ....................................................................................... S100
4.8. Reproductive and developmental toxicity .......................................................................... S100
4.9. Genotoxicity. ................................................................................................. S100
* Corresponding author. Tel.: +1 201 689 8089; fax: +1 201 689 8088.
E-mail address: dmcginty@RIFM.org (D. McGinty).
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.fct.2010.05.039

S98
D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S97–S101
4.9.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S100
4.9.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S100
4.10. Carcinogenicity . . ............................................................................................. S100
Conflict of interest statement . . ........................................................................................ S100
References . ........................................................................................................ S101
Introduction
This document provides a comprehensive summary of the toxicologic
review, including all human health endpoints, of 2-methylbutanol
when used as a fragrance ingredient. 2-Methylbutanol
(see Fig. 1; CAS Number 137-32-6) is a fragrance ingredient used
in cosmetics, fine fragrances, shampoos, toilet soaps and other
toiletries as well as in non-cosmetic products such as household
cleaners and detergents. This material has been reported to occur
in nature, with highest quantities observed in hop oil (VCF,
2009).
In 2006, a complete literature search was conducted on 2-methylbutanol.
On-line toxicological databases were searched including
those from the Chemical Abstract Services, [e.g., ToxCenter (which
in itself contains 18 databases including Chemical Abstracts)], and
the National Library of Medicine [e.g., Medline, Toxnet (which contains
14 databases)] as well as 26 additional sources (e.g., BIOSIS,
Embase, RTECS, OSHA, ESIS). In addition, fragrance companies were
asked to submit all test data.
The safety data on this material has never been reviewed by
RIFM (Research Institute for Fragrance Materials, Inc.). All relevant
references are included in this document. More details have been
provided for unpublished data. The number of animals, sex and
strain are always provided unless they are not given in the original
report or paper. Any papers in which the vehicles and/or the doses
are not given have not been included in this review. In addition,
Fig. 1. 2-Methylbutanol.
diagnostic patch test data with fewer than 100 consecutive patients
have been omitted.
1. Identification
1.1. Synonyms: active amyl alcohol; 1-butanol, 2-methyl-; secbutylcarbinol;
(±) 2-methyl-1-butanol; 2-methylbutyl alcohol;
2-methylbutan-1-ol.
1.2. CAS registry number: 137-32-6.
1.3. EINECS number: 205-289-9.
1.4. Formula: C 5 H 12 O.
1.5. Molecular weight: 88.15.
1.6. Council of Europe (2000): 2-methylbutanol was included
by the Council of Europe in the list of substances granted
B – information required – 28 day oral study (COE No. 2346).
1.7. FEMA (2001): Flavor and Extract Manufacturers’ Association
states: Generally Recognized as Safe as a flavor ingredient –
GRAS 20.
1.8. JECFA (2004): The Joint FAO/WHO Expert Committee on
Food Additives (JECFA No. 1199) concluded that the substance
does not present a safety concern at current levels
of intake when used as a flavouring agent.
2. Physical properties
2.1. Physical form: no information available.
2.2. Boiling point (calculated; EPA, 2010): 123.17 °C.
2.3. Flash point: no information available.
2.4. Henry’s law (calculated; EPA, 2010): 0.0000133 atm m 3 /mol
(25 °C).
2.5. Log K ow (calculated; EPA, 2010): 1.26.
2.6. Refractive index: no information available.
2.7. Specific gravity: no information available.
2.8. Vapor pressure (calculated; EPA, 2010): 2.5 mm Hg (20 °C);
4.54 mm Hg (25 °C); 606 Pa (25 °C).
2.9. Water solubility (calculated; EPA, 2010): 32,200 mg/l
(25 °C).
2.10. UV spectra available at RIFM, peaked at 200–215 nm range
and returns to baseline at 220–225 nm.
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2-methylbutanol.
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient mg/kg/day b
Anti-perspirant 0.5 1 1 0.01 0.007 0.000010
Bath products 17 0.29 0.001 0.02 0.007 0.000001
Body lotion 8 0.71 1 0.004 0.007 0.000030
Eau de toilette 0.75 1 1 0.08 0.007 0.000070
Face cream 0.8 2 1 0.003 0.007 0.000010
Fragrance cream 5 0.29 1 0.04 0.007 0.000070
Hair spray 5 2 0.01 0.005 0.007 0.000001
Shampoo 8 1 0.01 0.005 0.007 0.000001
Shower gel 5 1.07 0.01 0.012 0.007 0.000001
Toilet soap 0.8 6 0.01 0.015 0.007 0.000001
Total 0.0002
a
b
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.
Based on a 60-kg adult.

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S97–S101 S99
3. Usage
2-Methylbutanol is a fragrance ingredient used in many fragrance
compounds. It may be found in fragrances used in decorative
cosmetics, fine fragrances, shampoos, toilet soaps and other toiletries
as well as in non-cosmetic products such as household cleaners
and detergents. Its use worldwide is in the region of 0.01–0.1 metric
tons per annum (IFRA, 2004). The reported volume of use is for 2-
methylbutanol as used in fragrance compounds (mixtures) in all
finished consumer product categories. The volume of use is surveyed
by IFRA approximately every 4 years through a comprehensive
survey of IFRA and RIFM member companies. As such the
volume of use data from this survey provides volume of use of fragrance
ingredients for the majority of the fragrance industry.
The dermal systemic exposure in cosmetic products (see Table
1) is calculated based on the concentrations of the same fragrance
ingredient in ten types of the most frequently used personal care
and cosmetic products (anti-perspirant, bath products, body lotion,
eau de toilette, face cream, fragrance cream, hair spray, shampoo,
shower gel, and toilet soap). The concentration of the fragrance
ingredient in fine fragrances is obtained from examination of several
thousand commercial formulations. The upper 97.5 percentile
concentration is calculated from the data obtained. This upper 97.5
percentile concentration is then used for all 10 consumer products.
These concentrations are multiplied by the amount of product applied,
the number of applications per day for each product type,
and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account
for the length of time a product may remain on the skin and/or
likelihood of the fragrance ingredient being removed by washing.
The resultant calculation represents the total consumer exposure
(mg/kg/day) (Cadby et al., 2002, Ford et al., 2000).
This is a conservative calculation of dermal systemic exposure
because it makes the unlikely assumption that a consumer will
use these 10 products containing; which are all perfumed with
the upper 97.5 percentile level of the fragrance ingredient from a
fine fragrance type of product (Cadby et al., 2002, Ford et al.,
2000). The 97.5% percentile use level in formulae for use in cosmetics
in general has been reported to be 0.007% (IFRA, 2007), which
would result in a maximum daily exposure on the skin of
0.0002 mg/kg for high end users.
A maximum skin level is then determined for consideration of
potential sensitization. The exposure is calculated as the percent
concentration of the fragrance ingredient applied to the skin based
on the use of 20% of the fragrance mixture in the fine fragrance
consumer product (IFRA, 2007). The average maximum use level
in formulae that go into fine fragrances has been reported to be
0.001% (IFRA, 2007), assuming use of the fragrance oil at levels
up to 20% in the final product.
4. Toxicology data
4.1. Acute toxicity (see Table 2)
4.1.1. Oral studies
The acute oral LD 50 of 2-methylbutanol in rats (n = 5) was
reported to be 4.92 (3.75–6.46) ml/kg (4.92 g/kg). No additional
details were reported (Smyth et al., 1962).
The acute oral LD 50 of 2-methylbutanol in rats (not specified)
was reported to be 1000 mg/kg. No additional details were reported
(Nishimura et al., 1994).
The acute oral LD 50 of 2-methylbutanol in rats (not specified)
was reported to be 4.01 g/kg. No additional details were reported
(Rowe and McCollister, 1982).
2-Methylbutanol was given to Sprague dawley rats (5/sex) at
doses of 1.47, 2.15, 3.16, or 5.0 g/kg and observed for 14 days.
Table 2
Summary of acute toxicity studies.
Route Species NO. animals/
dose group
The acute oral LD 50 was reported to be 4.17 g/kg based on mortality
(1/10) at 3.16 g/kg and (8/10) at 5.0 g/kg (RIFM, 1979).
Wistar rats (5/sex) were given a single oral dose 3.0 or 5.0 g/kg
of 2-methylbutanol by gavage and observed for 14 days. No animals
died, and the LD 50 was determined to be greater than 5.0 g/
kg (RIFM, 1985).
4.1.2. Dermal studies
The acute dermal LD 50 of 2-methylbutanol in rabbits (n = 4) was
reported to be 3.54 ml/kg (3.54 g/kg). Contact time was 24 h and
observation time was 14 days. No additional details were reported
(Smyth et al., 1962; RIFM, 1979).
An acute dermal LD 50 value was reported to be 2.89 for 2-
methyl-1-butanol (Rowe and McCollister, 1982).
4.1.3. Inhalation studies
The maximum time for exposure of rats (6/dose) to concentrated
vapors of 2-methylbutanol without mortality was 8 h. The
chemical was administered undiluted, unless a lesser concentration
was necessary. Then the solution was made in water, or corn
oil (Smyth et al., 1962).
Rats were exposed to 2-methylbutanol by inhalation of saturated
atmosphere at 20 °C for 7 h. Mortality was not observed,
but escape behavior and intermittent respiration was noted (RIFM,
1979).
No mortality was observed when six rats were exposed to 2-
methylbutanol by inhalation of saturated vapors for 8 h. No further
information available (Rowe and McCollister, 1982).
4.1.4. Intraperitoneal studies
Mice were given 2-methylbutanol at doses of 200, 700, or
2000 mg/kg by intraperitoneal injection and observed for 14 days.
All animals in the 2000 mg/kg and 9/10 at 700 mg/kg died. The
LD 50 was estimated to be greater than 200 mg/kg but less than
700 mg/kg (RIFM, 1979).
Rats were given 2-methylbutanol at doses of 1000, or 2000 mg/
kg by intraperitoneal injection and observed for 14 days. Animals
in the 2000 mg/kg showed respiratory arrest and death. At
1000 mg/kg the rats showed sedation, irritation of the peritoneum
and injury of the lungs (Haggard et al., 1945 as cited in Greim,
2008).
4.1.5. Other studies
In isolated perfused livers of rats, 65.1 mmol 2-methylbutanol/l
were cytotoxic as evidenced by the release of liver enzymes into
the perfusate. The alcohols decreased the content of ATP in the liver.
The content of oxidized glutathione was increased. Lipid peroxidation
was not observed (Strubelt et al., 1999).
4.2. Skin irritation
4.2.1. Human studies
No available information.
LD 50
(g/kg)
References
Oral Rat 5 4.92 Smyth et al. (1962)
Oral Rat N/A 1.00 Nishimura et al. (1994)
Oral Rat N/A 4.01 Rowe and McCollister (1982)
Oral Rat 10 (5/sex) 4.17 RIFM (1979)
Oral Rat 10 (5/sex) >5.0 RIFM (1985)
Dermal Rabbit 4 3.54 Smyth et al. (1962)
Dermal Rabbit N/A 3.54 RIFM (1979)

S100
D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S97–S101
4.2.2. Animal studies
In a rabbit dermal irritation study (n = 5) undiluted 2-methylbutanol
resulted in Grade 2 irritation defined as the least visible
capillary injection from the undiluted material (Smyth et al., 1962).
In a rabbit dermal irritation study with two rabbits, undiluted
2-methylbutanol resulted in Grade 4.7 or moderate irritation with
some necrosis observed (RIFM, 1979).
4.3. Mucous membrane (eye) irritation
In a rabbit eye irritation study, 2-methylbutanol resulted in
Grade 8 injury where corneal necrosis was observed (Smyth
et al., 1962).
In a rabbit eye irritation study (n = 6), undiluted 2-methylbutanol
resulted in some turbidity at the cornea, inflammation on the
iris, and redness of the conjunctivae after observations for 72 h
(RIFM, 1979).
When a 0.005 ml of undiluted 2-methylbutanol (or an excess of
a 15% solution in propylene glycol; not specified) was instilled into
the eyes of rabbits moderate to severe burns and corneal necrosis
was observed (Rowe and McCollister, 1982).
4.4. Skin sensitization
No available information.
4.5. Phototoxicity and photoallergy
No available information.
4.6. Absorption, distribution and metabolism
4.6.1. Absorption
No available information.
4.6.2. Distribution
No available information.
4.6.3. Metabolism
4.6.3.1. In vivo studies in animals (see Table 3). Following intraperitoneal
administration of 1 g/kg undiluted 2-methylbutanol to rats;
blood was drawn for analysis 1 h after the first administration and
at subsequent intervals. There was total elimination of 7.6%, 5.6%
was recovered unchanged in the expired air and 2.0% unchanged
in the urine. Disappearance from blood was rapid, with neither
alcohol nor aldehyde detected after 10 h (Haggard et al., 1945).
Oxidation to the aldehyde and glucuronidation was demonstrated
for 2-methylbutanol with microsomes from rats pre-treated
with ethanol (Iwersen and Schmoldt, 1995).
2-Methylbutanol was administered to large chinchilla rabbits
(n = 3) by oral gavage at 25 m-mol/rabbit. Collected urine did not
Table 3
Summary of in vivo animal studies.
Route Species Results References
Intraperitoneal Rat 5.6% was recovered unchanged in
the expired air and 2.0%
unchanged in the urine
Oral (drinking
water)
Rat
Oxidation to the aldehyde and
glucuronidation was
demonstrated
Oral (gavage) Rabbit Excess glucuronide excretion
represented 9.6% of the
administered dose
Haggard
et al. (1945)
Iwersen and
Schmoldt
(1995)
Kamil et al.
(1953)
contain aldehydes or ketones, but did yield 9.6% of non-reducing
glucuronide (Kamil et al., 1953).
4.6.3.2. In vitro studies in animals. Rat liver microsomes metabolized
2-methylbutanol to yield approximately 8 nmol aldehyde
per minute per mg protein and 13 nmol glucuronide per min per
mg protein. The k m and V max for glucuronidation were 2 mmol/l
and 18 nmol/min/mg protein, respectively. The k m and V max for
microsomal oxidation were 4.6 mmol/l and 3.6 nmol/min/mg protein,
respectively. The microsomes were obtained from male Sprague–Dawley
rats that had been pre-treated for 2 weeks with 10%
ethanol in the drinking water (Iwersen and Schmoldt, 1995).
4.7. Repeated dose toxicity
No available information.
4.8. Reproductive and developmental toxicity
No available information.
4.9. Genotoxicity
4.9.1. In vitro studies
4.9.1.1. Bacterial test systems. Light absorption and luminescent
umu tests were used to investigate the genotoxicity of 2-methylbutanol
with Salmonella typhimurium TA1535/pSK1002 and TA1535/
pTL210. Results showed the umu test for light absorption of
TA1535/pSK102 to be negative, where as the umu test for luminescent
TA1535/pTL210 to be positive (Nakajima et al., 2006).
4.9.1.2. Studies in mammalian cells. In a study of the cytotoxic and
genotoxic effects of a number of alcohols and ketones, 2-methylbutanol
had an IC 50 (Inhibitory concentration resulting in 50% reduction
in colony formation) of 31 mM for human lung carcinoma cell
line A549. At 45 and 90 mM concentration of 2-methylbutanol,
there was no difference from controls in alkaline comet assay tail
moment in either A549 cells or Chinese hamster V79 cells. The comet
assay could not be performed in human peripheral blood cells
due to cytotoxicity. At methylbutanol concentrations of 23 and
45 mM, there was no difference, in the micronucleus test, from
controls in induction of micronuclei in V79 cells with or without
the addition of hepatic S-9 from Aroclor induced rats. Finally an
HPRT with Chinese hamster V70 fibroblast cells at concentrations
up to 46 mM (the highest non-toxic concentration) mutagenicity
was not observed (Kreja and Seidel, 2001, 2002a,b).
4.9.2. In vivo studies
No available information.
4.10. Carcinogenicity
No available information.
This individual Fragrance Material Review is not intended as a
stand-alone document. Please refer to A Safety Assessment of
Branched Chain Saturated Alcohols When Used as Fragrance Ingredients
(Belsito et al., 2010) for an overall assessment of this
material.
Conflict of interest statement
This research was supported by the Research Institute for Fragrance
Materials, an independent research institute that is funded
by the manufacturers of fragrances and consumer products con-

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S97–S101 S101
taining fragrances. The authors are all employees of the Research
Institute for Fragrance Materials.
References
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Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched
chain saturated alcohols when used as fragrance ingredients. Food Chem
Toxicol. 48 (S4), S1–S46.
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:
providing estimates for safety evaluation. Regul.Toxicol. Pharm. 36, 246–252.
Council of Europe, 2000. Partial Agreement in the Social and Public Health Field.
Chemically-defined flavouring substances. Group 2.1.3 Aliphatic alcohols,
branched chain. p. 60, number 2346. Council of Europe Publishing, Strasbourg.
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface
Suite for Microsoft Ò Windows, v 4.00 or insert version used]. United States
Environmental Protection Agency, Washington, DC, USA.
FEMA (Flavor and Extract Manufacturers Association), 2001. GRAS flavoring
substances 20. Food Technol. 55 (12), 1-17.
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria for
development of a database for safety evaluation of fragrance ingredients. Regul.
Toxicol. Pharm. 31, 166–181.
Greim, H. (Ed.), 2008. Pentanol-Isomeren. Toxikologisch-arbeitsmedizinische
Begründungen von MAK-Werten, Lieferung 44. Wiley-VCH, Weinheim.
Haggard, H.W., Miller, D.P., Greenberg, L.A., 1945. The amyl alcohols and their
ketones: their metabolic fates and comparative toxicities. J. Ind. Hyg. Toxicol. 27
(1), 1–14.
IFRA (International Fragrance Association), 2004. Use Level Survey, August 2004.
IFRA (International Fragrance Association), 2007. Volume of Use Survey, February
2007.
Iwersen, S., Schmoldt, A., 1995. ADH Independent metabolism of aliphatic alcohols:
comparison of oxidation and glucuronidation. Adv. Forensic Sci. 13 (4), 19–22.
JECFA, 2004. Safety evaluation of certain food additives. Aliphatic branched-chain
saturated and unsaturated alcohols, aldehydes, acids, and related esters.
Prepared by the Joint FAO/WHO Expert Committee on Food Additives (JECFA).
WHO Food Additives Series: 52. IPCS, WHO, Geneva.
Kamil, I.A., Smith, J.N., Williams, R.T., 1953. Studies in detoxication. 46. The
metabolism of aliphatic alcohols. The glucuronic acid conjugation of acyclic
aliphatic alcohols. Biochem. J. 53, 129–136.
Kreja, L., Seidel, H.J., 2001. Toxicology study of some often detected microbial
volatile organic compounds (MVOC). Umweltmed Forsch Prax. 6 (3), 159–163.
Kreja, L., Seidel, H.J., 2002a. Evaluation of the genotoxic potential of some microbial
volatile organic compounds (MVOC) with the comet assay, the micronucleus
assay and the HPRT gene mutation assay. Mutat. Res. 513 (1–2), 143–150.
Kreja, L., Seidel, H.J., 2002b. On the cytotoxicity of some microbial volatile organic
compounds as studied in the human lung cell line A549. Chemosphere 49 (1),
105–110.
Nakajima, D., Ishii, R., Kageyama, S., Onji, Y., Mineki, S., Morooka, N., Takatori, K.,
Goto, S., 2006. Genotoxicity of microbial volatile organic compounds. J. Health
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(LD50-value) of organic chemicals to mammals by solubility parameter (delta).
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on 2-methylbutanol. Unpublished report from BASF, Report number 55366.
RIFM, Woodcliff Lake, NJ, USA.
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oral toxicity of 2-methylbutanol in rats. Unpublished report from BASF, Report
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Food and Chemical Toxicology 48 (2010) S102–S109
Contents lists available at ScienceDirect
Food and Chemical Toxicology
journal homepage: www.elsevier.com/locate/foodchemtox
Review
Fragrance materials review on isoamyl alcohol
D. McGinty * , A. Lapczynski, J. Scognamiglio, C.S. Letizia, A.M. Api
Research Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
article
Keywords:
Review
Frangrance
info
abstract
A toxicologic and dermatologic review of isoamyl alcohol when used as a fragrance ingredient is presented.
Isoamyl alcohol is a member of the fragrance structural group branched chain saturated alcohols.
The common characteristic structural elements of the alcohols with saturated branched chain are one
hydroxyl group per molecule, and a C 4 –C 12 carbon chain with one or several methyl side chains. This
review contains a detailed summary of all available toxicology and dermatology papers that are related
to this individual fragrance ingredient and is not intended as a stand-alone document. A safety assessment
of the entire branched chain saturated alcohol group will be published simultaneously with this
document; please refer to Belsito et al. (2010) for an overall assessment of the safe use of this material
and all other branched chain saturated alcohols in fragrances.
Ó 2010 Published by Elsevier Ltd.
Contents
Introduction ....................................................................................................... S103
1. Identification . . . . . . . . . . . . . . . ....................................................................................... S103
2. Physical properties . . . . . . . . . . . ....................................................................................... S103
3. Usage. . . . . . ....................................................................................................... S103
4. Toxicology data . . . . . . . . . . . . . ....................................................................................... S104
4.1. Acute toxicity (see Table 2). ................................................................................... S104
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S104
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105
4.1.3. Intravenous studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105
4.1.4. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105
4.2. Skin irritation . . . ............................................................................................ S105
4.2.1. Human studies (see Table 3). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105
4.2.2. Animal studies (see Table 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105
4.3. Mucous membrane (eye) irritation. ............................................................................. S105
4.4. Skin sensitization ............................................................................................ S105
4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105
4.4.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105
4.5. Phototoxicity and photoallergy. ................................................................................ S105
4.6. Absorption, distribution, and metabolism ........................................................................ S105
4.6.1. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105
4.6.2. Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S106
4.7. Repeated dose toxicity. . ...................................................................................... S106
4.7.1. Subchronic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S106
4.7.2. Chronic studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S106
4.8. Reproductive and developmental ............................................................................... S107
4.9. Genotoxicity ................................................................................................ S107
4.9.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S107
4.9.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S107
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.
E-mail address: dmcginty@RIFM.org (D. McGinty).
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.fct.2010.05.040

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S102–S109 S103
4.10. Carcinogenicity . . ............................................................................................ S107
4.11. Neurotoxicity. ............................................................................................... S108
Conflict of interest statement . . . . . . . . ................................................................................. S108
References . . . . .................................................................................................... S108
Introduction
This document provides a comprehensive summary of the toxicologic
review of isoamyl alcohol when used as a fragrance ingredient
including all human health endpoints. Isoamyl alcohol (see
Fig. 1; CAS Number 123-51-3) is a fragrance ingredient used in cosmetics,
fine fragrances, shampoos, toilet soaps, and other toiletries
as well as in non-cosmetic products such as household cleaners
and detergents. It is a colorless liquid with a disagreeable alcohol
odor only becoming a pleasant fruity-winey odor at high dilutions
(Arctander, 1969). This material has been reported to occur in nature,
with the highest quantities observed in the brassica species of
mustard (VCF, 2009).
In 2006, a complete literature search was conducted on isoamyl
alcohol. On-line toxicological databases were searched including
those from the Chemical Abstract Services [e.g. ToxCenter (which
in itself contains 18 databases including Chemical Abstracts)],
and the National Library of Medicine [e.g. Medline, Toxnet (which
contains 14 databases)] as well as 26 additional sources (e.g. BIO-
SIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance companies
were asked to submit all test data.
The safety data on this material was last reviewed by Opdyke
(1979). All relevant references are included in this document. More
details have been provided for unpublished data. The number of
animals, sex, and strain are always provided unless they are not given
in the original report or paper. Any papers in which the vehicles
and/or the doses are not given have not been included in this
review. In addition, diagnostic patch test data with fewer than 100
consecutive patients have been omitted.
Fig. 1. Isoamyl alcohol.
1. Identification
1.1. Synonyms: 1-butanol, 3-methyl-; isobutyl carbinol; isopentanol;
isopentyl alcohol; 3-methyl-1-butanol; 3-methylbutan-1-ol.
1.2. CAS Registry Number: 123-51-3.
1.3. EINECS Number: 204-633-5.
1.4. Formula: C 5 H 12 O.
1.5. Molecular weight: 88.15.
1.6. Council of Europe (2000): isoamyl alcohol was included by
the Council of Europe in the list of substances granted A –
may be used in foodstuffs (COE Number 51).
1.7. FDA: isoamyl alcohol was approved by the FDA as flavor (21
CFR 172.515).
1.8. FEMA (1965): Flavor and Extract Manufacturers’ Association
states: Generally Recognized as Safe as a flavor ingredient –
GRAS 3 (2057).
1.9. JECFA (1996): the Joint FAO/WHO Expert Committee on
Food Additives (JECFA) concluded that the substance does
not present a safety concern at current levels of intake when
used as a flavoring agent (52).
1.10. OSHA: isoamyl alcohol was listed by the Occupational Safety
and Health Administration as PEL-TWA 100 ppm, 360 mg/
m 3 (for primary and secondary).
2. Physical properties
2.1. Physical form: colorless liquid with a disagreeable alcohol
odor and pungent, repulsive taste.
2.2. Flash point: 109 °F; CC.
2.3. Boiling point: 132 °C.
2.4. Henry’s law (calculated; EPA, 2010): 0.0000133 atm m 3 /mol
(25 °C).
2.5. Log K ow (measured; EPA, 2010): 1.16.
2.6. Specific gravity: 0.81.
2.7. Refractive index: 1.4.
2.8. Vapor pressure (calculated; EPA, 2010): 3.84 mm Hg at
(25 °C); 512 Pa (25 °C).
2.9. Water solubility (calculated; EPA, 2010): 41,580 mg/l at
25 °C.
2.10. UV spectra available at RIFM. Does not absorb UV light.
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing isoamyl alcohol.
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient (mg/kg/day) b
Anti-perspirant 0.5 1 1 0.01 0.01 0.000001
Bath products 17 0.29 0.001 0.02 0.01 0.000001
Body lotion 8 0.71 1 0.004 0.01 0.000001
Eau de toilette 0.75 1 1 0.08 0.01 0.000100
Face cream 0.8 2 1 0.003 0.01 0.000001
Fragrance cream 5 0.29 1 0.04 0.01 0.000100
Hair spray 5 2 0.01 0.005 0.01 0.000001
Shampoo 8 1 0.01 0.005 0.01 0.000001
Shower gel 5 1.07 0.01 0.012 0.01 0.000001
Toilet soap 0.8 6 0.01 0.015 0.01 0.000001
Total 0.0002
a
b
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.
Based on a 60-kg adult.

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D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S102–S109
Table 2
Summary of acute toxicity studies.
Route Species Number
of animals/
dose group
3. Usage
LD 50 (g/kg)
References
Oral Mice 4 >2.0 RIFM (2008)
Oral Rat N/A 4.36 Golovinskaya (1976)
Oral Rat N/A 1.3 Nishimura et al. (1994)
Oral Rat 4 1.3 (male) Purchase (1969)
4.0 (female)
Oral Rat 5 7.1 Smyth et al. (1969)
Oral Rat N/A >5.0 RIFM (1979)
Oral Rabbit 10–35 3.44 Munch (1972)
Dermal Rabbit 10 >5.0 RIFM (1976a)
Dermal Rabbit 4 3.97 Smyth et al. (1969)
Dermal Rabbit 6 4.0 RIFM (1979)
Intravenous Mice N/A 0.23 Chvapil et al. (1962)
Isoamyl alcohol is a fragrance ingredient used in decorative cosmetics,
fine fragrances, shampoos, toilet soaps, and other toiletries
as well as in non-cosmetic products such as household cleaners
and detergents. Its use worldwide is in the region 0.1–1.0 metric
tons/annum (IFRA, 2004). The reported volume of use is for isoamyl
alcohol as used in fragrance compounds (mixtures) in all finished
consumer product categories. The volume of use is surveyed
by IFRA approximately every four years through a comprehensive
survey of IFRA and RIFM member companies. As such the volume
of use data from this survey provides volume of use of fragrance
ingredients for the majority of the fragrance industry.
The dermal systemic exposure in cosmetic products (see Table 1)
is calculated based on the concentrations of the same fragrance
ingredient in 10 types of the most frequently used personal care
and cosmetic products (anti-perspirant, bath products, body lotion,
eau de toilette, face cream, fragrance cream, hair spray, shampoo,
shower gel, and toilet soap). The concentration of the fragrance
ingredient in fine fragrances is obtained from examination of several
thousand commercial formulations. The upper 97.5 percentile concentration
is calculated from the data obtained. This upper 97.5 percentile
concentration is then used for all 10 consumer products.
These concentrations are multiplied by the amount of product applied,
the number of applications per day for each product type,
and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account for
the length of time a product may remain on the skin and/or likelihood
of the fragrance ingredient being removed by washing. The
resultant calculation represents the total consumer exposure (mg/
kg/day) (Cadby et al., 2002; Ford et al., 2000).
This is a conservative calculation of dermal systemic exposure
because it makes the unlikely assumption that a consumer will
use these 10 products containing; which are all perfumed with
the upper 97.5 percentile level of the fragrance ingredient from a
fine fragrance type of product (Cadby et al., 2002; Ford et al.,
2000). The 97.5 percentile use level in formulae for use in cosmetics
in general has been reported to be 0.01% (IFRA, 2007), which
would result in a conservative calculated maximum daily exposure
on the skin of 0.0002 mg/kg for high end users of these products
(see Table 1).
A maximum skin level is then determined for consideration of
potential sensitization. The exposure is calculated as the percent
concentration of the fragrance ingredient applied to the skin based
on the use of 20% of the fragrance mixture in the fine fragrance
consumer product (IFRA, 2007). The maximum skin level that results
from the use of isoamyl alcohol in formulae that go into fine
fragrances has been reported to be 0.012% (IFRA, 2007), assuming
use of the fragrance oil at levels up to 20% in the final product.
4. Toxicology data
4.1. Acute toxicity (see Table 2)
4.1.1. Oral studies
As a preliminary study for a mouse micronucleus test, acute oral
toxicity was evaluated with four (2/sex) animals. The NMRI mice
were treated orally with the 0.1, 0.5, 1.0, or 2.0 g/kg of isoamyl
alcohol and examined for acute toxic symptoms at intervals of
around 1, 2–4, 6, 24, 30, and 48 h after administration. At the highest
dose of 2.0 g/kg bodyweight the toxic effects observed were a
reduction in spontaneous activity, eyelid closure, and ruffled fur.
No mortality was observed at the highest dose which indicated
the LD 50 to be greater than 2.0 g/kg (RIFM, 2008).
The acute oral LD 50 of isoamyl alcohol in rats was reported to be
4.36 g/kg (no further details provided) (Golovinskaya, 1976).
The oral LD 50 of isoamyl alcohol in rats was reported to be 1.3 g/
kg (no further details provided) (Nishimura et al., 1994).
The acute oral (gavage) LD 50 was evaluated in groups of 4 rats
with isoamyl alcohol at a dose range of 0.325–4.95 and 0.81–
12.0 g/kg (concentration not reported) in polyethylene glycol 200
for male and female, respectively. Deaths in female rats occurred
4 h after high doses (4.95 and 12.0 g/kg); none died in the 10 days
after the lower doses (0.81 and 2.0 g/kg). Males receiving the highest
doses of 4.95 g/kg and a group receiving 12.0 g/kg died within
4 h, and several at the lower doses of 0.81 and 2.0 g/kg died
1–5 days later. Histological examination of the liver revealed
hyperemia but very few degenerative changes. Females receiving
4.95 g/kg showed cloudy swelling and cast formation in the cortex
Table 3
Summary of human skin irritation studies.
Method Concentration Results References
Reactions Frequency (%)
48 h closed patch test 8% in petrolatum 0/25 0 RIFM (1976b)
5 min, occlusive patch test 75% in water 12/12 100 Wilkin and Fortner (1985a)
5 min, occlusive patch test 75% in water 3/3 100 Wilkin and Fortner (1985b)
5 min, occlusive patch test 75% in a hydrophilic ointment 12/12 100 Wilkin and Stewart (1987)
Table 4
Summary of animal irritation studies.
Method Dose (%) Species Reactions References
Single application of 5.0 g/kg 100 Rabbit Marked erythema and moderate edema RIFM (1976)
0.01 ml aliquot applied to the clipped skin 100 Rabbit Irritation observed Smyth et al. (1969)
Single application 100 Rabbit Very irritating RIFM (1979)

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S102–S109 S105
and a few pyknotic tubular cells in the medulla section of the kidney.
In females receiving 12.0 g/kg, the cortex showed signs of
necrosis with some tubular cells showing pyknosis. In males pyknosis
and hyperemia were seen in the outer zone of the medulla
in all groups, and tubular necrosis was seen in the cortex after
the two highest doses (2.0 and 4.95 g/kg). The calculated LD 50
was 4.0 g/kg (95% limits: 2.45–6.17 g/kg) for female and 1.3 g/kg
(95% limits: 0.67–2.41 g/kg) for male (Purchase, 1969).
Groups of five Carworth-Wistar male rats were administered a
single dose of undiluted isoamyl alcohol by gavage. The oral LD 50
of was reported to be 7.1 g/kg with limits of 4.82–10.4 g/kg (Smyth
et al., 1969).
Isoamyl alcohol was reported to have an LD 50 greater than 5.0 g/
kg in Sprague Dawley rats. The animals were given doses of 2.15 or
5.0 g/kg and observed for 14 days (RIFM, 1979).
The acute oral (gavage) LD 50 of isoamyl alcohol was reported to
be 39 mmol/kg (3.45 g/kg). Administration was via stomach tube
from a 50 ml syringe to groups of 10–35 rabbits (Munch, 1972).
4.1.2. Dermal studies
The acute dermal LD 50 of isoamyl alcohol was evaluated in 10
rabbits. Each animal received a single dermal application of undiluted
isoamyl alcohol at a dose of 5.0 g/kg. Clinical signs and/or
mortality were observed over a 14 day period. No deaths were observed.
Clinical signs included flaccidity, ataxia, loss of righting reflex
and diarrhea. The LD 50 was reported to be greater than 5.0 g/kg
(RIFM, 1976a).
The acute dermal LD 50 was evaluated in groups of four male albino
New Zealand rabbits. Undiluted isoamyl alcohol at 0.1 ml was
applied to the clipped trunk, and kept in place beneath an impervious
plastic film for 24 h (doses and skin area not provided). The
LD 50 was reported to be 3.97 g/kg with limits of 2.93–5.37 g/kg
(Smyth et al., 1969).
Isoamyl alcohol was reported to have a dermal LD 50 of 4 ml/kg
(4 g/kg) in rabbits. The animals were given undiluted doses of
isoamyl alcohol and observed for 8 days (RIFM, 1979).
4.1.3. Intravenous studies
The intravenous LD 50 of isoamyl alcohol in water was determined
in female white H strain mice. Using an approximate graphic
probit method, the LD 50 was calculated to be 2.64 mmol/kg
(233 mg/kg; no further details provided) (Chvapil et al., 1962).
The hemodynamic effects of isoamyl alcohol were studied in 56
anesthetized, open chest dogs. The material was administered i.v.
at a constant rate for 40–150 min. The infusion of 20 mg/kg/min
decreased heart rate, systemic arterial pressure, and myocardial
contraction force progressively and markedly. All dogs died during
the first hour of infusion (Nakano and Kessinger, 1972).
Isoamyl alcohol was injected into the vein of cat, under a light
ether anesthesia, to determine the lethal dose. In terms of the pure
alcohol of 0.26 ml/kg (260 mg/kg) was determined to be lethal
(Macht, 1920).
4.1.4. Inhalation studies
Smyth et al. (1969) reported no death up to 8 h when concentrated
vapors of isoamyl alcohol were exposed to rats by
inhalation.
Sensory irritation was evaluated in four Swiss male mice via
measurement of changes in respiratory rate during a 10 min exposure
to isoamyl alcohol. The concentration of isoamyl alcohol that
caused a 50% decrease in the respiratory rate (RD 50 ) of mice was
4452 ppm with 95% confidence limits of 2885–12,459 (Kane
et al., 1980).
Rats inhaled isoamyl alcohol as a steam vapor in an enriched
atmosphere at 20 °C. After a 7 h exposure, no animals died (RIFM,
1979).
4.2. Skin irritation
4.2.1. Human studies (see Table 3)
In a pre-test for a human maximization study, a 48 h closed
patch test was conducted on the volar forearms or backs of 25 volunteers
with 8% isoamyl alcohol in petrolatum. No irritation was
observed (RIFM, 1976b).
Patch tests were conducted on 27 (groups of 12, 12, and 3)
healthy volunteers with 75% aqueous solution of isoamyl alcohol.
Patches were applied to the subjects’ forearms, and were removed
after being occluded for 5 min. Irritation reactions were observed
in all volunteers (Wilkin and Fortner, 1985a,b; Wilkin and Stewart,
1987).
4.2.2. Animal studies (see Table 4)
Irritation was evaluated during a dermal LD 50 study. A single
application of 5.0 g/kg of neat isoamyl alcohol was made to 10 rabbits.
Marked or moderate edema were observed in 10/10 rabbits
(RIFM, 1976a).
Primary skin irritation was determined using groups of five albino
rabbits. A 0.01 ml aliquot of isoamyl alcohol was applied to
the clipped skin of the animals undiluted or as a solution in water,
propylene glycol or acetone. Irritation reactions were observed
(Smyth et al., 1969).
Isoamyl alcohol was reported to be very irritating when applied
undiluted to the skin of six rabbits. Irritation resolved after 8 days
(RIFM, 1979).
4.3. Mucous membrane (eye) irritation
An eye irritation test was conducted in five rabbits per dose. Isoamyl
alcohol (0.5 ml aliquot) was tested undiluted or as a solution
in propylene glycol and water. Irritant effects were observed
(Smyth et al., 1969).
An eye irritation test was conducted in two rabbits with undiluted
isoamyl alcohol. Irritation was observed up to 8 days in one
rabbit (RIFM, 1979).
4.4. Skin sensitization
4.4.1. Human studies
A maximization study was conducted on 25 (5 male, 20 female)
volunteers. Isoamyl alcohol at 8% in petrolatum was applied under
occlusion to the volar forearms or backs for five alternate days,
48 h periods. The sites were pre-treated for 24 h with 2.5% aqueous
sodium lauryl sulfate (SLS) under occlusion. The challenge phase
was conducted after a rest period of 10–14 days at sites pre-treated
for 1 h with 5–10% SLS. The challenge patch was removed after
48 h, and the site was read at the patch removal and 24 h after
the patch removal. No reactions were observed (RIFM, 1976b).
4.4.2. Animal studies
No data available.
4.5. Phototoxicity and photoallergy
No data available.
4.6. Absorption, distribution, and metabolism
4.6.1. Distribution
4.6.1.1. Human studies. Respiratory uptake of isoamyl alcohol was
investigated in four healthy volunteers. Test air concentration
was 25–200 ppm and it was inhaled for 10 min. The mean uptake
(determined using calculations based on exhalation percentages of
isoamyl alcohol to mixed exhaled air) for the last 5 min of the test

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D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S102–S109
respiration was 63% and the mean respiratory rate was 15.3 min 1
(Kumagai et al., 1998).
4.6.1.2. Animal studies. Groups of 10 rats per dose received 600 mg
of 20% isoamyl alcohol/l solution (either in ethanol or water) by
intraperitoneal injection in four equally divided portions of
2.5 ml/100 g of bodyweight, at 15 min intervals. Two hours after
administration, the blood concentration of isoamyl alcohol with
ethanol was maximal. It declined thereafter and was still detectable
at 10 h but not at 12 h. When isoamyl alcohol was administered
in water, its presence in the blood was discernible 2 h after
administration but not thereafter (Greenberg, 1970).
A single dose of 2.0 g/kg of isoamyl alcohol, in an aqueous solution
of 20%, was given orally to fasted six Wistar WAG rats. Blood
and urine were collected for up to 8 h for measurement of test
material levels. The blood level in mg/100 ml was 7 at 15 min, 9
at 30 min, 17 at 1 h, 8 at 1.5 h, 7 at 2 h, 3 at 4 h, and 1 at 8 h. Urinary
excretion was 0 (Gaillard and Derache, 1965).
After intraperitoneal administration of 1000 mg bodyweight,
the concentration of isoamyl alcohol in blood declined within 5 h
to non-detectable levels. An elimination half-life was not calculated.
For isoamyl alcohol 1.2% was excreted via urine and expired
air. Compared to other amyl alcohols tested by the authors, primary
alcohols were eliminated from the blood more quickly than
secondary and tertiary alcohols (Haggard et al., 1945).
4.6.2. Metabolism
4.6.2.1. Human studies. The glucuronidation of isoamyl alcohol and
other short-chained aliphatic alcohols was investigated in vitro
with human liver microsomes. The V max value was 3.3 nmol/min/
mg protein and the Km was determined as 13.3 mM. The glucuronidation
increased with chain length (C 2 –C 5 ) of the alcohols studied
(Jurowich et al., 2004).
The rate of oxidation of isoamyl alcohol by human skin alcohol
dehydrogenase was 183.3 nM/mg protein/min (Wilkin and Stewart,
1987).
4.6.2.2. Animal studies. A single oral (gavage) dose of 25 mmol/3 kg
rabbit (734.6 mg/kg) of isoamyl alcohol in water was given to
three chinchilla rabbits. Increases in the urinary excretion of glucuronides
were monitored. Of the dose, 9% was excreted in the urine
(at 24 h) as the glucuronide. The urine did not contain aldehydes or
ketones (Kamil et al., 1953).
In isolated perfused livers of rats, 65.1 mmol isoamyl alcohol/l
were cytotoxic as evidenced by the release of liver enzymes into
the perfusate. The alcohols decreased the content of ATP in the liver.
The content of oxidized glutathione was increased. Lipid peroxidation
was not observed (Strubelt et al., 1999).
Age-dependent glucuronidation activity was demonstrated
in vitro in the olfactory mucosa of 1 day, 1 week, 2 week, 3 month,
12 month, and 24 month old male Wistar rats with isoamyl alcohol
(Leclerc et al., 2002).
Oxidation to the aldehyde and glucuronidation was demonstrated
for isoamyl alcohol with microsomes from rats pre-treated
with ethanol (Iwersen and Schmoldt, 1995).
The rate of oxidative metabolism of isoamyl alcohol was about
0.1 mmol/g liver in rat liver homogenate and about 0.05 mM/g perfused
rat liver (Hedlund and Kiessling, 1969).
The Km-values of isoamyl alcohol with alcohol dehydrogenase
from human and horse liver were 0.07 and 0.08 mM, respectively
(Pietruszko et al., 1973).
4.7. Repeated dose toxicity
4.7.1. Subchronic studies
Groups of 10 Ash/CSE rats (5/sex) were administered 500 or
1000 mg/kg of isoamyl alcohol dissolved in corn oil by gavage,
7 days a week for 6 weeks. A group of 10 controls (5/sex) were
administered corn oil alone. Observations included mortality,
behavior, bodyweight, food and water consumption, renal concentration,
organ weights, and gross pathology. Blood was examined
for hemoglobin content, packed cell volume, and counts of erythrocytes,
reticulocytes, as well as total and differential leukocytes. Serum
was analyzed for the content of urea, glucose, total protein, and
albumin as well as activities of glutanic–oxalacetic and glutamic–
pyruvic trasaminases and lactic dehydrogenase. With 500 mg/kg,
a significant increase in the hemoglobin concentration and red
blood cell count of test females was observed when compared to
the controls, but the increases were not dose-related. With
1000 mg/kg, a lower pituitary weight in males was observed, but
when expressed relative to bodyweight, the decrease was not evident.
At both doses, red patches on the lungs of male and female
treated animals and control animals were found at the necropsy.
Histopathological examination of the lungs revealed lymphocyte
cuffing of the bronchi, but the incidence and severity were similar
in both the test and control animals. The authors have concluded
the NOAEL to be 1000 mg/kg in females and 500 mg/kg in males
(Carpanini et al., 1973).
Groups of 20 SPF-Wistar, Chbb:THOM rats (10/sex) were
administered isoamyl alcohol in drinking water at 1000 ppm
(80 mg/kg), 4000 ppm (320 mg/kg), and 16,000 ppm
(1280 mg/kg) for 90 days. A group of 20 controls (10/sex) were
administered drinking water alone. Parameters evaluated included
bodyweight, food and water consumption, clinical signs, mortality,
hematology, clinical chemistry, gross and microscopic pathology.
The erythrocyte count was slightly elevated in males treated with
4000 ppm (320 mg/kg). With 16,000 ppm (1280 mg/kg), an increase
in the erythrocyte count, a decrease in the mean corpuscular
volume, and a decrease in the mean corpuscular hemoglobin content
of the blood in male rats were observed. Compared to the controls,
a significant deviation from the control group leukocyte
count was observed in males at 1000 ppm (80 mg/kg), and in the
prothrombin time in females treated with 4000 and 16,000 ppm
(320 and 1280 mg/kg). However, these observed effects did not appear
to be relevant to the treatment. Ectopia of thymus tissue in
the region of the thyroid gland was observed in five males treated
with 16,000 ppm (1680 mg/kg). The no-observable-adverse-effectlevel
(NOAEL) of isoamyl alcohol was concluded to be 4000 ppm
(320 mg/kg) in males and 16,000 ppm (1680 mg/kg) in females
(Schilling et al., 1997; RIFM, 1991).
4.7.2. Chronic studies
Groups of 30 Ash/CSE rats (15/sex) were administered 150, 500,
and 1000 mg/kg of isoamyl alcohol dissolved in corn oil by gavage,
7 days a week for 17 weeks. A group of 30 controls (15/sex) were
administered corn oil alone. Observations included mortality,
behavior, bodyweight, food and water consumption, hematology,
serum analysis, urinalysis, renal concentration, organ weights,
and gross pathology. Microscopic pathology was examined for
the highest dose only. There were no effects associated with treatment
in the results of the hematological examinations, serum analyses,
urinary cell counts, renal concentration tests, or organ
weights. A slight reduced rate of bodyweight gain at the highest
dose level was shown to be due to a reduced food intake. Two rats
in the highest dose level died, but histopathological examination
showed that these deaths were due to dosing into the lungs and
not to any toxic effects of isoamyl alcohol. A female rat given
500 mg/kg/day developed a lipoma, which was not considered to

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S102–S109 S107
be due to treatment. The other histopathological changes seen
were related to mild infections in the animals and not to isoamyl
alcohol. The NOAEL was concluded to be 1000 mg/kg/day (Carpanini
et al., 1973).
Astill et al. (1996) gave 0 (water), 0 (vehicle), 50, 200, or
750 mg/kg bodyweight/day in 0.005% cremophor EL to B6C3F1
mice (50/sex). For 18 months, 5 days a week, animals were treated
with isoamyl alcohol by gavage. Increased mortality, and decreases
in bodyweight gains, and food consumption were observed at
750 mg/kg as well as fatty liver and hyperplasia of the forestomach
epithelium. A systemic NOAEL of 200 mg/kg bodyweight was
determined.
4.8. Reproductive and developmental
Groups of 25 pregnant rats were exposed to a vapor–air mixture
of isoamyl alcohol at concentrations of 0.5, 2.5, and 10 mg/l, 6 h/
day from gestation day (GD) 6–15. In rats exposed to 10 mg/l bodyweight
gain was decreased between GD 6 and 9 and increased between
GD 12–15, however no biologically relevant or
concentration related differences were apparent among the
groups. At 0.5 mg/l fetal examination revealed skeletal changes:
malformations of the sternebrae and/or the vertebral column. With
2.5 mg/l, the observed fetal anomalies included soft tissue changes
such as a globular shaped heart and dextrocardia, and skeletal
changes: malformations of the sternebrae and/or the vertebral column.
At 10 mg/l observed fetal anomalies included external
changes such as polydactyly and skeletal changes: malformations
of the sternebrae and/or the vertebral column. With all the tested
concentrations, retardations such as incomplete or missing ossification
of hyoid, skull bones, metacarpal or metatarsal bones, vertebral
bodies, and/or sternebrae were observed. The NOAEL for dams
was 2.5 and 10 mg/l for the fetuses (Klimisch and Hellwig, 1995;
RIFM, 1990a).
As a part of the same experiment, groups of 15 pregnant Himalayan
rabbits Chbbb:HM per dose were exposed to 0.5, 2.5, and
10 mg/l isoamyl alcohol on gestation days 7–19. At 10 mg/l a slight
retardation of bodyweight increase was observed throughout the
whole exposure period and was significant on GD 7–10. Also, at
10 mg/l an indication of an irritant eye effect (reddish, lid closure,
or slight discharge) was also observed during the exposure period.
In fetuses pseudoankylosis and soft tissue changes such as hypoplasia
of the gall bladder, bipartite ovary, dilated renal pelvis,
and/or separate origin of carotids were observed at all doses. However,
it was noted that these findings occurred at a similar incidence
rate in historical controls. Observed skeletal changes
included malformations of the sternebrae and/or the vertebral column,
the sternum and the ribs. They were seen in all groups without
apparent dose relationships or statistically significant
differences between the groups. The only significant differences
of note were due to the increased incidence of two specific types
of soft tissue variation (the separated origin of carotids and traces
of interventricular foramen/septum membranaceum) which occurred
without a clear concentration relationship. The NOAEL for
dams was 2.5 and 10 mg/l for the fetuses (Klimisch and Hellwig,
1995; RIFM, 1990b).
4.9. Genotoxicity
4.9.1. In vitro studies
4.9.1.1. Bacterial test systems. Isoamyl alcohol was negative in a
umu test for light absorption in Salmonella typhimurium TA1535/
pSK1002 at concentrations in which growth inhibition was 650%.
However, isoamyl alcohol was positive when tested in a umu test
for luminescence with S. typhimurium TA1535/pTL210 at concentrations
in which growth inhibition was 650% (Nakajima et al.,
2006).
4.9.1.2. Studies in mammalian cells (see Table 5). A Comet assay was
conducted on human lung carcinoma A549 cells and human
peripheral blood pB cells. Induced DNA damage was only observed
at cytotoxic concentrations of isoamyl alcohol such as 23, 46, and
91 mM (Kreja and Seidel, 2002).
An alkaline single cell gel electrophorese assay (comet assay)
was conducted on Chinese hamster V79 fibroblasts, and DNA damage
induced by isoamyl alcohol was observed at cytotoxic concentrations
of 23, 46, and 91 mM (Kreja and Seidel, 2002).
A micronucleus assay was conducted on Chinese hamster fibroblast
V79 cells, with isoamyl alcohol at concentrations of 5, 9, and
23 mM in the presence and absence of metabolic activation (S9).
No genotoxic effects were produced at any of the tested concentrations
(Kreja and Seidel, 2002).
No mutagenicity was produced in a hypoxanthine–guanine
phosphoribosyltransferase (HPRT) assay conducted on Chinese
hamster lung fibroblast cell line V79, with 51.5 mM of isoamyl
alcohol in the presence or absence of metabolic activation (S9)
(Kreja and Seidel, 2002).
4.9.2. In vivo studies
An in vivo micronucleus assay was conducted with bone marrow
cells of NMRI mice with isoamyl alcohol at doses of 500,
1000, and 2000 mg/kg. Ten animals (5/sex) were evaluated at 24
and 48 h after a single administration for the occurrence of micronuclei.
There was no increase in the frequency of detected micronuclei.
Isoamyl alcohol was determined to be non-mutagenic in
the micronucleus assay (RIFM, 2008).
4.10. Carcinogenicity
A group of 15 Wistar rats were administered 0.1 ml/kg (0.1 g/
kg) of isoamyl alcohol by gavage, twice a week up to the time of
their spontaneous deaths. The average total dosage was 27 ml
(27 g). The 25 controls were treated with 1 ml/kg (1 g/kg) of a
0.9% NaCl solution, twice weekly. The animals were weighed at
regular intervals, and most were subjected to hematological testing.
At the time of spontaneous death, a necropsy, histological
examinations of all organs, vertebrae, and femur, and additional
hematological tests were conducted. The average survival time of
the control animals was 643 days. A wide spectrum of tumors
was observed from bladder carcinoma, carcinoma of the kidney
pelvis, adenocarcinoma of the proventriculum to benign tumors
such as papillomae and occasional incipient infiltrative growth.
The number of malignant and benign tumors found was 0 and 3,
Table 5
Summary of studies in mammalian cells.
Test system Concentration (mM) Results References
Comet assay Human lung carcinoma A549 cells 23, 46, and 91 Not genotoxic Kreja and Seidel (2002)
Comet assay Human lung peripheral blood pB cells 46 and 91 Not genotoxic Kreja and Seidel (2002)
Comet assay Chinese hamster fibroblast V79 cells 23 and 91 Not genotoxic Kreja and Seidel (2002)
Micronucleus assay Chinese hamster fibroblast V79 cells 5, 9, and 23 Not genotoxic Kreja and Seidel (2002)
HPRT assay Chinese hamster lunch fibroblast V79 cells 51.5 Not genotoxic Kreja and Seidel (2002)

S108
D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S102–S109
respectively. The average survival time of test animals was
527 days, and the number of malignant and benign tumors found
was 4 and 3, respectively (Gibel et al., 1975).
As a part of the same experiment group of 24 Wistar rats were
subcutaneously administered 0.04 ml/kg (0.04 g/kg) of isoamyl
alcohol, once a week up to the time of their spontaneous deaths.
The average total dosage was 3.8 ml (3.8 g/kg). The controls were
subcutaneously treated with 1 ml/kg (1 g/kg) of a 0.9% NaCl solution,
twice weekly. The average survival time of the control animals
was 643 days, and the number of malignant and benign
tumors found was 0 and 2, respectively. The average survival time
of test animals was 592 days, and the number of malignant and benign
tumors found was 10 and 5, respectively. The tumors consisted
of pancreas adenomas, adenomas of the proventriculus
and of suprarenal glands, spleen fibromas to the benign small papillomas
or fibroadenomas (Gibel et al., 1975).
4.11. Neurotoxicity
Male albino SPF rats derived from the Wistar strain, or female
mice of the H strain were used to study the neurotoxicity of isoamyl
alcohol. Whole body exposures were carried out in 80-l glass
chambers with 1 rat or 2 mice. In total 16 rats (4/group) or 32 mice
were exposed. Less than 1 min after removal from the exposure
box, a short electrical impulse was applied through ear electrodes
to the animals to measure the biological effect of isoamyl alcohol.
Of the six time characteristics recorded, duration of toxic extension
of hind limbs was measured, as this was considered the most sensitive
and reproducible response measures. All animals were given
three control tests at weekly intervals before the 1st exposure.
Most animals went through 3–4 exposure to each concentration,
and the interval between exposures was at least 3 weeks. The concentration
that evoked a 30% depression in the recorded activity
(M) was determined to be 1700 ppm in rats and 950 ppm in mice
(Frantik et al., 1994).
Male Sprague–Dawley rats were divided into groups of four or
five and orally administered 325 mg/kg of isoamyl alcohol. Two
hours after administration acetylcholine, 3,4-dihydroxyphenylalanine
(DOPA), dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC),
homovanillic acid (HVA), norepinephrine, 3-methoxy-4-hydroxyphenylglycol
(MHPG), serotonin, and 5-hydroxyindoleacetic acid
(5HIAA) contents in the small-brain regions were measured. Under
the conditions of this study, a single dose of 325 mg/kg administered
by gavage to rats resulted in increases in 5HIAA in the midbrain
and MHPG in the medulla oblongata. Decreases occurred in
norepinephrine in the midbrain and in 5HIAA in the hypothalamus
(Kanada et al., 1994).
This individual Fragrance Material Review is not intended as a
stand-alone document. Please refer to A Safety Assessment of
Branched Chain Saturated Alcohols When Used as Fragrance Ingredients
(Belsito et al., 2010) for an overall assessment of this
material.
Conflict of interest statement
This research was supported by the Research Institute for Fragrance
Materials, an independent research institute that is funded
by the manufacturers of fragrances and consumer products containing
fragrances. The authors are all employees of the Research
Institute for Fragrance Materials.
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Food and Chemical Toxicology 48 (2010) S110–S114
Contents lists available at ScienceDirect
Food and Chemical Toxicology
journal homepage: www.elsevier.com/locate/foodchemtox
Review
Fragrance material review on 2,6-dimethyl-2-heptanol
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api
Research Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
article
Keywords:
Review
Fragrance
info
abstract
A toxicologic and dermatologic review of 2,6-dimethyl-2-heptanol when used as a fragrance ingredient is
presented. 2,6-Dimethyl-2-heptanol is a member of the fragrance structural group branched chain saturated
alcohols. The common characteristic structural elements of the alcohols with saturated branched
chain are one hydroxyl group per molecule, and a C 4 –C 12 carbon chain with one or several methyl side
chains. This review contains a detailed summary of all available toxicology and dermatology papers that
are related to this individual fragrance ingredient and is not intended as a stand-alone document. A safety
assessment of the entire branched chain saturated alcohol group will be published simultaneously with
this document; please refer to Belsito et al. (2010) for an overall assessment of the safe use of this material
and all other branched chain saturated alcohols in fragrances.
Ó 2010 Published by Elsevier Ltd.
Contents
Introduction ....................................................................................................... S111
1. Identification . . . . . . . . . . . . . . . ....................................................................................... S111
2. Physical properties . . . . . . . . . . . ....................................................................................... S111
3. Usage. . . . . . ....................................................................................................... S111
4. Toxicology data . . . . . . . . . . . . . ....................................................................................... S112
4.1. Acute toxicity (see Table 2). .................................................................................... S112
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S112
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S112
4.2. Skin irritation. ............................................................................................... S112
4.2.1. Human studies (see Table 3). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S112
4.2.2. Animal studies (see Table 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S112
4.3. Mucous membrane (eye) irritation. .............................................................................. S113
4.4. Skin sensitization. ............................................................................................ S113
4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S113
4.4.2. Maximization studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S113
4.4.3. Diagnostic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S113
4.4.4. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S113
4.5. Phototoxicity and photoallergy. . ................................................................................ S113
4.5.1. Phototoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S113
4.5.2. Photoallergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S114
4.6. Absorption, distribution and metabolism ......................................................................... S114
4.7. Repeated dose toxicity . . ...................................................................................... S114
4.8. Reproductive and developmental toxicity ......................................................................... S114
4.9. Genotoxicity. ................................................................................................ S114
4.10. Carcinogenicity . . ............................................................................................ S114
Conflict of interest statement . . ....................................................................................... S114
References . ....................................................................................................... S114
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.
E-mail address: dmcginty@RIFM.org (D. McGinty).
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.fct.2010.05.041

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S110–S114 S111
Introduction
This document provides a summary, including all human health
endpoints, of the toxicologic review of 2,6-dimethyl-2-heptanol
when used as a fragrance ingredient. 2,6-Dimethyl-2-heptanol
(see Fig. 1; CAS Number 13254-34-7) is a fragrance ingredient used
in cosmetics, fine fragrances, shampoos, toilet soaps and other toiletries
as well as in non-cosmetic products such as household
cleaners and detergents. It is a colorless liquid with a fresh, woody,
floral odor.
In 2006, a complete literature search was conducted on 2,6-dimethyl-2-heptanol.
On-line toxicological databases were searched
including those from the Chemical Abstract Services, [e.g., ToxCenter
(which in itself contains 18 databases including Chemical Abstracts)],
and the National Library of Medicine [e.g., Medline,
Toxnet (which contains 14 databases)] as well as 26 additional
sources (e.g., BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance
companies were asked to submit all test data.
The safety data on this material was last reviewed by Ford et al.
(1992). All relevant references are included in this document. More
details have been provided for unpublished data. The number of
animals, sex and strain are always provided unless they are not given
in the original report or paper. Any papers in which the vehicles
and/or the doses are not given have not been included in this
review. In addition, diagnostic patch test data with fewer than 100
consecutive patients have been omitted.
1. Identification
1.1. Synonyms: dimetol; freesiol; 2-heptanol, 2,6-dimethyl-; lolitol;
2,6-dimethylheptan-2-ol.
1.2. CAS Registry number: 13254-34-7.
1.3. EINECS number: 236-244-1.
1.4. Formula: C 9 H 20 O.
1.5. Molecular weight: 144.26.
HO
Fig. 1. 2,6-Dimethyl-2-heptanol.
2. Physical properties
2.1. Physical form: a colorless liquid with a fresh, woody, floral
odor.
2.2. Boiling point (calculated; EPA, 2010): 172.11 °C.
2.3. Flash point: 145°F; CC.
2.4. Henry’s law (calculated; EPA, 2010): 0.0000412 atm m 3 /mol
25 °C.
2.5. Log K ow : 3.0 at 45 °C.
2.6. Refractive index: 1.4259.
2.7. Specific gravity: 0.8135.
2.8. Vapor pressure (calculated; EPA, 2010): 0.2 mm Hg (20 °C);
0.364 mm Hg (25 °C); 48.5 Pa (25 °C).
2.9. Water solubility (calculated; EPA, 2010): 572 mg/l (25 °C).
2.10. UV spectra available at RIFM, does not absorb UV light.
3. Usage
2,6-Dimethyl-2-heptanol is a fragrance ingredient used in many
fragrance compounds. It may be found in fragrances used in decorative
cosmetics, fine fragrances, shampoos, toilet soaps and other
toiletries as well as in non-cosmetic products such as household
cleaners and detergents. Its use worldwide is in the region of 10–
100 metric tons per annum (IFRA, 2004). The reported volume of
use is for 2,6-dimethyl-2-heptanol as used in fragrance compounds
(mixtures) in all finished consumer product categories. The volume
of use is surveyed by IFRA approximately every four years through
a comprehensive survey of IFRA and RIFM member companies. As
such the volume of use data from this survey provides volume of
use of fragrance ingredients for the majority of the fragrance
industry.
The dermal systemic exposure in cosmetic products (see Table 1)
is calculated based on the concentrations of the same fragrance
ingredient in ten types of the most frequently used personal care
and cosmetic products (anti-perspirant, bath products, body lotion,
eau de toilette, face cream, fragrance cream, hair spray, shampoo,
shower gel, and toilet soap). The concentration of the fragrance
ingredient in fine fragrances is obtained from examination of several
thousand commercial formulations. The upper 97.5 percentile concentration
is calculated from the data obtained. This upper 97.5 percentile
concentration is then used for all 10 consumer products.
These concentrations are multiplied by the amount of product applied,
the number of applications per day for each product type,
and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account for
the length of time a product may remain on the skin and/or likelihood
of the fragrance ingredient being removed by washing. The
resultant calculation represents the total consumer exposure (mg/
kg/day) (Cadby et al., 2002; Ford et al., 2000).
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2,6-dimethyl-2-heptanol.
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient mg/kg/day b
Anti-perspirant 0.5 1 1 0.01 2.41 0.00200
Bath products 17 0.29 0.001 0.02 2.41 0.00004
Body lotion 8 0.71 1 0.004 2.41 0.00910
Eau de toilette 0.75 1 1 0.08 2.41 0.02410
Face cream 0.8 2 1 0.003 2.41 0.00190
Fragrance cream 5 0.29 1 0.04 2.41 0.02330
Hair spray 5 2 0.01 0.005 2.41 0.00020
Shampoo 8 1 0.01 0.005 2.41 0.00020
Shower gel 5 1.07 0.01 0.012 2.41 0.00030
Toilet soap 0.8 6 0.01 0.015 2.41 0.00030
Total 0.0614
a
b
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.
Based on a 60-kg adult.

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D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S110–S114
This is a conservative calculation of dermal systemic exposure
because it makes the unlikely assumption that a consumer will
use these 10 products containing; which are all perfumed with
the upper 97.5 percentile level of the fragrance ingredient from a
fine fragrance type of product (Cadby et al., 2002; Ford et al.,
2000). The 97.5 percentile use level in formulae for use in cosmetics
in general has been reported to be 2.41 (IFRA, 2007), which
would result in a maximum daily exposure on the skin of
0.0614 mg/kg for high end users (see Table 1).
A maximum skin level is then determined for consideration of
potential sensitization. The exposure is calculated as the percent
concentration of the fragrance ingredient applied to the skin based
on the use of 20% of the fragrance mixture in the fine fragrance
consumer product (IFRA, 2007). The average maximum use level
in formulae that go into fine fragrances has been reported to be
1.40% (IFRA, 2007), assuming use of the fragrance oil at levels up
to 20% in the final product.
4. Toxicology data
4.1. Acute toxicity (see Table 2)
4.1.1. Oral studies
Ten rats were given a single dose of 2,6-dimethyl-2-heptanol at
5.0 g/kg. Observations for mortality and or systemic effects were
made. At 5.0 g/kg, 2/10 deaths occurred within the first day. Symptoms
observed between 2 and 24 h were lethargy (in 3/8 rats),
ataxia, piloerection (in 2/8 rats), and some loss of righting reflex.
At necropsy two of the rats showed redness through the lungs
and stomach. The acute oral LD 50 in rats was resolved to be greater
than 5.0 g/kg (RIFM, 1976a).
Rats were orally given 2,6-dimethyl-2-heptanol as a 31.6–50%
emulsion in olive oil. Observations for mortality and/or systemic
effects were made. The acute oral LD 50 in rats was calculated to
be greater than 6.8 g/kg (RIFM, 1979).
4.1.2. Dermal studies
The acute LD 50 in rabbits exceeded 5.0 g/kg based on 0 deaths in
10 animals tested at that dose. Ten rabbits received a single dermal
application at a dose level of 5.0 g/kg bodyweight. Mortality and/or
systemic effects were not observed (RIFM, 1976a).
4.2. Skin irritation
Table 2
Summary of acute toxicity studies.
Route Species No. animals/
dose group
LD 50 (g/kg)
References
Oral Rats 10 5.0 RIFM (1976a)
Oral Rats NA 6.8 RIFM (1979)
Dermal Rabbits 10 5.0 RIFM (1976a)
Table 3
Summary of human irritation studies.
Method
Dose
(%)
Vehicle Results References
Maximization 10 Petrolatum No irritation RIFM (1976b)
(pre-test)
Phototoxicity 10 1:1 Ethanol/acetone No irritation RIFM (1983)
(control)
HRIPT (pre-test) 2 Dimethyl phthalate No irritation RIFM (1969)
HRIPT (pre-test) 5 Alcohol SDA 39C No irritation RIFM (1971a)
HRIPT (pre-test) 5 Alcohol SDA 39C No irritation RIFM (1972)
4.2.1. Human studies (see Table 3)
In an irritation screen for a maximization test, 10% 2,6-dimethyl-2-heptanol
in petrolatum was applied to the forearms or
backs of 25 subjects for 48 h under occlusion. No irritation was observed
(RIFM, 1976b).
Irritation was assessed during an associated phototoxicity
study. Six healthy female volunteers, 20–40 years old were used.
The vehicle was 1:1 ethanol/acetone. Prior to the application of
2,6-dimethyl-2-heptanol, 36 test sites (each 2 cm 2 ) were marked
on the back (1.5 cm apart). 2,6-Dimethyl-2-heptanol was then applied
in a dose volume of 0.025 ml/2 cm 2 in 1:1 ethanol/acetone.
The right hand test site was covered and served as an irritancy control
site. No effects were observed in any of the subject’s exposed
to 10% 2,6-dimethyl-2-heptanol in 1:1 ethanol/acetone without
irradiation (irritancy control sites) (RIFM, 1983).
A preliminary primary irritation study was conducted prior to
the associated Human Repeated Insult Patch Test (HRIPT) to
determine irritation potential of 2,6-dimethyl-2-heptanol. A pilot
group of 10 healthy male and female subjects, ranging in age
from 18 to 72 were used. The 10 subjects in the pilot group became
part of the full complement of 57 subjects that started
the associated HRIPT. By the end of the induction period, these
10 individuals had had 11 induction applications as compared
to the remaining individuals who were subjected to 10 induction
applications. At 2% 2,6-dimethyl-2-heptanol no effects were observed
(RIFM, 1969).
Irritation was assessed with a panel of 10 volunteers during
preliminary test for an HRIPT. The test patch consisted of a 1 1
inch Webril swatch and 0.5 ml aliquot of 5% 2,6-dimethyl-2-heptanol
in alcohol SDA 39C. A series of nine 24 h exposures over three
successive weeks caused little to no irritation (RIFM, 1971a).
A preliminary primary irritation study was conducted prior to
the associated Repeated Insult Patch Test to determine irritation
potential. Thirty-five subjects (10 males and 25 females) completed
the study. The test patch was a 1 inch square of Webril
swatch with 0.5 ml of 5% 2,6-dimethyl-2-heptanol in alcohol SDA
39C. A series of nine 24 h exposures over three successive weeks
caused little to no irritation (RIFM, 1972).
4.2.2. Animal studies (see Table 4)
As part of an associated acute toxicity study with a 5 g/kg neat
application of 2,6-dimethyl-2-heptanol, rabbits were observed for
irritation. Slight redness in 2, moderate redness in 8, slight edema
in 1, and moderate edema in 9 animals was observed (RIFM,
1976a).
2,6-Dimethyl-2-heptanol was applied to the intact and abraded
skin of six rabbits. The undiluted material produced strong irritation.
The Primary Irritation Index was reported as 5.13. (RIFM,
1979).
To determine the degree of irritation with 5% 2,6-dimethyl-2-
heptanol, dermal occluded patches (0.5 ml) were applied to the
clipped intact and abraded skin of three rabbits. Animals were
Table 4
Summary of animal irritation studies.
Method
Dermal
application
Dermal
application
Dermal
application
Phototoxicity
(control)
Dose
(%)
Species Results
References
100 Rabbits Slight to moderate
erythema and edema
RIFM (1976a)
100 Rabbits Strong irritation RIFM (1979)
observed
5 Rabbits No irritation RIFM (1972)
10 Guinea
Pigs
No irritation
RIFM (1981a,b)

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S110–S114 S113
immobilized for the 24 h exposure, and then evaluated 48 h after
removal. Irritation was not observed (RIFM, 1971b).
A minimum of four groups of four albino guinea pigs were patch
tested to both flanks for a reaction time of 48 h. Four hours after
the removal of the patches, the left flanks of the two experimental
groups (A and B) were irradiated with UV-A or UV-B light. Groups C
and D were controls, where C did not receive radiation and group D
was not pre-treated. No reactions were observed in the control
Group C where animals were treated with 10% 2,6-diemthyl-2-
heptanol but not irradiated (RIFM, 1981a,b).
4.3. Mucous membrane (eye) irritation
Undiluted 2,6-dimethyl-2-heptanol produced strong irritation
when applied to the surface of the rabbit eye. The Primary Irritation
Index was reported as 29.8. Further details reported in German
(RIFM, 1979).
Aliquots of 0.1 ml 2,6-dimethyl-2-heptanol at 5% in alcohol SDA
39C were instilled into the eyes of three healthy albino rabbits.
Both the treated and control eyes were examined every 24 h for
4 days, then again on the 7th day. Moderate conjunctival irritation
such as redness, chemosis, and discharge were observed, but returned
to normal by day 7 (RIFM, 1971c).
4.4. Skin sensitization
4.4.1. Human studies
4.4.1.1. Induction studies (see Table 5).
4.4.1.2. Human repeated insult patch test. Human Repeated Insult
Patch Tests (HRIPT) were conducted to determine if 2,6-dimethyl-2-heptanol
would induce dermal sensitization in human
volunteers. Patches were applied to the inner surface of the right
and left deltoid area of each subject. Patches were occluded and remained
in place for 48 h. The patches were then removed and read
for any reactions. Alternating rotation of the sites was made for a
total of 10 applications. A 2-week rest period followed the application
of the last patch. After the rest period, the challenge patch was
applied in the identical manner that the previous patches were applied,
except that the test patch was applied in duplicate, one to
the inner surface of each deltoid area. Patches remain in place for
48 h after which time they were removed and scored for reactions.
Fifty-three subjects (35 female and 18 male) ranging in age
from 18 to 72, completed the study. 2,6-Dimethyl-2-heptanol
(0.5 cc) in dimethyl phthalate was applied to individual absorbent
patches. At 72 and 144 h readings were made to detect any delayed/retarded
responses. Five minor adhesive tape reactions were
recorded but not repeated during the challenge tests. There were
no sensitization reactions observed in any of the 53 subjects during
the challenge phase of the study. Under the conditions of the study,
2% 2,6-dimethyl-2-heptanol in dimethyl phthalate was not considered
a sensitizer in humans subjects (RIFM, 1969).
A1 1 inch Webril swatch with 0.5 ml of 5% 2,6-dimethyl-2-
heptanol was applied to the upper arms of 45 subjects (33 female,
12 male) ranging in age from 16 to 60. There were no sensitization
reactions observed in any of the 45 subjects during the challenge
Table 5
Summary of human skin sensitization studies.
Test method Test concentration Results References
HRIPT 2 0/53 RIFM (1969)
HRIPT 5 0/10 RIFM (1971)
0/35 RIFM (1972)
MAX 10 0/25 RIFM (1976a)
phases of these studies. Under these conditions, 5% 2,6-dimethyl-
2-heptanol in alcohol SDA 39C was not considered a sensitizer in
humans subjects (RIFM, 1971b, 1972).
4.4.2. Maximization studies
A human maximization (MAX) test was conducted on 25 healthy
volunteers (19 female and 6 males), ages 18–43 years old. Application
was on the volar forearm or back of all subjects for five alternate
days, 48 h periods. The patch site was pre-treated for 24 h with 2.5%
aqueous SLS under occlusion. Following a 10-day rest period, a challenge
patch of 10% 2,6-dimethyl-2-heptanol was applied to a different
site for a 48 h period under occlusion. Prior to challenge, 5–10%
SLS was applied to the site for one hour before application of 2,6-dimethyl-2-heptanol.
The challenge site was read at patch removal
and 24 h thereafter. There were no instances of contact sensitization
by 2,6-dimethyl-2-heptanol (RIFM, 1976a).
4.4.2.1. Cross-sensitization. No data available on this material.
4.4.3. Diagnostic studies
No data available on this material.
4.4.4. Animal studies
4.4.4.1. Maximization test. A guinea pig maximization test according
to the Kligman (1969) method was conducted. Induction consisted
of a series of six intradermal injections of 10% 2,6-
dimethyl-2-heptanol with and without FCA, followed six to eight
days later with a 48 h occluded patch application. Animals were
challenged 12–14 days later by an occluded 24 h (20% in acetone)
patch application. Reactions were read 24 and 48 h after patch removal.
Positive reactions were not observed (Watanabe et al.,
1988).
4.4.4.2. Local Lymph Node Assay (LLNA). No data available on this
material.
4.5. Phototoxicity and photoallergy
4.5.1. Phototoxicity
4.5.1.1. Human studies. A test was performed on six female volunteers
to determine the phototoxic potential of 2,6-dimethyl-2-
heptanol. The light source was a bank of four ‘blacklight’ fluorescent
tubes with an emission spectrum of 320–400 mm housed in
a reflector unit. Prior to the application 36 test sites (2 cm 2 ) with
a 1.5 separation between each were marked on the back using a
metal stamp and Gentian Violent solution. The sites were loaded
by micro-pipette with the test material at a dose of 0.25 ml per
2cm 2 area. Thirty minutes later the sites were exposed to UV A-
irradiation. Observations were made at 4, 24, 48, and 72 h after
the application. No evidence was noted to indicate that at a concentration
of 10% the material will produce a phototoxic reaction
in humans (RIFM, 1983).
4.5.1.2. Animal studies. A minimum of four groups of four albino
guinea pigs were patch tested on both flanks for a reaction time
of 48 h. Four hours after the removal of the patches, the left flanks
of the two experimental groups (A and B) were irradiated with UV-
A or UV-B light. Groups C and D were controls, where C did not receive
radiation and group D was not pre-treated. The light sources
were both Westinghouse FS 40. The ‘‘black lamp” had a spectrum
between 320 and 400 nm and a radiation time of 30 min; whereas
the ‘‘sunlamp” had a spectrum of 280–370 nm and radiation time
of 15 min. Skin reactions were measured 4, 24, and 48 h after radiation.
Slight irritation was observed 4 h after application of 10%
2,6-dimethyl-2-heptanol in ethanol in 1/8 animals in Group A, B
and D. However, by 48 h all irritation had cleared (RIFM, 1981a).

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D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S110–S114
4.5.2. Photoallergy
4.5.2.1. Human studies. No data available on this material.
4.5.2.2. Animal studies. Guinea pigs of both sexes, divided in groups
of eight animals each, were shaved on the upper dorsal area. About
one hour later, 0.1 ml of 10% 2,6-dimethyl-2-heptanol in rectified
alcohol was applied to 8 cm 2 of the test area. After this pretreatment,
the animals were exposed to the UV B-irradiation for 15 0
and thereafter to UV A-irradiation for 4 h (Westinghouse black
light tubes) from a distance of 25 cm. The application of the test
material and the following irradiation were performed every second
day, a total of nine times in 18 days. Observations for irritation
were made 24 h after each application. After a 10-day rest period
the guinea pigs were again shaved on both flanks and the test area
was marked. A 0.025 ml sample was applied to a 2 cm 2 area. Then
only the left flank was irradiated. Observations were made and 24
and 48 h after the challenge. At 10% 2,6-dimethyl-2-heptanol in
rectified alcohol showed no photosensitizing potential under the
conditions of this test (RIFM, 1981b).
4.6. Absorption, distribution and metabolism
No data available on this material.
4.7. Repeated dose toxicity
No data available on this material.
4.8. Reproductive and developmental toxicity
No data available on this material.
4.9. Genotoxicity
No data available on this material.
4.10. Carcinogenicity
No data available on this material.
This individual Fragrance Material Review is not intended as a
stand-alone document. Please refer to A Safety Assessment of
Branched Chain Saturated Alcohols When Used as Fragrance Ingredients
(Belsito et al., 2010) for an overall assessment of this
material.
Conflict of interest statement
This research was supported by the Research Institute for Fragrance
Materials, an independent research institute that is funded
by the manufacturers of fragrances and consumer products containing
fragrances. The authors are all employees of the Research
Institute for Fragrance Materials.
References
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chain
saturated alcohols when used as fragrance ingredients. Food Chem. Toxicol. 48
(S4), S1–S46.
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:
providing estimates for safety evaluation. Regul. Toxicol. Pharm. 36, 246–252.
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface
Suite for Microsoft Ò Windows, v 4.00 or insert version used]. United States
Environmental Protection Agency, Washington, DC, USA.
Ford, R.A., Api, A.M., Letizia, C.S., 1992. Monographs on fragrance raw materials, 2,6-
dimethyl-2-heptanol. Food Chem. Toxicol. 30 (Suppl.), 23.
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria for
development of a database for safety evaluation of fragrance ingredients. Regul.
Toxicol. Pharm. 31, 166–181.
IFRA (International Fragrance Association), 2004. Use Level Survey, August 2004.
IFRA (International Fragrance Association), 2007. Volume of Use Survey, February
2007.
Kligman, A.M., 1969. The identification of contact allergens by animal assay. The
guinea pig maximization test. J. Invest. Dermatol. 52 (3), 268–276.
RIFM (Research Institute for Fragrance Materials, Inc.), 1969. Sensitization and
irritation studies of 2,6-dimethyl-2-heptanol. Unpublished report from
Givaudan, 30 June. Report number 41345. RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1971a. Eye irritation study
with 2,6-dimethyl-2-heptanol in rabbits. Unpublished report from International
Flavors and Fragrances, Report number 53500. RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1971b. Repeated insult patch
test with 2,6-dimethyl-2-heptanol. Unpublished report from International
Flavors and Fragrances, Report number 53498. RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1971c. Skin irritation study
with 2,6-dimethyl-2-heptanol in rabbits. Unpublished report from International
Flavors and Fragrances, Report number 53501. RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1972. Repeated insult patch
test with 2,6-dimethyl-2-heptanol. Unpublished report from International
Flavors and Fragrances, Report number 53499. RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1976a. Acute toxicity studies
in rats, mice, rabbits and guinea pigs. RIFM report number 2019, October 08.
RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1976b. Report on human
maximization studies. RIFM report number 1797, November 04. RIFM,
Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1979. Acute toxicity studies
on 2,6-dimethyl-2-heptanol. Unpublished report from BASF, 08 February.
Report number 4458. RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1981a. Guinea pig assay of
photosensitizing potential of 2,6-dimethyl-2-heptanol. Unpublished report
from Givaudan, 09 July. Report number 41343. RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1981b. Determination of
phototoxicity of 2,6-dimethyl-2-heptanol in guinea pigs. Unpublished report
from Givaudan, 07 April. Report number 41346. RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1983. 2,6-Dimethyl-2-
heptanol: Phototoxicity test on a fragrance raw material in humans.
Unpublished report from Givaudan, 23 September. Report number 41344.
RIFM, Woodcliff Lake, NJ, USA.
Watanabe, S., Kinosaki, A., Kawasaki, M., Yoshida, T., Kaidbey, K., 1988. The contact
sensitizing potential of (+)- and ( )-hydroxycitronellal. In flavors and
fragrances: a world perspective. Proceedings of 10th International Congress of
Essential Oils, 11/86, pp. 1029–1038.

Food and Chemical Toxicology 48 (2010) S115–S129
Contents lists available at ScienceDirect
Food and Chemical Toxicology
journal homepage: www.elsevier.com/locate/foodchemtox
Review
Fragrance material review on 2-ethyl-1-hexanol
D. McGinty * , J. Scognamiglio, C.S. Letizia, A.M. Api
Research Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
article
Keywords:
Review
Fragrance
info
abstract
A summary of the safety data available for 2-ethyl-1-hexanol when used as a fragrance ingredient is presented.
2-Ethyl-1-hexanol is a member of the fragrance structural group branched chain saturated alcohols
in which the common characteristic structural element is one hydroxyl group per molecule, and a C 4
to C 12 carbon chain with one or several methyl side chains. This review contains a detailed summary of all
available toxicology and dermatology papers that are related to this individual fragrance ingredient and is
not intended as a stand-alone document. A safety assessment of the entire branched chain saturated alcohol
group will be published simultaneously with this document; please refer to Belsito et al. (2010) for an
overall assessment of the safe use of this material and all other branched chain saturated alcohols in
fragrances.
Ó 2010 Published by Elsevier Ltd.
Contents
Introduction . . . .................................................................................................... S116
1. Identification . . .................................................................................................... S116
2. Physical properties . . . . . . . . . . . . . . . . . ................................................................................. S116
3. Usage. . . . . . . . . .................................................................................................... S116
4. Toxicology data .................................................................................................... S117
4.1. Acute toxicity (see Table 2). .................................................................................... S117
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S117
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S117
4.1.3. Intraperitoneal (ip) studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S117
4.1.4. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S118
4.2. Skin irritation. ............................................................................................... S118
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S118
4.2.2. Animal studies (see Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S118
4.3. Mucous membrane (eye) irritation (see Table 4) ................................................................... S118
4.4. Skin sensitization. ............................................................................................ S118
4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S118
4.4.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S119
4.5. Phototoxicity and photoallergy. . ................................................................................ S119
4.6. Absorption, distribution and metabolism ......................................................................... S119
4.6.1. Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S119
4.6.2. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S119
4.6.3. Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S119
4.7. Repeated dose toxicity (see Table 6) . . . .......................................................................... S120
4.7.1. Two to 30-day studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S120
4.7.2. Subchronic (31–90 days) studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S122
4.7.3. Chronic (90+ days) studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S122
4.8. Reproductive and developmental toxicity (see Table 7) .............................................................. S123
4.9. Genotoxicity. ................................................................................................ S124
4.9.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S124
4.9.2. In vivo studies (see Table 10) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S125
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.
E-mail address: dmcginty@RIFM.org (D. McGinty).
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.fct.2010.05.042

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4.10. Carcinogenicity . . ............................................................................................ S125
4.10.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S125
4.10.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S125
4.11. Miscellaneous studies (see Table 12). . . .......................................................................... S125
Conflict of interest statement . . ....................................................................................... S127
References . ....................................................................................................... S127
Introduction
This document provides a summary of the toxicologic review,
including all human health endpoints, of 2-ethyl-1-hexanol when
used as a fragrance ingredient. 2-Ethyl-1-hexanol (see Fig. 1; CAS
Number 104-76-7) is a fragrance ingredient used in cosmetics, fine
fragrances, shampoos, toilet soaps and other toiletries as well as in
non-cosmetic products such as household cleaners and detergents.
It is a colorless, oily liquid with mild, sweet and slightly floral-rosy
odor of considerable tenacity (Arctander, 1969). This material has
been reported to occur in nature, with highest quantities observed
in tea (VCF, 2009).
In 2007, a complete literature search was conducted on 2-ethyl-
1-hexanol. On-line toxicological databases were searched including
those from the Chemical Abstract Services, [e.g. ToxCenter
(which in itself contains 18 databases including Chemical Abstracts)],
and the National Library of Medicine [e.g. Medline, Toxnet
(which contains 14 databases)] as well as 26 additional sources
(e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance
companies were asked to submit all test data.
The safety data on this material was last reviewed by Opdyke,
1978. All relevant references are included in this document. More
details have been provided for unpublished data. The number of
animals, sex and strain are always provided unless they are not given
in the original report or paper. Any papers in which the vehicles
and/or the doses are not given have not been included in this
review. In addition, diagnostic patch test data with fewer than 100
consecutive patients have been omitted.
1. Identification
1.1. Synonyms: 2-Ethylhexanol; 1-hexanol, 2-ethyl-
1.2. CAS registry number: 104-76-7.
1.3. EINECS number: 203-234-3.
1.4. Formula: C 8 H 18 O.
1.5. Molecular weight: 130.23.
1.6. JECFA (1998): The Joint FAO/WHO Expert Committee on
Food Additives (JECFA No. 267) concluded that the substance
does not present a safety concern at current levels of intake
when used as a flavoring agent.
1.7. FEMA (1970): Flavor and Extract Manufacturers’ Association
states: Generally Recognized as Safe as a flavor ingredient –
GRAS 4 (3151).
HO
Fig. 1. 2-Ethyl-1-hexanol.
2. Physical properties
1.1. Physical form: Colorless, oily liquid with mild, sweet and
slightly floral-rosy odor.
1.2. Boiling point (calculated; EPA, 2010): 188.52 °C.
1.3. Flash point: 167°F;CC.
1.4. Henry’s law (calculated; EPA, 2010): 0.000031 atm m 3 /mol
25 °C.
1.5. Log K ow (calculated): 2.73.
1.6. Refractive index: no information available.
1.7. Specific gravity: 0.833.
1.8. Vapor pressure (calculated; EPA, 2010): 0.06 mm Hg (20 °C);
0.185 mm Hg (25 °C); 24.6 Pa (25 °C).
1.9. Water solubility (calculated; EPA, 2010): 1379 mg/l (25 °C).
1.10. UV spectra available at RIFM, peaks at 210–215 nm and
returns to baseline at 400 nm; minor absorption from 290–
400 nm.
3. Usage
2-Ethyl-1-hexanol is a fragrance ingredient used in many fragrance
compounds. It may be found in fragrances used in decorative
cosmetics, fine fragrances, shampoos, toilet soaps and other
toiletries as well as in non-cosmetic products such as household
cleaners and detergents. Its use worldwide is in the region of
0.1–1.0 metric tons per annum (IFRA, 2004). The reported volume
of use is for 2-ethyl-1-hexanol as used in fragrance compounds
(mixtures) in all finished consumer product categories. The volume
of use is surveyed by IFRA approximately every four years through
a comprehensive survey of IFRA and RIFM member companies. As
such the volume of use data from this survey provides volume of
use of fragrance ingredients for the majority of the fragrance
industry.
The dermal systemic exposure in cosmetic products (see Table 1)
is calculated based on the concentrations of the same fragrance
ingredient in ten types of the most frequently used personal care
and cosmetic products (anti-perspirant, bath products, body lotion,
eau de toilette, face cream, fragrance cream, hair spray, shampoo,
shower gel, and toilet soap). The concentration of the fragrance
ingredient in fine fragrances is obtained from examination of several
thousand commercial formulations. The upper 97.5 percentile
concentration is calculated from the data obtained. This upper 97.5
percentile concentration is then used for all 10 consumer products.
These concentrations are multiplied by the amount of product applied,
the number of applications per day for each product type,
and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account
for the length of time a product may remain on the skin and/or
likelihood of the fragrance ingredient being removed by washing.
The resultant calculation represents the total consumer exposure
(mg/kg/day) (Cadby et al., 2002; Ford et al., 2000).
This is a conservative calculation of dermal systemic exposure
because it makes the unlikely assumption that a consumer will
use these 10 products containing; which are all perfumed with
the upper 97.5 percentile level of the fragrance ingredient from a
fine fragrance type of product (Cadby et al., 2002; Ford et al.,
2000). The 97.5 percentile use level in formulae for use in cosmet-

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S115–S129 S117
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2-ethyl-1-hexanol.
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture a Ingredient mg/kg/day b
Anti-perspirant 0.5 1 1 0.01 0.02 0.000020
Bath products 17 0.29 0.001 0.02 0.02 0.000001
Body lotion 8 0.71 1 0.004 0.02 0.000080
Eau de toilette 0.75 1 1 0.08 0.02 0.000200
Face cream 0.8 2 1 0.003 0.02 0.000020
Fragrance cream 5 0.29 1 0.04 0.02 0.000190
Hair spray 5 2 0.01 0.005 0.02 0.000001
Shampoo 8 1 0.01 0.005 0.02 0.000001
Shower gel 5 1.07 0.01 0.012 0.02 0.000001
Toilet soap 0.8 6 0.01 0.015 0.02 0.000001
Total 0.0005
a
b
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.
Based on a 60-kg adult.
ics for 2-ethyl-1-hexanol has been reported to be 0.02% (IFRA,
2007), which would result in a maximum daily exposure on the
skin of 0.0005 mg/kg for high end users (see Table 1).
A maximum skin level is then determined for consideration of
potential sensitization. The exposure is calculated as the percent
concentration of the fragrance ingredient applied to the skin based
on the use of 20% of the fragrance mixture in the fine fragrance
consumer product (IFRA, 2007). The average maximum use level
in formulae that go into fine fragrances has been reported to be
0.008% (IFRA, 2007), assuming use of the fragrance oil at levels
up to 20% of the final product.
4. Toxicology data
4.1. Acute toxicity (see Table 2)
4.1.1. Oral studies
In a study with a total of 85 rats, it was determined that the
lethal dose of 2-ethyl-1-hexanol by oral gavage was 3.2 g/kg
(Hodge, 1943).
In a structure–activity study of a large number of organic solvents,
it was reported that the oral LD 50 of 2-ethyl-1-hexanol in
rats was 2.049 g/kg (Nishimura et al., 1994).
The acute oral LD 50 of 2-ethyl-1-hexanol in groups of five
non-fasted, Carworth–Wistar male rats was reported to be 2.46
(1.82–3.33) g/kg. No additional details were reported (Smyth
et al., 1969).
Table 2
Summary of acute toxicity studies.
Route Species No.
animals/
dose group
LD 50
(g/kg)
References
Oral Rat 5–15 3.2 Hodge (1943)
Oral Rat N/A 2.049 Nishimura et al. (1994)
Oral Rat 5 2.46 Smyth et al. (1969)
Oral Rat N/A 7.1 Shaffer et al. (1945)
Oral Rat N/A 3.2 Bar and Griepentrog
(1967)
Dave and Lidman (1978)
Schmidt et al. (1973)
Oral Rat 5 3.73 Scala and Burtis (1973)
Dermal Rabbit 4 2.38 Smyth (1969)
Dermal Rabbit 10 >5.0 RIFM (1977)
Dermal Rabbit 4 >2.6 Scala and Burtis (1973)
Intraperitoneal Rat 5–15 0.65 Hodge (1943)
Intraperitoneal Rat 5 0.5– Dave and Lidman (1978)
1.0
Intraperitoneal Mice 5–15 0.78 Hodge (1943)
In a study primarily addressing the toxicity of diethylhexyl
phthalate, it was reported that the oral LD 50 of 2-ethyl-1-hexanol
in 90–120 g male Wistar rats is 7.1 (5.5–9.1) g/kg. No additional
details are reported (Shaffer et al., 1945).
The oral LD 50 of 2-ethyl-1-hexanol in rats was reported to be
3.2 g/kg. No additional details are reported (Bar and Griepentrog,
1967; Dave and Lidman, 1978).
The oral LD 50 of 2-ethyl-1-hexanol in rats was reported to be
3.29 (2.87–3.79) g/kg (Schmidt et al., 1973).
The oral LD 50 for 2-ethyl-1-hexanol in Sprague–Dawley rats (5/
dose) was reported to be 3.73 g/kg. The principal clinical signs
were central nervous system depression and labored respiration.
The depression included inactivity, ataxia, limb sprawling, depressed
righting and placement reflexes, prostration, and coma.
The intensity of the signs was related to dose. The signs of effect
had an early onset, and recovery was complete by the second or
third day. Where deaths occurred, they were seen in the first
24 h. Gross necropsy revealed some evidence of gastrointestinal
irritation (Scala and Burtis, 1973).
In a study to investigate the mechanism of action for induction
of peroxisome proliferation by several compounds including 2-
ethyl-1-hexanol, it was reported that a single dose of 100 mg/kg
administered by oral gavage to Fischer 344 rats resulted in no difference
from controls in hepatic acyl CoA oxidase or catalase activity
5 h after dosing (Bojes and Thurman, 1994).
4.1.2. Dermal studies
The dermal LD 50 of 2-ethyl-1-hexanol in groups of four male albino
New Zealand rabbits was reported to be 2.38 (1.7–3.34) g/kg.
No additional details are reported (Smyth et al., 1969).
The dermal LD 50 of 2-ethyl-1-hexanol in 10 rabbits was reported
to be >5.0 g/kg. One of 10 animals died on day 12, but the
necropsy was reported to be normal in the animal that died. Skin
irritation with moderate redness and edema was reported in all
10 animals (RIFM, 1977).
The dermal LD 50 for 2-ethyl-1-hexanol applied occlusively for
24 h to rabbits (4/dose) was reported to be >2.6 g/kg. There were
no clinical signs indicative of systemic effects at the highest level
tested. Dermal irritation was dose-dependent (Scala and Burtis,
1973).
4.1.3. Intraperitoneal (ip) studies
In a study with 102 mice, it was determined that the lethal ip
dose in mice was approximately 0.78 g/kg. 2-Ethyl-1-hexanol
was also administered to 101 rats as ip injections to determine
an LD 50 of 0.65 g/kg. Clinical signs included irregular gait, dragging
of hind limbs, gasping without cyanosis, insensibility and sleepiness
at high doses. The 2-ethyl-1-hexanol was rapidly anaesthetic
in mice as well as rats (Hodge, 1943).

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Dave and Lidman (1978) reported a literature value from the
Handbook of Toxicology of 0.65 g/kg for the ip LD 50 of 2-ethyl-1-
hexanol in rats. In a separate study, Sprague–Dawley rats (5/sex/
dose) were given undiluted 2-ethyl-1-hexanol at doses of 0.05,
0.1, 0.5, 1.0, or 5.0 g/kg. Observations were made continuously over
14-days. The ip LD 50 was reported to be between 0.5 and 1.0 g/kg.
At doses of 1.0 and 5.0 g/kg coma and death were observed in the
rats within two hours. At 0.5 g/kg, the animals went into comas in
5 min, but then recovered and survived throughout the experimental
period. At the post-mortem examinations, no pathological
changes were noted.
4.1.4. Inhalation studies
No deaths were reported when 10 rats, mice, and guinea pigs
were exposed by whole body inhalation for 6 h to air bubbled
through 2-ethyl-1-hexanol to yield a nominal chamber concentration
of 227 ppm (ml/m 3 ). Clinical signs indicated moderate local
irritation and slight to moderate systemic effects. Local irritation
involved the mucous membranes of the eyes, nose, throat, and
respiratory passages and was manifest as blinking, lacrimation,
preening, nasal discharge, salivation, gasping, and chewing movements.
Responses were temporary and all animals had recovered
within 1 h after termination of exposure. Gross necropsy findings
were confined to areas of slight hemorrhage in the lungs. All other
tissues and organs were normal in appearance (Scala and Burtis,
1973).
4.2. Skin irritation
4.2.1. Human studies
In a maximization test pre-screen, 2-ethyl-1-hexanol at 4% was
applied to the backs of 29 healthy male volunteers for 48 h under
occlusion. No subject had any irritation (RIFM 1976).
4.2.2. Animal studies (see Table 3)
Uncovered application of undiluted 2-ethyl-1-hexanol to the
clipped skin on the underbelly of five rabbits for 24 h produced
irritation Grade 3 (moderate) on a 10-Grade scale with Grade 2
representing the least visible capillary injection from undiluted
material, Grade 6 representing necrosis from undiluted material,
and Grade 10 representing necrosis from a 0.01% solution with propylene
glycol or water (Smyth et al., 1969).
In an acute dermal toxicity test in which 0.10, 0.316. 1.00, and
3.16 mg/kg of undiluted 2-ethyl-1-hexanol was applied occlusively
for 24 h to the clipped intact abdominal skin of rabbits, 2-ethyl-1-
hexanol was reported to cause moderate dermal irritation (Scala
and Burtis, 1973).
In an acute dermal toxicity test in which 5 g/kg was applied to the
skin of rabbits, moderate redness and edema was observed in all 10
treated animals. No additional details are reported (RIFM, 1977).
4.3. Mucous membrane (eye) irritation (see Table 4)
2-Ethyl-1-hexanol was reported to be a severe eye irritant when
applied undiluted in a 0.1 ml dose to the left eye of each of six
Table 3
Summary of animal irritation studies.
Method Dose (%) Species Reactions References
Patch test 100 Rabbits Moderate Smyth et al. (1969)
irritation
Patch test 100 Rabbits Moderate Scala and Burtis (1973)
irritation
Patch test 100 Rabbits Moderate
erythema and
edema
RIFM (1977)
rabbits. Observations were made at 1, 4, and 24 h and 2, 3, 4, and
7 days. Median irritation scores according to the Draize system
were 19, 20, and 0 at 24 h, 72 h, and 7 days, respectively. Corneal
dullness, opacity (widespread corneal opacity), vascularization,
irritates, conjunctival erythema, chemosis, and discharge were all
observed (Scala and Burtis, 1973).
Application of 2-ethyl-1-hexanol to the eyes of rabbits produced
irritation Grade 5 on a 10-Grade scale with Grade 5 representing
‘‘severe burn” from 0.005 ml of undiluted material and
Grade 10 representing severe burn from 0.5 ml of a 1% solution
with propylene glycol or water (Smyth et al., 1969; Carpenter et
al., 1946).
In a TSCA 8(e) submission, it was reported that 2-ethyl-1-hexanol
produced persistent corneal effects in rabbits (EPA, 1991,
1992).
Draize rabbit eye irritation scores of 9, 30, 39, 35, and 51 were
reported for 1%, 3%, 10%, 30%, and 100% 2-ethyl-1-hexanol, respectively,
in a study designed to evaluate the predictive value of
changes in corneal thickness for quantitating eye irritation
(Kennah et al., 1989).
Schmidt et al. (1973) conducted an eye irritation study in rabbits
with a single application of 2-ethyl-1-hexanol, undiluted or
in solution with oil at 50%, 25%, or 12.5%. Reactions were graded
after 18–24 h. There were no effects on the cornea for all concentrations,
and at 12.5%. Conjunctival redness, swelling, lacrimation,
and discharge were observed at remaining concentrations. These
effects did not reverse within 96 h with the undiluted concentration
(Schmidt et al., 1973).
4.4. Skin sensitization
4.4.1. Human studies
4.4.1.1. Induction studies.
4.4.1.1.1. Human repeated insult patch test (HRIPT). No information
available.
4.4.1.1.2. Maximization studies. In a human maximization study
involving 29 subjects, 2-ethyl-1-hexanol was applied in petrolatum
at 4% under occlusion to the forearms for a total of five alternate
days, 48 h periods. Each application was preceded by a 24 h
occlusive treatment of the patch sites with 5% aqueous sodium lauryl
sulfate. Following a 10–14 day rest period, challenge patches
were applied to fresh sites on the scapular back under occlusion
for 48 h. The challenge sites were pretreated for 30 min with a
5% aqueous sodium lauryl sulfate solution. Challenge sites were
evaluated at 48 and 72 h, there were no positive reactions to 2-
ethyl-1-hexanol (RIFM, 1976).
Table 4
Summary of eye irritation studies.
Dose (%) Vehicle Reactions References
100 – Severe eye irritant Scala and Burtis
(1973)
100 – Severe burn Smyth et al.
(1969)
Carpenter and
Smyth (1946)
N/A N/A Persistent corneal effects EPA (1992)
100, 30, 10,
3, or 1
PEG a Eye irritation observed at all
concentrations
Kennah et al.
(1989)
100, 50, 25,
12.5
N/A No effects to the cornea
Conjunctival redness, swelling,
lacrimation, and discharge
100%: not reversed at 96h
12.5%: no effects observed
Schmidt et al.
(1973)
a
PEG, polyethylene glycol.

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S115–S129 S119
4.4.1.1.3. Cross-sensitization. No information available.
4.4.1.1.4. Diagnostic studies. No information available.
4.4.2. Animal studies
No information available.
4.5. Phototoxicity and photoallergy
No information available.
4.6. Absorption, distribution and metabolism
4.6.1. Absorption
In a comparison of in vitro percutaneous absorption in rat and
human skin (n = 12 for rat and human skin), it was reported that
the absorption rates were 0.22 ± 0.09 and 0.038 ± 0.014 mg/cm 2 /h
in rat and human skin. The permeability constants were 2.59 ±
1.10 10 4 cm/h for rats and 4.54 ± 1.66 10 5 cm/h for humans.
The ratio of the permeability constants (rat/human) of 5.78 indicates
that 2-ethyl-1-hexanol penetrated full thickness rat skin
more rapidly than it penetrated human stratum corneum (Barber
et al., 1992).
Dermal absorption in the rat was determined to be 5.2% of a
dose of 1000 mg 2-ethyl-1-hexanol/kg body weight applied for
6 h. An absorption rate of 0.57 mg/cm 2 /h and a terminal half-life
of 77 h were calculated (Deisinger et al., 1994).
4.6.2. Distribution
No information available.
4.6.3. Metabolism
4.6.3.1. In vivo studies in animals. Single oral gavage administration
of 14 C labeled 2-ethyl-1-hexanol was given to Fischer 344 rats (4/
group) at 50 mg/kg so that absorption, distribution, metabolism,
and elimination (ADME) could be studied. A repeated oral dose
of 50 mg/kg (unlabeled 2-ethyl-1-hexanol) was also given to rats
for 14 consecutive days. On the final (15th day) the rats were given
a 50 mg/kg dose of 14 C labeled 2-ethyl-1-hexanol. All applications
were neat. The oral doses were eliminated rapidly, predominantly
in urine and feces. Urinary excretion accounted for 56–60% of the
administered dose, with all but about 2% of administered dose excreted
in the first 24 h. Urinary metabolites eliminated were predominately
glucuronides of oxidized metabolites, including
glucuronides of 2-ethyladipic acid, 2-ethylhexanoic acid, 5-hydroxy-2-ethylhexanoic
acid, and 6-hydroxy-2-ethylhexanoic acid. Fecal
excretion accounted for 13–15% of the dose, primarily between
8 and 24 h after dosing. Sodium hydroxide breath traps accounted
for 8–14% of the dose, primarily in the first 24 h. Silica gel breath
traps accounted 0.25–0.28% following oral dosing. There was some
evidence of metabolic saturation at the high dose, and no evidence
of metabolic induction following pretreatment with unlabeled
compound for 14 days. The total recovery for the low, high, and repeated
doses ranged was 94–97% (Deisinger et al., 1994, 1993).
Single oral gavage administration of 14 C labeled 2-ethyl-1-hexanol
was given to Fischer 344 rats (4/group) at 500 mg/kg so that
absorption, distribution, metabolism, and elimination (ADME)
could be studied. After oral administration to rats, 69–75% of a
dose of 500 mg 14 C-labeled 2-ethyl-1-hexanol/kg body weight
was excreted in the urine within 96 h. About 13–15% of the dose
was excreted in the feces and about the same amount was exhaled.
More than 50% of the dose was excreted within 24 h (Deisinger
et al., 1993, 1994).
2-Ethyl-1-hexanol was efficiently absorbed following oral
administration of a 14 C labeled dose and was rapidly excreted in
respiratory CO 2 (6–7%), feces (8–9%), and urine (80–82%) with
essentially complete elimination in 28 h. The amount of radiolabel
recovered in CO 2 matched the amount of unlabeled 2-heptanone
plus 4-heptanone recovered from urine in study in which both labeled
and unlabeled compound were administered, suggesting
that both types of metabolite may have been derived from the major
urinary metabolite, 2-ethylhexanoic acid, by decarboxylation,
following partial beta-oxidation. The radio-labeled CO 2 appeared
not to be derived from acetate (urinary acetic acid and liver and
brain cholesterol were not labeled) or by reductive decarboxylation
(heptane was not present). Other identified metabolites were
2-ethyl-5-hydroxyhexanoic acid, 2-ethyl-5-ketohexanoic acid, and
2-ethyl-1,6-hexadecanoic acid. Only about 3% of the dose was excreted
unchanged. In vitro incubation with mammalian alcohol
dehydrogenase resulted in a V max of 0.30 lmol/min/mg protein
and a K m value of 0.74 mM (Albro, 1975).
In a study of DNA binding of diethylhexylphthalates and related
compounds, it was reported that radio-labeled 2-ethyl-1-hexanol
was not bound to hepatic DNA of Fischer 344 rats 24 h following
oral gavage administration (Albro et al., 1982).
It was reported that oral administration of 2.55 g of 2-ethyl-1-
hexanol to a rabbit resulted in urinary excretion (24 h) of the glucuronide
of alpha-ethylhexanoic acid (Kamil et al., 1953).
It was reported that urinary glucuronide ester accounted for
86.9% of a 25 mMol dose of 2-ethyl-1-hexanol administered by gavage
to a rabbit weighing approximately 3 kg (Kamil et al., 1953).
In the same ADME study, two groups of Fischer 344 rats (4/
group) received a 6 h dermal application (1 g/kg) of 14 C labeled
2-ethyl-1-hexanol. Pyrex glass containment cells (exposure area
of 2.27 cm 2 ) were covered and adhered to the clipped back of eight
rats. Blood pharmacokinetics were studied on four of the eight rats.
Dermal dosing resulted in only about 5% absorption of the applied
dose. Dermal dosing led to a recovery of 1.41% of the dose in silica
gel breath traps compared to 0.25–0.28% following oral dosing. The
small portion of the dose that was absorbed dermally was eliminated
primarily in the urine, with smaller amounts eliminated in
the feces, and as 14 CO 2 in the breath. Urinary metabolites eliminated
were predominately glucuronides of oxidized metabolites,
including glucuronides of 2-ethyladipic acid, 2-ethylhexanoic acid,
5-hydroxy-2-ethylhexanoic acid, and 6-hydroxy-2-ethylhexanoic
acid (Deisinger et al., 1994, 1993).
An i.v. injection of 2-ethyl-1-hexanol (1 mg/kg in saline) was given
to two groups of Fischer 344 rats (4/group). Blood pharmacokinetics
was studied on four of the eight rats; on the other four rats
ADME was evaluated. Urinary excretion was rapid with 53% of the
dose recovered within 8 h of dosing. The next largest portions
recovered were from the sodium hydroxide breath traps at 22.9%
and fecal excretion at 3.8%. The terminal half-life was estimated
to be 60 h (Deisinger et al., 1993, 1994).
Asano and Yamakawa (1950) reported that following a subcutaneous
injection to rabbits with 11 g of 2-ethyl-1-hexanol over
10 days, a volatile urinary metabolite (believed to be 2-ethylcaproic
acid) and a non-volatile metabolite (believed to be the bis-pphenylphenacyl
ester of 2-ethyl adipic acid) was formed. Their
assessment was based on comparison of the melting points of
the isolated metabolites and synthesized compounds.
4.6.3.2. In vitro studies in animals (see Table 5). Primary rat hepatocyte
cultures were used to compare the effects of some alkyl phthalate
esters on peroxisomal enzyme activities. Linear diesters and
their constituent monoesters and alcohols were compared with
branched chain 2-eythylhexyl derivatives. There was no significant
difference between 2-ethyl-1-hexanol treated and control cells in
activities of cyanide-insensitive palmitoyl-CoA oxidation, a specific
peroxisomal marker. Yet, there was a six fold increase with 1 mM 2-
ethyl-1-hexanol on carnitine acyl transferase activity (P < 0.01). The
authors concluded that the measurement of carnitine acyl transfer-

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D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S115–S129
Table 5
Summary of in vitro animal studies.
Test system in vitro Species Concentration Results References
Hepatocyte cultures Rat 0.2 or 1 mM (DMSO) No significant differences in peroxisomal enzyme activities Gray et al. (1983)
Liver, lung, and kidney
homogenates
Rat 40 mg (DEHP) and 20 mg Tween
80
Hydrolyses DEHP to mono-(2-ethylhexyl)phthalate and 2-
ethylhexanol
Carter et al.
(1974)
ase alone was not an adequate criterion for assessing peroxisomal
effects in cultured hepatocytes (Gray et al., 1983).
It was reported that 2-ethyl-1-hexanol is one of the metabolites
produced from diethylhexyl phthalate by rat liver, lung, and kidney
homogenates (Carter et al., 1974).
4.7. Repeated dose toxicity (see Table 6)
4.7.1. Two to 30-day studies
4.7.1.1. Dermal studies. 2-Ethyl-1-hexanol was administered by occluded
patch doses to Fischer 344 rats for five days, followed by
2 days untreated, followed by 4 days treated at 0, 500, or
1000 mg/kg/day. Treatment-related clinical signs of toxicity were
restricted to the skin at the treatment site and included exfoliation
(minimal severity) at both doses and transient erythema (days
4–7) (graded as barely perceptible) at the high dose. There were
no differences from control in food consumption, water consumption,
body weight, or weight gain. There was a statistically significant
decrease in lymphocytes compared to control for females at
the high dose and statistically significant increases in triglycerides
for both males and females at both doses. There was a statistically
significant reduction in absolute spleen weight at 1000 mg/kg/day
and in females only at 500 mg/kg/day. Spleen weight relative to
both body weight and brain weight were also reduced in females
at both 500 and 1000 mg/kg/day. There were no other effects on
absolute or relative organ weights in males. There is no discussion
of gross necropsy or histopathological findings. (EPA, 1992b;
Weaver et al., 1989).
For 12 days, 2-ethyl-1-hexanol was applied to the shaved backs
of 10 rats at 2 ml/kg body weight/day (1600 mg/kg body weight/
day). Observations included a decrease in absolute and relative
thymus weights, liver granulomas, bronchiectasis in the lung, renal
tubular epithelial necroses, edematous heart and testes, as well as
decreased spermatogenesis (Schmidt et al., 1973).
4.7.1.2. Oral studies. 2-Ethyl-1-hexanol was included in a study to
further investigate the relationship between peroxisome proliferation
and induction of cytosolic epoxide hydrolase in mouse liver.
Male C57BI/6 mice were given 10,000 ppm (1500 mg/kg body
weight/day) of 2-ethyl-1-hexanol in their diet for 4 days. At this
dose microsomal epoxide hydrolases were unaffected, but activity
of the cytosolic epoxide hydrolases increased (Lundgren et al., 1988).
In a study of the hepatic effects of DEHP and its metabolites,
2-ethyl-1-hexanol was administered by oral gavage to male Wistar
rats for 7 days at 850, 1335, and 1425 mg/kg/day. Livers were excised
for biochemical and histological evaluations. 2-Ethyl-1-hexanol,
like DEHP, resulted in decreased glucose-6-phosphatase
activity. An increase in relative liver weight, biphenyl-4-hydroxylase
activity, and cytochrome P-450 content per mg microsomal
protein, was observed when compared to controls. Additionally,
there was a similar increase in histochemical alcohol dehydrogenase
activity in the centrilobular area of the liver lobule, and electronmicroscopy
studies showed an increase in microbodies and
dilation of the endoplasmic reticulum. In contrast to DEHP,
succinate dehydrogenase activity was not decreased and aniline-
4-hydroxylase activity was not increased by 2-ethyl-1-hexanol
treatment compared to controls (Lake, 1974, 1975).
In contrast to treatment with DEHP and MEHP, treatment with
2-ethyl-1-hexanol at dietary levels of 50–2500 ppm (5–250 mg/kg
body weight/day) for 7 days did not prevent orotic acid induced
hepatic triglyceride accumulation. Also, the hepatic enzymes involved
in lipid transport and metabolism did not increase (Morton
and Rubin, 1979).
Fischer 344 rats (10/sex/dose) were treated by oral gavage with
undiluted 2-ethyl-1-hexanol for 5 days, followed by 2 days untreated,
followed by 4 days treated at 0, 100, 330, 1000, or
1500 mg/kg/day. The NOEL was 100 mg/kg/d. At 100 mg/kg/day,
no treatment related effects were observed for any in-life, clinical
pathology, gross necropsy, or histopathology parameters. Treatment-related
dose-dependent effects seen at 330 mg/kg/day and
higher included hypoactivity, ataxia, prostration, delayed righting
reflex, muscle twitch, lacrimation, and urine stained fur. Food consumption
and body weights were decreased. Total leukocytes and
lymphocytes and spleen weight and size were decreased. Lymphoid
necrosis in the spleen and thymic atrophy and lymphoid cell degeneration
in the thymus were also observed. Liver weight was increased.
Stomach weight was increased and histopathological
findings of the stomach included hyperkeratosis, mucosal hyperplasia,
edema, exocytosis, and gastritis. Absolute and relative testes
weights were decreased at the highest dose. Absolute and relative
kidney weights were increased at 1000 mg/kg/day, and relative kidney
weight was increased at 1500 mg/kg/day. However, there were
no histopathological findings in testes or kidneys (EPA, 1992b).
2-Ethyl-1-hexanol was administered to Fischer 344 rats via the
drinking water continuously for 9 days at 0, 308 ppm (half-saturated)
and 636 ppm (saturated). Mean intake was estimated to
be 61.1 and 151.1 mg/kg/day for males and 73.4 and 173.5 mg/
kg/day for females at the low and high doses, respectively. There
were no clinical signs of toxicity and no differences from control
in food consumption, body weight, or weight gain. There were statistically
significant increases in water consumption for both dose
levels. There were no alterations in hematology or clinical chemistry
parameters. There were no effects on absolute or relative organ
weights. Exposure of Fischer 344 rats to 2-ethyl-1-hexanol in
drinking water for 9 days at the maximum possible concentration
did not result in any significant toxicological changes (EPA, 1992b;
Weaver et al., 1989).
The administration of 2-ethyl-1-hexanol to male Swiss–Webster
mice (6/group) in the diet at a concentration of 2%
(2857 mg/kg body weight/day) for 10 days resulted in a significant
increase in absolute liver weight, significantly raised activities of
cytoplasmic and microsomal epoxide hydrolases and glutathione-
S-transferase and a significant increase in the cytoplasmic and
microsomal protein content of the liver (Hammock and Ota, 1983).
2-Ethyl-1-hexanol was microencapsulated in the diet at doses
of 0.46%, 0.92%, 1.38% or 2.75% (a mean daily substance intake of
500, 980, 1430, or 2590 mg/kg body weight/day in 10 males and
540, 1060, 1580, or 2820 mg/kg body weight/day in 10 females)
for 11 days. All groups exhibited reductions in feed consumption,
cholesterol, triglycerides and alanine-aminotransferases. Increased
relative stomach and liver weights were also observed. Overall the
authors felt the NOEL under these study conditions was less than
0.46% (500, or 540 mg/kg/day) microcapsules in the feed of male
and female rats (EPA, 1992c).

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S115–S129 S121
Table 6
Summary of repeated dose studies.
Method Dose Species Results References
9 day Dermal
(occluded)
0, 500, or 1000 mg/kg/day Rat P500 mg/kg Body weight/day: exfoliation (minimal severity),
spleen weight decreased; serum triglycerides increased (females);
1000 mg/kg body weight: transient erythema (days 4–7) (graded
as barely perceptible), decreased absolute spleen weight,
lymphocytes decreased
12 day Dermal 2 ml/kg Body weight/day
(1600 mg/kg body weight/
day)
4 day Oral (In food) 10,000 ppm (1500 mg/kg
body weight/day)
7 day Oral (gavage) 800, 1335, or 1425 mg/kg/
day
EPA (1992b)
Weaver et al. (1989)
Rat
Absolute and relative thymus weights decreased, liver
granulomas, bronchiectasis in the lung, renal tubular epithelial
necroses, edematous heart and testes and decreased
spermatogenesis
Schmidt et al. (1973)
Mice Activity of the cytosolic epoxide hydrolases increased. Lundgren et al. (1988)
Rat
Decreased: glucose-6-phosphatase activity
Increased: liver weight, biphenyl-4-hydroxylase activity, and
cytochrome P-450
Lake (1974, 1975)
7 day Oral (In food) 5–250 mg/kg/day Rat No effects Morton and Rubin
(1979)
9 day Oral (gavage) 0, 100, 330, 1000, 1500 mg/ Rat NOEL 100 mg/kg/day EPA (1992b)
kg/day
9 day Oral (drinking
water)
61.1 or 151.1 mg/kg/day
(males)
73.4 or 173.5 mg/kg/day
(females)
Rat Significant increase in water consumption EPA (1992b), Weaver
et al. (1989)
10 days Oral (in food) 2857 mg/kg body weight/
day
11 day Oral (in food) 500, 980, 1430, or 2590 mg/
kg/day (males)
540, 1060, 1580, or
2820 mg/kg/day (females)
11 day Oral (gavage) Nine doses in propylene
glycol of 100, 330, 1000, or
1500 mg/kg/day
11 day Oral (gavage) 0, 100, 330, 1000 or
1500 mg/kg/day
11 day Oral (gavage) Nine doses: 0, 100, 330,
1000, or 1500 mg/kg body
weight/day, in an aqueous
emulsion in Cremophor EL
Mice
Rat
Mice
Rats and Mice
B6C3F1 mice
(10/sex)
2857 mg/kg body weight/day: absolute liver weight, activities of
cytoplasmic and microsomal epoxide hydrolase and glutathione-
S-transferase and the cytoplasmic and microsomal protein
content of the liver increased
NOAEL < 500 (m) or 540 (f) mg/kg bodyweight/day P 500 (m) or
540 (f) mg /kg/d: relative stomach weights increased females (f);
triglycerides and alanine aminotransferase decreased, males (m);
feed consumption significantly decreased (m)
NOEL between 100 and 330 mg/kg body weight/day
Toxic effects in the 330 – 1500 mg/kg dosage groups
Decreased (rat) body weights at 1500 mg/kg
Increased relative liver/stomach weights, and gross lesions (rats)
at 1000 and 1500 mg/kg/day. Kidney weights were increased in
females at 330 mg/kg/day.
Systemic NOAEL 100 mg/kg body weight/day
300 mg/kg body weight/day: acanthosis with hyperkeratosis in
the forestomach; P 1000 mg/kg body weight/day: relative liver
(males) and stomach weights (female) increased, hypertrophy of
hepatocytes; 1/20 deaths.
1500 mg/kg body weight/day: ataxia, lethargy, piloerection,
abdominal or lateral position and loss of consciousness; clinical
chemistry and hematology, no substance-related changes; 5/20
deaths.
Hammock and Ota
(1983)
EPA (1992c)
EPA (1992d)
Astill et al. (1996a)
EPA (1992e)
14 day Oral (gavage) 0–1750 mg/kg/day Rats and mice Marked toxicity at the highest dose Kieth et al. (1992)
14 day Oral (gavage) 130 mg/kg/day Rat No hepatomegaly, peroxisome proliferation, hypolipidemia, or Rhodes et al. (1984)
testicular atrophy
21 day Oral (In food) 20 mg/kg/day Rat Decreased serum cholesterol and triglyceride levels Moody and Reddy
(1982)
21 day Oral 833 mg/kg/day Rat Increased liver weights Yamada (1974)
21 day Oral (gavage) 950 mg/kg/day Rat Increased absolute and relative liver weights. Slightly increased Hodgson (1987)
hepatic peroxisome levels and pCoA activity
21 day Oral (gavage 1000, 1500 mg/kg body
weight/day
Rat
1000 mg/kg body weight/day: 30% increase in liver-to-bodyweight
ratio; peroxisome cell fraction and peroxisome density in
Barber and Topping
(1995)
the liver increase 500 mg/kg body weight/day: mortality
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)
weight in sunflower oil,
controls 10 ml oil/kg body
weight
90 day (inhaled) 15, 40, 120 ppm Rat No substance-related effects were observed NOAEL: 120 ppm Klimisch et al. (1998)
91 day Oral (gavage) 0, 25, 250 or 500 mg/kg
(five consecutive days a
week)
18 months Oral
(gavage)
24 months Oral
(gavage)
50, 200, or 750 (five
consecutive days a week)
50, 150, or 500 (five
consecutive days a week)
Rats and Mice
Mice
Rats
NOEL: 125 mg/kg/day
Decreased body weight gain, gross lesions, serum ALT activities,
total protein, albumin concentration, and serum cholesterol
Increased pCoA activity (rats) at 500 mg/kg
Lethargy, unkemptness, reductions in body weight gain, and
increased mortality compared to controls
Astill et al. (1996a)
Astill et al. (1996b)
Astill et al. (1996b)
At doses of 100, 330, 1000, or 1500 mg/kg body weight/day 2-
ethyl-1-hexanol (in propylene glycol) was administered nine times
by gavage to 10 male and 10 female B6C3F1 mice over a period of
11 days. Toxic effects, such as gross lesions in the forestomach, increased
relative and absolute stomach and liver weights, or clinical
signs (ataxia, lethargy, piloerection, hypothermy, and loss of

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D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S115–S129
consciousness) were observed in the 330–1500 mg/kg body
weight/day dosage groups. The authors felt the NOEL was between
100 and 330 mg/kg bodyweight/day (EPA, 1992d).
In a preliminary study 2-ethyl-1-hexanol was administered as
an aqueous emulsion by oral gavage for 11 days to 10 male and female
Fischer 344 rats and B6C3F1 mice at 0, 100, 330, 1000, or
1500 mg/kg/day. Clinical signs in treated animals were ataxia,
lethargy, and lateral/abdominal posturing in rats (at 1000 and
1500 mg/kg/day) and mice (1500 mg/kg/day). One female mouse
from the 1000 mg/kg/day dose group died, and 5/10 died at
1500 mg/kg/day. There were no mortalities in rats. Significant decreases
in mean rat body weights were observed at 1500 mg/kg on
day 10. Significant increases were observed in relative liver and
stomach weights of both male and female rats at 1000 and
1500 mg/kg/day. Kidney weights were significantly increased in
females at 330 mg/kg/day. Gross lesions in the rats were observed
in 2/10 males at 1000 mg/kg/day and 4/10 males and 7/10 females
at 1500 mg/kg/day. The dose level of 500 mg/kg/day was selected
as a tolerable upper dose based on this 11 day study (Astill,
1996a).
Oral toxicity of 2-ethyl-1-hexanol was studied in B6C3F1 mice
after administration by gavage (aqueous emulsion) for 11 days.
In total, nine applications of 0, 100, 330, 1000, or 1500 mg/kg were
given to 10 male and 10 female mice per group. Some toxic effects
were observed, such as increases in liver and stomach weights
(absolute and relative), foci in the forestomach, hyperkeratosis
and focal/multifocal acanthosis, or clinical signs (ataxia, lethargy,
piloerection, abdominal/lateral position, and loss of consciousness)
in the 330–1500 mg/kg dosage groups. The authors reported the
NOEL was between 100 and 330 mg/kg of 2-ethyl-1-hexanol
(EPA, 1992e).
Kieth et al. (1992) studied the dose response for peroxisome
proliferation due to 2-ethyl-1-hexanol in rats and mice. Rats and
mice, 5/sex/dose, were dosed by oral gavage for 14 days with up
to 6.74 mmol/kg (2500 mg/kg/day) diethylhexyl adipate (DEHA)
or 13.5 mmol/day (1750 mg/kg/day) of 2-ethyl-1-hexanol. 2-
Ethyl-1-hexanol exhibited marked toxicity in male and female rats
at doses of 8 mmol/kg/day (1160 mg/kg/day) and higher; the animals
were killed in extremis. Such toxicity was not noted for DEHA.
Both compounds resulted in dose-dependent increased liver
weights and peroxisome proliferation in both rats and mice, with
DEHA being about twice as potent, on a molar basis, as 2-ethyl-
1-hexanol. Since DEHA is metabolized to 2 M equivalents of 2-
ethyl-1-hexanol. These data suggest that 2-ethyl-1-hexanol is the
proximate peroxisome proliferator of DEHA.
Rhodes et al. (1984) reported that in contrast to results from
previously reported high dose studies, treatment of male Wistarderived
rats by oral gavage with 1 mmol/kg/day (130 mg/kg/day)
2-ethyl-1-hexanol for 14 days resulted in no hepatomegaly, peroxisome
proliferation, hypolipidemia, or testicular atrophy. In contrast,
diethylhexylphthalte at 1 mmol/kg/day (390 mg/kg/day)
produced hepatic effects.
It was reported that serum cholesterol and triglyceride levels
were significantly decreased in male F-344 rats fed ground rat
chow diet containing 2% v/w (20 mg/kg body weight/day) 2-
ethyl-1-hexanol for three weeks (Moody and Reddy, 1982).
The subacute toxicity was tested in 2-ethyl-1-hexanol for three
weeks by oral administration. Five rats were dosed at 1 ml/kg
(833 mg/kg) and a statistical increase (p < 0.05) in liver weight
was observed (no further details given) (Yamada, 1974).
Fischer 344 rats were given doses of 2-ethyl-1-hexanol at 100,
320, and 950 mg/kg/day in a 21-day gavage study. There was no
apparent treatment affect on food intake, although there was a significant
decrease in body weight gain in the 950 mg/kg/day group.
A dose-related increase in cyanide-insensitive pamitoyl CoA oxidation
was observed at 320 and 950 mg/kg/day (Hodgson, 1987).
Male and female rats were given 1000 mg 2-ethyl-1-hexanol/kg
body weight/day by gavage for 3 weeks. The test substance caused
a 30% increase in liver-to-body-weight ratio, an increase in the peroxisome
cell fraction and peroxisome density in the liver (Barber
and Topping, 1995).
Ten rats were given 0, 330, 660, 930 mg/kg body weight in sunflower
oil by gavage 5 days per week for 22 days. At the highest
dose, 930 mg/kg, one animal died and body weight was decreased
on day 17 (Schmidt et al., 1973).
4.7.2. Subchronic (31–90 days) studies
A 90 day subchronic inhalation study was performed on Wistar
rats (10/sex/group) at concentrations of 15, 40, and 120 ppm. The
rats were put into an inhalation chamber of glass/steel construction
(manufactured by BASF AG, Ludwigshafen Germany). Pressure
( 10.2 to 10.1 P) and temperature (23.1–23.8 °C) were measured
continuously. Females of the 40 and 120 ppm exposure group
had a decreased body weight gain, whereas the males of the
15 ppm group showed an increase. No clinical signs or mortality
were observed throughout the study. The authors stated that the
differences in body weight/body weight gain are incidental, not
dose-related and therefore of no toxicological significance. There
were no macroscopic findings attributable to the material, or increase
in the cyanice-insensitive palmitoyl Co A oxidation in any
treatment group. Based on the results of this test the NOAEL of inhaled
2-ethyl-1-hexanol was 120 ppm (corresponding to
638.4 mg/m 3 ) (Klimisch, 1998).
4.7.3. Chronic (90+ days) studies
Male and female F344 rats and B63F1 mice (10/sex/dose) were
administered 2-ethyl-1-hexanol by oral gavage at doses of 0, 25,
250, or 500 mg/kg/day for 13 weeks. One female mouse at
250 mg/kg/day died during treatment, but there were no other
mortalities in rats or mice. Decreased body weight gain, 7% in male
and 6% in female rats, was observed at 500 mg/kg starting at week
4 (males) and week 11 (females). Decreases in serum ALT activities,
and serum cholesterol concentrations were observed. Males, at
500 mg/kg, had a decrease in total protein and albumin concentration.
Significant differences in the relative organ weights from the
control rats were moderate and limited to the brain, kidney, liver,
stomach, and testes at 250 and 500 mg/kg/day. Gross lesions in
both rats and mice were seen at 500 mg/kg/day only. Dose-related
microscopic findings were limited to the forestomach and liver at
500 mg/kg/day in rats and mice. No increases in palmitoyl Coenzyme
A activity were seen in the livers of any mice. Increased activity
was observed in rats of the 500 mg/kg/day group. A NOEL of
125 mg/kg/day was concluded (Astill, 1996a).
2-Ethyl-1-hexanol was given by oral gavage to B6C3F1 mice and
Fischer 344 rats (50/sex) as an emulsion with Cremophor in double-distilled
water. Mice received 50, 200, or 750 mg/kg/day for
18 months in a volume of 10 ml/kg body weight. Rats received
50, 150, or 500 mg/kg/day for 24 months in a volume of 10 ml/kg
body weight. Mortality in male rats (38%) was not dose related,
however female mortality in the 500 mg/kg/day amounted to
52% of the animals in the group. Mice showed a marked increase
in male and female mortality at 750 mg/kg/day, so dosing stopped
at week 78. Weight gains were significantly different from controls
to treated rats at 50, 150, and 500 mg/kg/day (males), as well as
150, and 500 mg/kg/day (females). Weight gains were significantly
different from control to treated mice at 200, and 750 mg/kg/day
(males), as well as 750 mg/kg/day (females). Male and female rats
did not show any differences in food consumption, but mice had a
significant decrease at 750 mg/kg/day. Clinical observations revealed
poor general condition, lethargy, poor grooming, and labored
breathing in rats. There were no instances of poor general
condition or labored breathing in mice. Moderate increase in focal

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S115–S129 S123
lesions and discolorations of the lung were observed in rats of the
high dose. In the rat only the 50 mg/kg/day group was associated
with small statistically significant increases in relative female
stomach weight. The mice showed no changes, besides a slight increase
in testes weight, in relative organ weights at 50 and 200 mg/
kg/day (Astill, 1996b).
4.8. Reproductive and developmental toxicity (see Table 7)
In a study of potential teratogenic effects of DEHP and its
metabolites, 2-ethyl-1-hexanol was administered to pregnant
Wistar rats by oral gavage on gestation day 12, and fetuses were
examined on day 20. A dose of 6.25 mmol/kg (1 ml/kg; 833 mg/
kg) 2-ethyl-1-hexanol resulted in 2.0% fetuses with malformations,
compared to 22.2% at 12.5 mmol/kg (2 ml/kg; 1666 mg/kg) and 0%
for controls. At 1666 mg/kg, the percent survivors with hydronephrosis
or malformations of the cardiovascular system, tail, limbs,
or other were 7.8, 0, 4.9, 9.7, and 1.0, respectively (Ritter et al.,
1987).
In a preliminary developmental toxicity test of 60 chemicals in
female CD-1 mice, it was reported that 2-ethyl-1-hexanol administered
by oral gavage at 1525 mg/kg/day on gestation days 6–15 resulted
in 17/49 maternal deaths, and values significantly lower
than control values for maternal weight gain, viable litters, live
births per litter, and fetal percent survival, birth weight and weight
gain (Hardin et al., 1987).
In a study of differential prenatal toxicity of a series of alcohols,
2-ethyl-1-hexanol was administered by oral gavage to Wistar rats
on gestation days 6 to 19 at doses of 0, 1, 5, and 10 mmol/kg/day,
equivalent to 0, 130, 650, and 1300 mg/kg/day. Maternal toxicity
was evident at 650 and 1300 mg/kg/day, with significant differences
from control in maternal body weight on days 15 and 20.
There was one death at 650 mg/kg/day attributed to gavage error.
In the 1300 mg/kg/day group there were six deaths attributed to
treatment, on days 9, 10, and 13. Fetuses were also affected at
the maternally toxic doses, with significant differences from control
in post-implantation loss, resorptions, fetal weight, number
and percent fetuses and litters with malformations and variations,
and number and percent fetuses with developmental retardations.
The maternal and the fetal NOAEL in this study were 130 mg/kg/
day (Hellwig and Jackh, 1997).
In a study of the effects of DEHP and its major metabolites on
Sertoli cells and gonocytes of 3-day old CD Sprague Dawley rats
(4/group), it was reported that 2-ethyl-1-hexanol administered
by oral gavage at 1.28 mmol/kg (167 mg/kg) had no effects, while
DEHP and MEHP at equimolar doses resulted in large, multinucleated
gonocytes and a decrease in the number of BrdU labeled Sertoli
cells. (Li et al., 2000).
In a study of the effects of DEHP and its metabolites on rat testis
in vivo and in vitro, it was reported that oral gavage doses daily for
five days of 2.7 mmol/kg (350 mg/kg) of 2-ethyl-1-hexanol did
not induce testicular damage in 35 day old male Sprague Dawley
rats and in vitro administration of 2-ethyl-1-hexanol did not enhance
germ-cell detachment from mixed primary cultures of Sertoli
and germ cells from 35-day old male Sprague Dawley rats,
while MEHP had effects on these parameters. 2-Ethyl-1-hexanol
(200 lM for 24 or 48 h) did not result in an increase of germ-cell
detachment in rat testicular-cell cultures (Gray, 1986; Gray and
Beamand, 1984; Sjöberg et al., 1986).
Groups of 28 CD-1 Swiss mice were given >99% pure 2-ethyl-1-
hexanol microencapsulated in their diet at concentrations of 0,
0.009, 0.03, and 0.09% from days 0–17 of pregnancy. This corresponded
to calculated doses of 0.13, 43, and 129 mg/kg body
weight/day. No maternal toxicity was observed and the birth rate
was 93–96% in all groups. All of the litters survived and all gestational
parameters were normal. There were no external, visceral,
or skeletal malformations and no increase in variations occurred.
The authors concluded that 2-ethyl-1-hexanol plays essentially
no role in the expression of DEHP-induced maternal and developmental
toxicity (NTP, 1991; Price et al., 1991).
2-Ethyl-1-hexanol was given to female Sprague Dawley rats (6/
group) by gavage so that developmental toxicity could be evaluated.
On gestation day (GD) 11.5 dosed administration of 0, 6.25,
9.38, or 12.5 mmol in corn oil (0, 813, 1219, 1625 mg/kg body
weight) was followed by an 8 h intubation with 32 lCi 65 Zn.
Maternal food intake decreased, and the 65 Zn was retained in the
liver. The percentage of resorptions was not affected. The authors
concluded that 2-ethyl-1-hexanol did not elicit a profile of
Table 7
Summary of reproductive and developmental toxicity studies.
Method Dose mg/kg body weight/day Species Results References
Oral 833, and 1666 Rat 2% malformations (833 mg/kg)
Ritter et al. (1987)
22.2% malformations (1666 mg/kg)
Oral 1525 Mouse 17/49 maternal deaths
Hardin et al. (1987)
Significantly lower maternal weight gain, viable litters, live births/
litter, fetal survival, and fetal weight
Oral 0, 130, 650, and 1300 Rat Maternal toxicity at 650 and 1300 mg/kg/day.
Hellwig and Jackh (1997)
Maternal and fetal NOAEL 130 mg/kg/day
Oral 167 Rat No effects Li et al. (2000)
Oral 350 Rat Did not induce testicular damage Sjöberg et al. (1986)
Gray et al. (1984)
Gray (1986)
Oral 0.13, 43 and 129 CD-1 Swiss mice
(28 f/group)
NOAEL maternal and developmental toxicity: 129 mg/kg body weight/
day but no toxic dose tested
NTP (1991), Price et al.
(1991)
no maternal toxicity; all of the litters survived and all gestational
parameters were normal.
Oral 0, 813, 1219, 1625 Rat P1219 mg/kg body weight: maternal food intake decreased; 1625 mg/
kg body weight: percentage of 65 Zn retained in maternal liver increase
Bui et al. (1998),
Taubeneck (1996)
The percentage of resorptions was not affected; 1625 mg/kg body
weight: percentage of 65 Zn retained in the embryos decreased
Whole 850 mg/m 3 Rat No effects Nelson et al. (1989)
body
Dermal 0, 420, 840, 1680, 2520 Rat NOAEL was 2520 mg/kg/day Fisher et al. (1989)
Tyl et al. (1992)
In vitro 200 uM Rat No effect Moss et al. (1988)
In vitro 200 uM Rat Did not induce dissociation of germinal cells from Sertoli Cells Gangolli (1982)

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D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S115–S129
maternal or developmental toxicity compared to that of its parent
compound, DEHP (Bui et al., 1998; Taubeneck, 1996).
When pregnant Sprague Dawley rats were exposed by whole
body exposure 7 h per day on gestation days 1–19 to 850 mg/m 3
2-ethyl-1-hexanol, the maximum vapor concentration that could
be achieved without increasing exposure chamber temperature
above 80° F, overall mean food consumption was decreased compared
to control, but there were no significant differences in
maternal weight, water intake, corpora lutea per ovary, resorptions
per litter, numbers of females or males per litter, or fetal weight of
females or males, and no external, visceral, or skeletal malformations
were observed (Nelson et al., 1989).
There were no developmental effects when 2-ethyl-1-hexanol
was administered by occluded cutaneous application to Fischer
344 rats 6 h per day on gestation days 6–15 at doses of 0, 0.5,
1.0, 2.0, and 3.0 ml/kg/d (0, 420, 840, 1680, or 2520 mg/kg/day)
in a range-finding study (8/group) or at 0, 0.3, 1.0, and 3.0 ml/kg/
day (0, 252, 840, or 2520 mg/kg/day) in the main study (25/group).
Maternal weight gain was reduced at 1680 mg/kg and 2520 mg/kg/
day. Persistent exfoliation and crusting and erythema were seen in
both studies at 840, 1680, and 2520 mg/kg/day. Maternal liver, kidney,
thymus, spleen, adrenal, and uterine weights and gestational
and fetal parameters were unaffected by treatment. There were
no treatment related increases in incidence of individual or pooled
external, visceral, or skeletal malformations or variations. The
NOAELs for maternal toxicity were 252 mg/kg/day based on skin
irritation and 840 mg/kg/day based on systemic toxicity. The
developmental NOAEL was at least 2520 mg/kg/day, with no teratogenicity
(Fisher et al., 1989; Tyl et al., 1992).
It was reported that 2-ethyl-1-hexanol had no effect in vitro on
lactate and pyruvate production by Sertoli cell enriched cultures
derived from 28 day old Sprague Dawley rats, whereas phthalate
monoesters known to cause testicular atrophy in vivo increased
Sertoli cell lactate production and lactate/pyruvate ratio (Moss
et al., 1988).
It was reported that 200 lM 2-ethyl-1-hexanol in vitro did not
induce dissociation of germinal cells from Sertoli cells in cultures
of rat seminiferous tubules (Gangolli, 1982).
4.9. Genotoxicity
4.9.1. In vitro studies
4.9.1.1. Bacterial test systems (see Table 8). In Salmonella typhimurium
(strains TA98, TA100, TA1535, TA1537, and TA1538 and
Eschericia coli (strain WP2uvrA) 2-ethyl-1-hexanol was found to
be non-mutagenic with and without addition of the S9 mix from
the livers of male Sprague–Dawley rats (Shimizu et al., 1985).
In a study of 34 phthalates and related chemicals, 2-ethyl-1-
hexanol was found to be non-mutagenic in S. typhimurium strains
TA98, TA100, TA1535, and TA1537 with and without addition of
microsomes from Aroclor induced rats and Syrian hamsters (Zeiger
et al., 1982).
2-Ethyl-1-hexanol was found to be non-mutagenic in
S. typhimurium strains TA98, TA100, TA1535, TA1537, TA 1538,
and TA2637 with and without metabolic activation (Agarwal et
al., 1985).
Salmonella typhimurium (strains not specified), 2-ethyl-1-hexanol
was found to be non-mutagenic with and without addition of
rat liver microsomes (Barber et al., 1985).
2-Ethyl-1-hexanol was not mutagenic in S. typhimurium (strains
TA98, TA100, TA1535, TA1537, and TA1538) tested with and without
addition of microsomes from Aroclor induced rats (Kirby et al.,
1983).
2-Ethyl-1-hexanol was found to be non-mutagenic in
S. typhimurium strains TA98 and TA100 with and without addition
of rat liver microsomes (Warren et al., 1982).
At 500 ug/disk, 2-ethyl-1-hexanol was found to be non-mutagenic
in the Rec-assay with Bacillus subtilis strains H17 and M45
(Tomita et al., 1982).
Urine from Sprague–Dawley rats dosed by oral gavage for
15 days with 1000 mg/kg 2-ethyl-1-hexanol was found to be
non-mutagenic in S. typhimurium strains TA98, TA100, TA1535,
TA1537, and TA1538 with and without addition of rat liver microsomes
or beta-glucuronidase/arylsulfatase (DiVincenzo et al., 1983,
1985).
2-Ethyl-1-hexanol was found to be mutagenic S. typhimurium
strain TA 100 in an 8-azaguanine resistance assay (Seed, 1982).
In a study of the thermal decomposition products of phthalates
and poly(vinyl) chloride, 2-ethyl-1-hexanol was reported to cause
DNA damage in the Rec-assay with B. subtilis strains HA101(rec+)
and Rec-4 (rec ) (Saido et al., 2003).
4.9.1.2. Studies in mammalian cells (see Table 9). 2-Ethyl-1-hexanol
was found to be non-mutagenic in the L5178Y TK ± mouse lymphoma
cell mutagenicity assay. Doses of 0.01, 0.05, 0.25, 0.5, and
1.0 ul/plate representing nontoxic, toxic, and/or maximum tolerated
doses were selected based on preliminary toxicity studies
(Kirby et al., 1983).
Table 9
Summary of mammalian cell studies.
Method Species Results References
Mouse lymphoma cell
mutagenicity assay
Mouse Non-mutagenic Kirby et al.
(1983)
Cytogenetic assay Rat Did not induce
unscheduled DNA
synthesis
Hodgson
et al.
(1982)
Balb 3T3
transformation
assay
Chromosomal
aberration assay
Rat
Hamster
Did not induce
transformation
Did not increase frequency
of chromosomal
aberrations
EPA (1983)
Phillips
et al.
(1982)
Table 8
Summary of bacterial studies.
Method Bacterial strains Results References
Ames test S. typhimurium TA 98, 100, 1535, 1537, 1538 and E. coli WP2uvrA Non-mutagenic Shimizu et al. (1985)
Ames test S. typhimurium TA 98, 100, 1535, 1537 Non-mutagenic Zeiger et al. (1982)
Ames test S. typhimurium TA 98, 100, 1535, 1537, 1538, 2637 Non-mutagenic Agarwal et al. (1985)
Ames test S. typhimurium (unspecified) Non-mutagenic Barber et al. (1985)
Ames test S. typhimurium TA 98, 100, 1535, 1537, 1538 Non-mutagenic Kirby et al. (1983)
Ames test S. typhimurium TA 98, 100, Non-mutagenic Warren et al. (1982)
Rec-assay B. subtilis H17 and M45 Non-mutagenic Tomita et al. (1982)
Ames test S. typhimurium TA 98, 100, 1535, 1537, 1538 Non-mutagenic DiVincenzo et al. (1983), (1985)
Resistance assay S. typhimurium TA 100 Mutagenic Seed (1982)
Rec-assay B. subtilis HA101 (rec+) and Rec-4 (rec-) Mutagenic Saido et al. (2003)

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S115–S129 S125
2-Ethyl-1-hexanol was evaluated for its ability to induce
unscheduled DNA synthesis (UDS) in primary rat hepatocytes
cultures prepared from Fischer 344 rats. Cells were treated simultaneously
with test compound and tritiated thymidine for 1 h.
2-ethyl-1-hexanol did not induce UDS in this assay (Hodgson
et al., 1982, abstract).
2-Ethyl-1-hexanol was tested and found to not induce transformation
in an assay for in vitro transformation of Balb 3T3 cells with
metabolic activation by primary rat hepatocytes obtained from
Fischer 344 rats. The compound was tested over the concentration
range of 96–180 nl/ml. This concentration range corresponded to
approximately 31.7–72% survival in the concomitant cytotoxicity
test. The positive control treatments of cyclophosphamide induced
a total of 26 foci among 18 flasks; therefore, the sensitivity of the
assay appeared normal (EPA, 1983).
2-Ethyl-1-hexanol over a 1.5–2.8 mM concentration range did
not cause a statistically significant increase in frequency of chromosomal
aberrations compared to control in Chinese Hamster
ovary cells (Phillips et al., 1982).
4.9.2. In vivo studies (see Table 10)
In the in vivo mouse micronucleus assay using the B6C3F1
mouse and in the Balb 3T3 transformation assay, 2-ethyl-1-hexanol
was found to be non-mutagenic in the presence and absence
of a co-cultivated rat hepatocyte activation system (Barber et al.,
1985; Astill et al., 1986).
Male Fischer 344 rats were dosed by oral gavage for five consecutive
days with 0.02, 0.07, and 0.21 ml/kg/day of 2-ethyl-1-hexanol.
When compared to controls, there was no increase in
chromatid and chromosome breaks. The mitotic index was also
not affected in bone marrow cells (Putman et al., 1983).
A dominant lethal study was conducted in ICR/SIM mice treated
orally with 2-ethyl-1-hexanol. Dose levels of 250, 500, and
1000 mg/kg/day representing the MTD, were selected based on a
preliminary acute toxicity study. The animals were treated by oral
gavage daily for five consecutive days. After treatment, each male
was housed with two virgin females per week for eight consecutive
weeks to span the spermatogenic cycle. Females were sacrificed on
day 14–17 of caging with males and scored for pregnancy, living
fetuses, and early and late fetal deaths. Fertility indices and average
numbers of dead and total implants per pregnancy were within
the normal range. It was concluded that 2-ethyl-1-hexanol did not
induce dominant lethal mutations after oral administration
(Rushbrook et al., 1982).
4.10. Carcinogenicity
4.10.1. In vitro studies
In a tumor initiation/promotion study of diethylhexyl phthalate
and its hydrolysis products, 2-ethyl-1-hexanol was evaluated in an
Table 10
Summary of in vivo studies.
Method Species Results References
Mouse
micronucleus
assay
Balb 3T3
transformation
assay
B6C3F1
mouse
Rat
Non-mutagenic
Non-mutagenic
Barber et al.
(1985)
Astill et al.
(1986)
Cytogenetic assay Rat No effects Putman et al.
(1983)
Dominant lethal
study
Mouse Did not induce dominant
lethal mutations
Rushbrook
et al. (1982)
in vitro promotion potential study with mouse epidermis-derived
JB6 cells. 2-Ethyl-1-hexanol did not promote JB6 cells to anchorage
independence (Ward et al., 1986).
A cell transformation assay with BALB 3T3 cells did not induce a
significant number of transformed foci (Barber et al., 1985).
4.10.2. In vivo studies
2-Ethyl-1-hexanol was given to male and female rats and mice
by gavage five times a week in 0.005% aqueous Cremophor EL (rats:
0 (water), 0 (vehicle), 50, 150, 500 mg/kg body weight/day,
24 months; mice: 0 (water), 0 (vehicle), 50, 200, 750 mg/kg body
weight/day, 18 months). The incidences of carcinomas and basophilic
foci in the liver increased in female mice with the dose
and attained statistical significance in the highest dose group compared
with the vehicle control group but not with the water control
group. The time-adjusted incidence of hepatocellular
carcinomas in female mice (13.1%) was outside the normal range
(0–2%), but in male mice (18.8%) was within the historical control
range at the testing facility (0–22%). No adenomas were observed.
The number of basophilic liver foci was increased in male mice in
the mid dose group only (Table 5). The authors considered the liver
tumors in the mouse to be inconclusive because the incidence of
hepatocarcinoma precursors did not significantly increase with
the dose. Nevertheless, they concluded that 2-ethylhexanol is
weakly or questionably carcinogenic for the female mouse. Under
the conditions of this study 2-ethyl-1-hexanol was not oncogenic
to rats. Doses of 150 and 500 mg/kg body weight/day led to reduced
body weight gains and in some animals to lethargy and poor
grooming which proves that the maximum tolerated dose was
reached. At the end of the study the mortality was about 52% in
the high dose group females and about 28% in the other groups
(Table 11; Astill et al., 1996b).
4.11. Miscellaneous studies (see Table 12)
In studies in perfused livers from starved female Sprague–Dawley
rats, 2-ethyl-1-hexanol (3 mM or 0.39 g) in the perfusion
media (Krebs–Henseleit buffer pH 7.4, 37 °C saturated with 95%
O 2 :5%CO 2 ) inhibited oxygen uptake in periportal, but not centrilobular
regions, and caused damage primarily in the periportal regions,
as reflected by trypan blue staining. 2-Ethyl-1-hexanol
perfusion also resulted in lactate dehydrogenase release into the
perfusion effluent. In isolated mitochondria from the treated livers,
oxygen uptake was inhibited in the presence of succinate with ADP
and stimulated in the presence of succinate without ADP, indicating
an uncoupling of oxidative phosphorylation. It was proposed
that peroxisome proliferators accumulate in the liver due to their
lipophilicity where they inhibit actively respiring mitochondria
in periportal regions of the liver lobule and cause local toxicity
(Keller et al., 1990, 1992).
In an investigation of the effect of 2-ethyl-1-hexanol on fatty
acid metabolism, it was reported that rates of ketone body production
by perfused livers from starved female Sprague–Dawley
rats were decreased about 60% by 200 uM (0.026 g) 2-ethyl-1-
hexanol in the perfusion media (Krebs–Henseleit buffer pH 7.4,
37 °C saturated with 95% O 2 :5%CO 2 ). Studies were conducted
to determine the site of inhibition of fatty acid oxidation. Rates
of ketone body production in the presence of oleate, which requires
transport of the corresponding CoA compound into the
mitochondria, were reduced by 2-ethyl-1-hexanol. In contrast, ketone
body production from hexanoate, which is activated in the
mitochondria, was not affected by 2-ethyl-1-hexanol. Basal and
oleate-stimulated H 2 O 2 productions were not affected by 2-
ethyl-1-hexanol, indicating that beta-oxidation was not altered
by the compound. Based on these data, it was concluded that
2-ethyl-1-hexanol inhibits beta-oxidation of fatty acids in

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D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S115–S129
Table 11
Study of the carcinogenicity of 2-ethyl-1-hexanol administered to B6C3F1 mice by oral gavage for 18 months (Astill et al., 1996b) – liver findings.
Dose (mg/kg body weight/day) Water control Vehicle control 50 mg/kg 200 mg/kg 750 mg/kg
Congestion m 1/50 0/50 0/50 0/50 7/50 2
f 1/50 0/50 0/50 3/50 2/50
Peripheral fatty infiltration m 0/50 0/50 0/50 1/50 31/50 3
f 0/50 1/50 0/50 3/50 22/50 3
Basophilic foci m 4/50 4/50 5/50 12/50 1 6/50
f 2/50 1/50 2/50 4/50 6/50 1
Focal hyperplasia m 2/50 7/50 4/50 9/50 10/50
f 1/50 0/50 3/50 4/50 1 1/50
Adenomas m 0/50 0/50 0/50 0/50 1/50
Carcinomas m 4/50 6/50 6/50 7/50 9/50
f 1/50 0/50 1/50 3/50 5/50 1
Compared with the vehicle control (Fisher’s exact test).
1 p < 0.05,
2 p < 0.01,
3 p < 0.001, f, female; m, male.
Table 12
studies on the mechanism of hepatotoxicity of 2-ethyl-1-hexanol.
Test system Concentration Results References
Isolation of mitochondria from
perfused rat livers
Perfused livers
Isolated cylinders of periportal and
pericentral regions of the liver
lobule
70 lM, 3 mM in the
perfusion medium
200 lM in the
perfusion medium
0.1–3 mM:
incubation of plugs
2-Ethyl-1-hexanol in the perfusion media: inhibition of the oxygen uptake in
periportal, but not centrilobular regions; damage primarily in the periportal regions,
as reflected by trypan blue staining; lactate dehydrogenase release into the perfusion
effluent.
Isolated mitochondria from the perfused livers: inhibition of the oxygen uptake in the
presence of succinate with ADP and stimulation in the presence of succinate without
ADP, indicating an uncoupling of oxidative phosphorylation.
It was proposed that peroxisome proliferators accumulate in the liver due to their
lipophilicity where they inhibit actively respiring mitochondria in periportal regions
of the liver lobule and cause local toxicity.
2-Ethyl-1-hexanol in the perfusion media: rates of ketone body production were
decreased about 60%; rates of ketone body production in the presence of oleate, which
requires transport of the corresponding CoA compound into the mitochondria, were
reduced by 2-ethyl-1-hexanol; in contrast, ketone body production from hexanoate,
which is activated in the mitochondria, was not affected by 2-ethyl-1-hexanol; basal
and oleate-stimulated H 2 O 2 productions were not affected by 2-ethyl-1-hexanol,
indicating that beta-oxidation was not altered by the compound;Based on these data,
it was concluded that 2-ethyl-1-hexanol inhibits beta-oxidation of fatty acids in
mitochondria but not in peroxisomes.
Incubation of plugs with 0.1 to 3 mM 2-ethyl-1-hexanol: extensive cell damage
assessed from LDH leakage in incubations at 800 lMO 2 but significantly less injury at
200 lMO 2 ; Concomitantly, inhibition of urea synthesis by over 80% at 800 lMO 2 , but
less than 50% at 200 lMO 2 ; Plugs isolated from both regions of the liver were affected
similarly by 2-ethyl-1-hexanol and O 2 .
The authors concluded that these data indicate that 2-ethyl-1-hexanol toxicity is
dependent on oxygen tension in isolated sublobular regions of the liver lobule, and
therefore it is unlikely that drug delivery can explain the selective injury to periportal
regions in studies with perfused liver.
GST from rats and mice Up to 15 mM Cytosolic GST activity (substrates: 1,2-dichloro-4-nitrobenzene- or 1,2-epoxy-3-(pnitrophenoxy)-propane)
was only weakly inhibited in rats (IC 50 70 mM or no
inhibition up to 10 mM) and mice (IC 50 23 mM or 15 mM), in contrast to the effects of
other peroxisome proliferators (e.g. DEHP, MEHP)
Rat liver homogenates 2.5 to 15 mM Concentration-dependent reduction in the activities of aniline hydroxylase and
aminopyrine-N-demethylase
Keller et al.
(1990, 1991,
1992)
Badr et al.
(1990)
Liang et al.
(1991)
Law and Moody
(1989, 1991)
Agarwal et al.
(1982) Seth
(1982)
Kupffer cells in culture Up to 0.9 mM No effect on the Kupffer cell superoxide production Rose et al.
(1999)
Kupffer cells in culture Up to 3 mM No effect on the cytosolic free calcium concentrations in Kupffer cells up to 2 mM
(Wy-16,643 had an effect at 1,25 mM), only at 3 mM increase of the free calcium
Hijioka et al.
(1991)
concentration
Mitochondrial fraction from rat liver 1% Little inhibitory effect on mitochondrial respiration at a concentration of 1% Takahashi
(1977)
Cultured hepatocytes 10, 100, 500 lM Inhibition of GJIC was observed, no cytotoxicity in the tested concentration range, a
NOEL for GJIC was observed, n.f.i.
Lington et al.
(1994)
ADP, adenosine diphosphate; CoA, Coenzyme A; DEHP, di(2-ethylhexyl) phthalate; GJIC, gap junctional intercellular communication; GST, glutathione-S-transferase; MEHP,
mono-(2-ethylhexyl) phthalate; n.f.i., no further information; LDH, lactate dehydrogenase.

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S115–S129 S127
mitochondria but not in peroxisomes. Treatment of rats ip with
0.32 g/kg 2-ethyl-1-hexanol deceased plasma ketone bodies, increased
hepatic triglycerides, and increased lipid predominantly
in periportal regions of the liver lobule. It was concluded, data
indicates that alterations in hepatic fatty acid metabolism in periportal
regions of the liver lobule may be early events in peroxisome
proliferation (Badr et al., 1990).
To determine whether the selective toxicity of 2-ethyl-1-hexanol
for the periportal region in the perfused rat liver (fasted female
Sprague–Dawley rats, pretreated with phenobarbital 1 mg/l for at
least 7 days) was due to local oxygen tension or drug delivery,
isolated cylinders of periportal and pericentral regions of the liver
lobule were collected with a micropunch following brief perfusion
of the organ. Incubation of liver punch biopsy samples with
0.1–3 mM (0.01–0.39 g) 2-ethyl-1-hexanol caused extensive cell
damage assessed from lactose dehydrogenase (LDH) leakage in
incubations at 800 uM O 2 but significantly less injury at 200 uM
O 2 . Concomitantly, urea synthesis was inhibited by over 80% at
800 uM O 2 , but less than 50% at 200 uM O 2 . Liver punch biopsy
samples isolated from both regions of the liver were affected similarly
by 2-ethyl-1-hexanol and O 2 . The authors concluded that
these data indicate that 2-ethyl-1-hexanol toxicity is dependent
on oxygen tension in isolated sublobular regions of the liver lobule,
and therefore it is unlikely that drug delivery can explain the selective
injury to periportal regions in studies with perfuse liver (Liang
et al., 1991).
A study was conducted to determine how peroxisome proliferators
and 2-ethyl-1-hexanol, up to 15 mM, would affect mouse and
rat liver glutathione S-transferases (GST) in vitro. Cytosolic GST
activity was only weakly inhibited in rats and mice when compared
to the effects of other peroxisome proliferators (Law and
Moody, 1989, 1991).
The in vitro effects of 2-ethyl-a-hexanol on the activity of aminopyrine
N-demethylase and aniline hydroxylase were studied.
Aliquots of 2.5–15 mM were used the enzyme assay. A concentration
dependent reduction in the activities of aniline hydroxylase
and aminopyrine-N-demthylase was observed (Agarwal et al.,
1982; Seth, 1982).
Kupffer cells and hepatocytes were isolated to study cell proliferation.
Incubation of 2-ethyl-1-hexanol with Kupffer cells in culture
up to 0.9 mM had no effect of the superoxide production
(Rose et al., 1999). Furthermore, there were no effects on the cytosolic
free calcium concentrations in Kupffer cells up to 2 mM. At
3 mM an increase of free calcium concentration was observed,
whereas, Wy-16,643 had an effect at 1.25 mM (Hijioka et al., 1991).
The effects of 2-ethyl-1-hexanol at 1% on mitochondrial respiration
of Wistar rat livers were investigated. Little inhibitory effects
were observed (Takahashi, 1977).
Inhibition of gap junctional intercellular communication (GJIC)
was observed for 2-ethyl-1-hexanol in cultured hepatocytes from
B 6 C 3 F 1 female mice and F344 female rats. Reversible effects were
observed following the removal of the compound, and 2-ethyl-1-
hexanol was not considered the most potent metabolite for inhibition
to the GJIC (Lington et al., 1994).
This individual Fragrance Material Review is not intended as
a stand-alone document. Please refer to a safety assessment
of branched chain saturated alcohols when used as fragrance
ingredients (Belsito et al., 2010) for an overall assessment of this
material.
Conflict of interest statement
This research was supported by the Research Institute for
Fragrance Materials, an independent research institute that is
funded by the manufacturers of fragrances and consumer products
containing fragrances. The authors are all employees of the Research
Institute for Fragrance Materials.
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(Contents continued from outside back cover)
D. McGinty, J. Scognamiglio,
C. S. Letizia and A. M. Api
D. McGinty, J. Scognamiglio,
C. S. Letizia and A. M. Api
D. McGinty, A. Lapczynski,
J. Scognamiglio, C. S. Letizia and
A. M. Api
D. McGinty, J. Scognamiglio,
C. S. Letizia and A. M. Api
D. McGinty, J. Scognamiglio,
C. S. Letizia and A. M. Api
S93–S96
S97–S101
S102–S109
S110–S114
S115–S129
Fragrance material review on 3-methyl-1-pentanol
Fragrance material review on 2-methylbutanol
Fragrance materials review on isoamyl alcohol
Fragrance material review on 2,6-dimethyl-2-heptanol
Fragrance material review on 2-ethyl-1-hexanol

FOOD AND CHEMICAL TOXICOLOGY
VOLUME 48 (2010) SUPPLEMENT 4
CONTENTS
A Safety Assessment of Saturated Branched Chain Alcohols when used as
Fragrance Ingredients
D. Belsito, D. Bickers, M. Bruze,
P. Calow, H. Greim, J. M. Hanifin,
A. E. Rogers, J. H. Saurat, I. G. Sipes,
H. Tagami, and The RIFM Expert
Panel
D. McGinty, J. Scognamiglio,
C. S. Letizia and A. M. Api
D. McGinty, J. Scognamiglio,
C. S. Letizia and A. M. Api
D. McGinty, J. Scognamiglio,
C. S. Letizia and A. M. Api
D. McGinty, J. Scognamiglio,
C. S. Letizia and A. M. Api
D. McGinty, J. Scognamiglio,
C. S. Letizia and A. M. Api
D. McGinty, J. Scognamiglio,
C. S. Letizia and A. M. Api
D. McGinty, J. Scognamiglio,
C. S. Letizia and A. M. Api
D. McGinty, S. P. Bhatia,
J. Scognamiglio, C. S. Letizia and
A. M. Api
D. McGinty, J. Scognamiglio,
C. S. Letizia and A. M. Api
D. McGinty, J. Scognamiglio,
C. S. Letizia and A. M. Api
D. McGinty, C. S. Letizia and
A. M. Api
D. McGinty, J. Scognamiglio,
C. S. Letizia and A. M. Api
S1–S46
S47–S50
S51–S54
S55–S59
S60–S62
S63–S66
S67–S69
S70–S72
S73–S78
S79–S81
S82–S84
S85–S88
S89–S92
A safety assessment of branched chain saturated alcohols when used as
fragrance ingredients
Fragrance material review on 3,5,5-trimethyl-1-hexanol
Fragrance material review on 3,7-dimethyl-7-methoxyoctan-2-ol
Fragrance material review on 4-methyl-2-pentanol
Fragrance material review on 2-methylundecanol
Fragrance material review on 3,4,5,6,6-pentamethylheptan-2-ol
Fragrance material review on isodecyl alcohol
Fragrance material review on isooctan-1-ol
Fragrance material review on isotridecan-1-ol (isomeric mixture)
Fragrance material review on isononyl alcohol
Fragrance material review on 6,8-dimethylnonan-2-ol
Fragrance material review on 2-ethyl-1-butanol
Fragrance material review on 2,6-dimethyl-4-heptanol
(Contents continued on inside back cover)
Available online at www.sciencedirect.com
Fd Chem. Toxic. is indexed/abstracted in Analyt. Abstr., Aqua. Abstr.,
Biosis Data., CAB Inter., CABS (Current Awareness in Biological Sciences),
Cam. Sci. Abstr., Chem. Abstr. Serv., Chem. Haz. in Indus.,
Curr. Cont. ISI/BIOMED Database, Curr. Cont. Sci. Cit. Ind.,
Curr. Cont. SCISEARCH Data., Excerp. Med., Health & Saf. Sci. Abstr.,
Ind. Med., Int. Pack., MEDLINE, Res. Alert, Tox. Abstr.
http://www.elsevier.com/locate/foodchemtox
ISSN 0278-6915
48(S4) S1–S130 (2010)
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