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48/S3 FOOD AND CHEMICAL TOXICOLOGY Vol. 48/S3 (2010) S1–S110 ELSEVIER 

Volume 48, Supplement 3, January 2010 ISSN 0278-6915 

Food and 

Chemical 

Toxicology 

A Safety Assessment of Non-cyclic Alcohols with 

Unsaturated Branched Chain when used 

as Fragrance Ingredients 

Editors 

J F Borzelleca 

A R Boobis

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, 

2450 SE Oak Tree Court Ankeny, IA 50021-7102, USA 

GARY 

WILLIAMS 

Department of Pathology, New York Medical College, Basic Science 

Building, Room 413, Valhalla, NY 10595, USA 

SAMUEL 

M. COHEN 

Department of Pathology and Microbiology, University of Nebraska 

Medical Center, 983135 Nebraska Medical Center, 

Omaha, NE 68198-3135 

P. BALDRICK, UK 

J. K. CHIPMAN, UK 

T. F. X. COLLINS, USA 

Y. P. DRAGAN, USA 

L. O. DRAGSTED, Denmark 

L. FERGUSON 

S. J. S. FLORA, India 

ERGUSON, New Zealand 

H. R. GLATT, Germany 

W. H. GLINSMANN 

LINSMANN, USA 

Y. HASHIMOTO, Japan 

A. W. HAYES, USA 

Y. HUA, China 

S. KACEW 

ACEW, Canada 

Review Editor 

SUSAN 

M. BARLOW 

Harrington House, 8 Harrington Road, 

Brighton, East Sussex BN1 6RE, UK 

Associate Editors 

International Editorial Board 

I. KIMBER, UK 

S. KNASMULLER 

NASMÜLLER, Austria 

B. LAKE, UK 

R. W. LANE, USA 

M. I. LUSTER, USA 

D. McGREGOR, France 

P. MAGEE, UK 

H. I. MAIBACH, USA 

K. MORGAN, USA 

R. J. NICOLOSI, USA 

D. RAY, UK 

K. ROZMAN, USA 

W. H. M. SARIS, The Netherlands 

IVONNE 

RIETJENS 

AFSG/Division of Toxicology, Wageningen University, PO Box 8000, 

6700 EA Wageningen, The Netherlands 

DAVID 

J. BRUSICK 

Brusick Consultancy, 123 Moody Creek Road, VA 23024, Bumpass, 

Virginia, USA 

MICHAEL 

W. PARIZA 

Department of Food Microbiology and Toxicology, University of 

Wisconsin at Madison, 176 Microbial Sciences Building, 

1550 Linden Drive Madison, WI 53706, USA 

R. C. SHANK 

M. SMITH, The Netherlands 

Y.-J. SURH, South Korea 

R. G. TARDIFF, USA 

S. L. TAYLOR, USA 

J. A. THOMAS 

HANK, USA 

HOMAS, USA 

E. VAVASOUR, Canada 

H. VERHAGEN 

A. VISCONTI, Italy 

X. WANG 

S. YANNAI, Israel 

ERHAGEN, The Netherlands 

ANG, People’s Republic of China 

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(Contents continued from outside back cover) 

D. McGinty, C. S. Letizia and 

A. M. Api 


A. M. Api 


A. M. Api 

D. McGinty, L. Jones, C. S. Letizia and 

A. M. Api 


A. M. Api 

S93–S96 

S97–S100 

S101–S102 

S103–S107 

S108–S110 

Fragrance material review on 4-methyl-3-decen-5-ol 

Fragrance material review on 2-methyl-3-buten-2-ol 

Fragrance material review on 2-hexadecen-1-ol, 3,7,11,15-tetramethyl 

Fragrance material review on 7-nonen-2-ol, 4,8-dimethyl- 

Fragrance Material Review on 6-ethyl-3-methyloct-6-en-1-ol

Food and 

Chemical 

Toxicology 

For a full and complete Guide for Authors, please go to http://www.elsevier.com/locate/foodchemtox 

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A Safety Assessment of Non-cyclic Alcohols with 

Unsaturated Branched Chain when used 

as Fragrance Ingredients

Disclaimer 

The journal’s peer review process has been applied to the Group summary but responsibility for the content of the 

monographs rests with RIFM. Both the Publisher and the Editors wish to make it clear that the data and opinions 

appearing in the individual monographs are the sole responsibility of each author. 

Profs. A.R. Boobis, J.F. Borzelleca – Editors-in-Chief 

Dr. S. Barlow – Reviews Editor

Food and Chemical Toxicology 48 (2010) S1–S42 

Contents lists available at ScienceDirect 

Food and Chemical Toxicology 

journal homepage: www.elsevier.com/locate/foodchemtox 

Review 

A safety assessment of non-cyclic alcohols with unsaturated branched chain 

when used as fragrance ingredients q 

The RIFM expert panel 

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 

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 Avenue, 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, Isafjordvej 66, Roskilde, DK 4000, 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, Mail Code CH16D, 3303 SW Bond Avenue, Portland, Oregon 97239-4501, USA 

g Boston University School of Medicine, Department of Pathology and Laboratory Medicine, 715 Albany Street, L-804, Boston, MA 02118-2526, USA 

h Hospital Cantonal Universitaire, Clinique et Policlinique de Dermatologie, 24, Rue Micheli-du-Crest, Geneve 14 1211, 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 

Contents 

1. Chemical identity, regulatory status, and exposure . . . . . . . . . . ................................................................ S12 

1.1. Rationale for grouping alcohols with unsaturated branched chain . . ...................................................... S12 

1.2. Occurrence and use. . . . . ......................................................................................... S12 

1.3. Estimated consumer exposure . . . . . . . . . . . . ......................................................................... S12 

2. Toxicokinetics. . ...................................................................................................... S12 

2.1. Dermal route of exposure ......................................................................................... S12 

2.1.1. Human studies . . . . . . . . . . . . .............................................................................. S12 

2.1.2. Animal studies . . . . . . . . . . . . .............................................................................. S13 

2.2. Oral route of exposure . . ......................................................................................... S13 

2.3. Respiratory route of exposure . . . . . . . . . . . . ......................................................................... S13 

3. Metabolism. . . . ...................................................................................................... S13 

3.1. Conjugation . . . . . . . . . . . ......................................................................................... S13 

3.2. Oxidation of the Carbon chain . . . . . . . . . . . . ......................................................................... S13 

3.3. Oxidation of the alcohol group. . . . . . . . . . . . ......................................................................... S14 

3.4. Hydrogenation of double bonds . . . . . . . . . . . ......................................................................... S14 

4. Toxicological studies . . . . . . . . . . . . . . . ................................................................................... S14 

4.1. Acute toxicity . . . . . . . . . ......................................................................................... S14 

4.2. Repeated dose toxicity . . ......................................................................................... S14 

4.2.1. Dermal studies . . . . . . . . . . . . .............................................................................. S14 

4.2.2. Oral studies. . . . . . . . . . . . . . . .............................................................................. S15 

4.2.3. Inhalation studies . . . . . . . . . . .............................................................................. S17 

4.3. Genotoxicity . . . . . . . . . . ......................................................................................... S17 

4.3.1. In vitro genotoxicity studies. . .............................................................................. S18 

4.3.2. In vivo genotoxicity studies . . .............................................................................. S18 

4.4. Carcinogenicity . . . . . . . . ......................................................................................... S18 

4.5. Reproductive and developmental toxicity . . . ......................................................................... S18 

4.5.1. Fertility . . .............................................................................................. S18 

4.5.2. Developmental toxicity . . . . . .............................................................................. S21 

4.6. Skin irritation . . . . . . . . . ......................................................................................... S21 


q All correspondence should be addressed to: A.M. Api, 50 Tice Boulevard, 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 2009 Elsevier Ltd. All rights reserved. 

doi:10.1016/j.fct.2009.11.007

S2 

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S42 

4.6.2. Animal studies . . . . . . . . . ................................................................................. S25 

4.7. Mucous membrane irritation . . . . . . . . . . ............................................................................ S25 

4.8. Skin sensitization ............................................................................................... S28 

4.8.1. Human studies . . . . . . . . . ................................................................................. S28 


4.9. Phototoxicity and photoallergenicity . . . . ............................................................................ S28 

4.10. Miscellaneous studies . . . . . . . . . . . . . . . ............................................................................ S29 

4.10.1. Hepatotoxicity . . . . . . . . ................................................................................. S29 

4.10.2. Effects on nervous system . . . . . . . . . . . . . . . ................................................................. S32 

5. Summary . . ......................................................................................................... S32 

5.1. Exposure summary . . . . . . . . . . . . . . . . . . ............................................................................ S32 

5.2. Toxicokinetics summary . . . . . . . . . . . . . . ............................................................................ S32 

5.3. Metabolism summary . . . . . . . . . . . . . . . . ............................................................................ S32 

5.4. Acute toxicity summary . . . . . . . . . . . . . . ............................................................................ S35 

5.5. Repeated dose toxicity summary . . . . . . . ............................................................................ S35 

5.6. Genotoxicity summary . . . . . . . . . . . . . . . ............................................................................ S35 

5.7. Carcinogenicity summary . . . . . . . . . . . . . ............................................................................ S36 

5.8. Reproductive and developmental toxicity summary. . . . . . . . ............................................................ S36 

5.8.1. Fertility . . . . . . . . . . . . . . . ................................................................................. S36 

5.8.2. Developmental toxicity . . ................................................................................. S37 

5.8.3. Estrogenic activity . . . . . . ................................................................................. S37 

5.9. Skin irritation summary . . . . . . . . . . . . . . ............................................................................ S37 

5.10. Mucous membrane summary. . . . . . . . . . ............................................................................ S38 

5.11. Skin sensitization summary . . . . . . . . . . . ............................................................................ S38 

5.12. Phototoxicity and photoallergenicity summary. . . . . . . . . . . . ............................................................ S38 

6. Conclusion . ......................................................................................................... S38 

Conflict of interest statement . . ......................................................................................... S39 

References . ......................................................................................................... S39 

1. Chemical identity, regulatory status, and exposure 

This report summarizes chemical and toxicological data relevant 

to the risk assessment of the use of some branched chain 

unsaturated non-cyclic alcohols as fragrance ingredients. 

1.1. Rationale for grouping alcohols with unsaturated branched chain 

The group consists of eight primary, nine primary allylic, four 

secondary, one secondary allylic, five tertiary and 15 tertiary allylic 

non-cyclic alcohols. The names and structures of the materials reviewed 

are shown in Table 1. Their common characteristic structural 

elements are one hydroxyl group per molecule, a C 4 to C 16 

carbon chain with one or several methyl or ethyl side chains and 

up to four non-conjugated double bonds. Of these materials, 24 

have been previously reviewed in RIFM’s Safety Assessment on 

Terpene Alcohols (Belsito et al., 2008). These substances are identified 

in Table 1. In addition, several non-cyclic 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. 

Two members contain all the structural features listed above 

but do not contain a branched side chain ((2E,6Z)-nona-2,6-dien- 

1-ol, (Z)-2-penten-1-ol). It has been shown in the perfused rat liver 

that branching does not consistently alter the hepatotoxicity of C3 

and C4-alcohols (of the alcohols under review 3-methyl-2-buten- 

1-ol and its unbranched homologue 2-buten-1-ol were tested, 

and the hepatotoxicity of both compounds was similar), which is 

evaluated as one of the critical effects (Strubelt et al., 1999; RIFM, 

2002c). Therefore, both straight-chain alcohols ((2E,6Z)-nona-2,6- 

dien-1-ol, (Z)-2-penten-1-ol) can be evaluated together with 

branched chain alcohols. One member of the group, dihydromyrcenol, 

is a 1:1 mixture of the branched chain alcohol 2,6-dimethyl- 

7-octen-2-ol and its formate. It is an isomer of 7-octen-2-ol, 

2-methyl-6-methylene-, dihydro derivative, which is also under 

review. Although studies on the metabolism of dihydromyrcenol 

are lacking, it is known that esters like formates are metabolized 

to the corresponding alcohol and formic acid (JECFA, 1998). Once 

taken up by the body, the formate of 2,6-dimethyl-7-octen-2-ol 

will be metabolized to 2,6-dimethyl-7-octen-2-ol and formic acid. 

Therefore, this mixture can be evaluated together with branched 

chain alcohols. 

Due to their structural similarity, these alcohols also share common 

metabolic pathways (see below). As metabolism is crucial for 

toxicokinetics and toxicity, these alcohols are expected to have the 

same target organs (liver and kidney) as was shown for selected 

compounds. As the data base for these alcohols is limited, additional 

data on pharmacokinetics, metabolism, genotoxicity and 

systemic toxicity of the structurally related non-cyclic unsaturated 

branched alcohols, citronellol, dehydrolinalool, 6,7-dihydrolinalool, 

farnesol, geraniol, linalool, nerol, and nerolidol (cis and isomer 

unspecified), from an evaluation of terpene alcohols (Belsito et al., 

2008) have been used. 

Data for citronellol, geraniol, linalool, 3-methyl-2-buten-1-ol, 

nerol and phytol show that the alcohols share common metabolic 

pathways (see Section 3). 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 undergo further oxidation to an 

aldehyde, a carboxylic acid, and CO 2 , 

– hydrogenation of the double bonds, 

– excretion of the unchanged parent compound. 

In most cases, metabolism yields innocuous metabolites. Some 

materials, however, may generate alpha, beta-unsaturated compounds, 

e.g. aldehydes formed from primary allylic alcohols, or un-

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S42 S3 

Table 1 

Material identification, summary of volume of use, and dermal exposure. 

Material Synonyms Structure Worldwide Dermal systemic 

metric tons a exposure in 

cosmetic products 

(mg/kg/day) 

Maximum 

skin level b 

Subgroup: primary 

dl-Citronellol c 

C 10 H 20 O 

CAS# 106-22-9 Citronellol >1000 0.13 8.2 

LogK ow : 3.1 at 35 °C 3,7-Dimethyl-6-octen-1-ol 

Molecular weight: 156.27 6-Octen-1-ol, 3,7-dimethyl- 

Vapor pressure: 0.009 mm Hg at 

20 °C e 

Water solubility: 105.5 mg/l at 

25 °C e 

l-Citronellol c 

C 10 H 20 O 

CAS# 7540-51-4 (-)-3,7-Dimethyloct-6-en-1-ol 

Henry’s law: 0.0000568 atm m 3 / 

(S)-3,7-Dimethyl-6-octen-1-ol 10–100 0.07 1.4 

mol at 25 °C e 

LogK ow : 3.56 e 6-Octen-1-ol, 3,7-dimethyl-, (S)- 

Molecular weight: 156.27 


20 °C e 


25 °C e 

(+)-(R)-Citronellol c 

C 10 H 20 O 

CAS# 1117-61-9 (+)-beta-Citronellol 


(R)-3,7-Dimethyloct-6-en-1-ol 10–100 0.0005 f 0.02 


LogK ow : 3.56 e 6-Octen-1-ol, 3,7-dimethyl-, (R)- 



25 °C e 


25 °C e 

3,7-Dimethyloct-7-en-1-ol c 

C 10 H 20 O 

CAS# 141-25-3 alpha-Citronellol 


mol at 25 °C e unspecified) 

7-Octen-1-ol, 3,7-dimethyl- (isomer 

LogK ow 3.63 e 1–10 0.04 0.8 


Vapor pressure: 0.000262 mm Hg 

at 25 °C e 


25 °C e 

6-Ethyl-3-methyloct-6-en-1-ol 

C 11 H 22 O 

6-Ethyl-3-methyloct-6-ene-1-ol 

6-Ethyl-3-methyl-6-octen-1-ol 

CAS# 26330-65-4 3-Methyl-6-ethyl-6-octen-1-ol 1–10 0.0005 f 0.02 

Molecular weight 170.29 6-Octen-1-ol, 6-ethyl-3-methyl- 

(continued on next page)

S4 


Table 1 (continued) 




(mg/kg/day) 

Maximum 

skin level b 

Rhodinol c 

C 10 H 20 O 

CAS# 6812-78-8 3,7-Dimethyl-(6-or 7-)octen-1-ol 


3,7-Dimethyl-7-octen-1-ol 1–10 0.11 0.94 


LogK ow 3.63 e 7-Octen-1-ol, 3,7-dimethyl-,(S)- 



20 °C e 

Water solubility: 181.5 mg/l at 25 °C e 

2,6,10-Trimethylundeca-5,9-dienol 

C 14 H 26 O 

CAS# 24048-14-4 Dihydroapofarnesol 

Henry’s law: 0.000183 atm m 3 /mol 25 °C e 5,9-Undecadien-1-ol, 2,6,10-trimethyl- 0.01–0.1 0.02 0.04 

LogK ow 5.36 e 


Vapor pressure: 0.000176 mm Hg at 25 °C e 


Subgroup: primary allylic 

Farnesol c 

C 15 H 26 O 

CAS# 4602-84-0 2,6,10-Dodecatrien-1-ol, 3,7,11-trimethyl- 

Henry’s law: 0.000252 atm m 3 /mol 25 °C e Farnesyl alcohol 1–10 0.007 0.66 

LogKow: 5.77 e Trimethyl dodecatrienol 

Molecular weight: 222.37 3,7,11-Trimethyl-2,6,10-dodecatrien-1-ol 

Vapor pressure: 1000 0.11 5.3 d 

Molecular weight: 154.25 Meranol 

Vapor pressure: 0.02 mm Hg at 20 °C e 2,6-Octadien-1-ol, 3,7-dimethyl-, (e)- 


2-Hexadecen-1-ol, 3,7,11,15- 

tetramethyl- 

C 20 H 40 O 

CAS# 7541-49-3 3,7,11,15-Tetramethyl-2- 

hexadecen-1-ol 

LogKow 8.32 e 


Vapor pressure: 0.000000524 mm Hg 25 °C e 





(mg/kg/day) 

Maximum 

skin level b 

3-Methyl-2-buten-1-ol 

C 5 H 10 O 

CAS# 556-82-1 

Henry’s law: 0.0000138 atm m3/mol 25 °C e 2-Buten-1-ol, 3-methyl- 

LogK ow 1.17 e Prenol 1–10 0.0005 0.01 

Molecular weight: 86.13 Vapor pressure: 1.4 mm Hg 

at 20 °C e 

Water solubility: 40940 mg/l at 25 °C e 

Nerol c 

C 10 H 18 O 

Allerol 

cis-2,6-Dimethyl-2,6-octadien-8-ol 

CAS# 106-25-2 cis-3,7-Dimethyl-2,6-octadien-1-ol 

Henry’s law: 0.0000589 atm m 3 /mol 25 °C e 100–1000 0.06 1.12 

LogKow: 3.47 e Neraniol 

Molecular weight: 154.25 Nergenol 

Vapor pressure: 0.0159 mm Hg at 25 °C e 2,6-Octadien-8-ol, 2,6-dimethyl-,(z) 


(2E,6Z)-Nona-2,6-dien-1-ol 

C 9 H 16 O 

CAS# 28069-72-9 

LogKow 2.87 e 2,6-Nonadien-1-ol, (E,Z)- 

Henry’s law: 0.0000319 atm m 3 /mol 25 °C e 2-trans-6-cis-Nonadien-1-ol Z E 

0.1–1 0.0003 0.05 


Vapor pressure: 0.0105 mm at Hg 25 °C e 

OH 


(Z)-2-Penten-1-ol 

C 5 H 10 O 

CAS# 1576-95-0 

Henry’s law: 0.0000117 atm m 3 /mol 25 °C e 2-Penten-1-ol, (Z)- 

LogKow 1.12 e cis-Pent-2-en-1-ol 0.001–0.01 0.0005 f 0.02 



Z 


Phytol 

C20H40O 

CAS# 150-86-7 2-Hexadecen-1-ol, 3,7,11,15-tetramethyl-,[R- 

[R*,R*-(E)]]- 

Henry’s law: 0.000965 atm m 3 /mol 25 °C e [R-[R*,R*-(E)]]-3,7,11,15-Tetramethyl- 2- 

hexadecen-1-ol 

HO 

0.1–1 0.01 0.2 



Vapor pressure:

S6 






(mg/kg/day) 

Maximum 

skin level b 

Tetrahydromuguol c 

C 10 H 20 O 

CAS# 41678-36-8 3,7 & 2,6-Dimethyl-2-octenol 


mol 25 °C e 

3,7-Dimethylocten-2-ol 1–10 0.0005 f 0.02 

LogKow 3.56 e Tetrahydro allo-ocimenol 



25 °C e 


25 °C e 

Subgroup: secondary 

Methylheptenol 

C 8 H 16 O 

CAS# 1335-09-7 


Heptenol, methyl- 0.01–0.1 0.0005 f 0.02 

mol 25 °C e 

LogK ow 2.65 e Methylheptenol 


Vapor pressure: 0.0608 mm at Hg 

25 °C e 


2-Methyl-2-hepten-6-ol 

C8H16O 

CAS# 1569-60-4 5-Hepten-2-ol, 6-methyl- 

Henry’s law: 0.0000322 atm m 3 /mol 

6-Hydroxy-2-methyl-2-heptene 0.01–0.1 0.001 0.01 

25 °C e 

LogK ow 2.57 e 6-Methylhept-5-en-2-ol 




7-Nonen-2-ol, 4,8-dimethyl- 

C 11 H 22 O 

CAS# 40596-76-7 4,8-Dimethylnon-7-en-2-ol 0.01–0.1 0.0005 f 0.02 

Molecular weight: 170.3 Homocitronellol 

3,5,6,6-Tetramethyl-4- 

methyleneheptan-2-ol 

C 12 H 24 O 4 

CAS# 81787-06-6 


2-Heptanol, 3,5,6,6-tetramethyl-4- 

mol 25 °C e methylene- 




25 °C e 

0.01–0.1 0.0005 f 0.02 


25 °C e 

Subgroup: secondary allylic


( ) 




(mg/kg/day) 

Maximum 

skin level b 

4-Methyl-3-decen-5-ol 

C 11 H 22 O 

CAS# 81782-77-6 

Henry’s law: 0.0000753 atm m 3 /mol 25 °C e 3-Decen-5-ol,4-methyl- 

LogK ow : 3.9 at 30 °C e Undecavertol 100–1000 0.04 1.5 




Subgroup: tertiary 

Dihydromyrcenol 

C 10 H 20 O 

CAS# 18479-58-8 Dimyrcetol 

Henry’s law: 0.0000407 atm m 3 /mol 25 °C e 3,7-Dimethyl-1-octen-7-ol >1000 0.33 6.8 

LogK ow : 3.0 at 30 °C 7-Octen-2-ol, 2,6-dimethyl- 




7-Octen-2-ol, 2-methyl-6-methylene-, dihydro 

derivative 

C10H20O 

CAS# 53219-21-9 2-Methyl-6-methyleneoct-7-en-2-ol,dihydro 

derivative; 

Henry’s law: 0.0000481 atm m 3 /mol 25 °C e 7-Octen-2-ol, 2-methyl-6-methylene-, 

dihydro deriv 

LogK ow : 3.6 e 


Vapor pressure: 0.2270 torr 

Water solubility: 869 mg/l (24 h & 

72 h stirring) 


C 10 H 20 O 

CAS# 18479-51-1 


1,2-Dihydrolinalool 

25 °C e 

HO 

100–1000 0.49 6.8 

LogKow 3.52 e 6-Octen-3-ol, 3,7-dimethyl- 1–10 0.01 0.14 



25 °C e 


Myrcenol c 

C 10 H 18 O 

CAS# 543-39-5 7-Hydroxy-7-methyl-3-methylene-1-octene 

Henry’s law: 0.0000292 atm m 3 /mol 25 °C e 3-Methylene-7-methyl-1-octene-7-ol 1–10 0.0005 f 0.02 

LogK ow 3.46 e 7-Methyl-3-methylene-1-octene-7-ol 


Vapor pressure: 0.05 mm Hg at 20 °C e 2-Methyl-6-methyleneoct-7-en-2-ol 

Water solubility: 260.9 mg/l at 25 °C e 7-Octen-2-ol, 2-methyl-6-methylene-ol 


S8 






(mg/kg/day) 

Maximum 

skin level b 

Ocimenol c 

C 10 H 18 O 

CAS# 5986-38-9 2,6-Dimethyl-5,7-octadien-2-ol 

Henry’s law: 0.0000344 atm m 3 /mol 25 °C e 5,7-Octadien-2-ol, 2,6-dimethyl- 0.01–0.1 0.0005 f 0.02 





Subgroup: tertiary allylic 

Dehydrolinalool c 

C 10 H 16 O 

CAS# 29171-20-8 Dehydro-beta-linalool; 

LogK ow : 2.75 e 3,7-Dimethyloct-6-en-1-yn-3-ol; 1000 0.32 4.3 

Molecular weight: 154.25 3,7-Dimethyl-1,6-octadien-3-ol; 

Vapor pressure: 0.5027 torr; 0.2 mbar at 20 °C 3,7-Dimethylocta-1,6-dien-3-ol; 

Water solubility: 1.45 g/l at 20 C Licareol; 

d-Linalool c 

Linalol; 

Linalyl alcohol; 

1,6-Octadien-3-ol, 3,7-dimethyl-; 

2,7-Octadien-6-ol, 2,6-dimethyl-; 

Petinerol 

C 10 H 18 O 

CAS# 126-90-9 (S)-3,7-Dimethyl-1,6-octadien-3-ol 

Henry’s law: 0.0000423 atm m 3 /mol 25 °C e 3,7-Dimethylocta-1,6-dien-3-ol 

LogK ow : 3.38 e 1,6-Octadien-3-ol, 3,7-dimethyl-, (S)-





(mg/kg/day) 

Maximum 

skin level b 

(5Z)-2,6-Dimethylocta-3,5-dien-2-ol c 

10–100 0.0005 f 0.02 

C 10 H 18 O 

CAS# 18675-16-6 Muguol 


3,5-Octadien-2-ol, 2,6-dimethyl-, (5Z)- 0.1–1 0.0005 f 0.02 

25 °C e 

LogKow 3.3 e 


Vapor pressure: 0.0366 mm Hg at25 °C e 


(5E)-2,6-Dimethyl-3,5-octadien-2-ol c 

C 10 H 18 O 

CAS# 18675-17-7 3,5-Octadien-2-ol, 2,6-dimethyl-, (E,E)- 0.1–1 0.0005 f 0.02 


25 °C e 

LogKow 3.3 e 



25 °C e 


3,7-Dimethyl-4,6-octadien-3-ol c 

C10H18O 

CAS# 18479-54-4 4,6-Octadien-3-ol, 3,7-dimethyl OH 0.1–1 0.09 0.67 


25 °C e 

LogK ow :3.3 e 



25 °C e 



C 10 H 20 O 

CAS# 18479-49-7 6,7-Dihydrolinalool OH 


1-Octen-3-ol, 3,7-dimethyl- 25 °C e 

LogK ow :3.47 e 



25 °C e 


Geranyl linalool c 

C 20 H 34 O 

CAS# 1113-21-9 1,6,10,14-Hexadecatetraen-3-ol, 3,7,11,15- 

tetramethyl-, (E,E)- 


0.01–0.1 0.001 0.01 

E,E-3,7,11,15-Tetramethyl-1,6,10,14- 

25 °C e hexadecatetraen-3-ol 

LogKow 7.97 e 



25 °C e 


25 °C e (continued on next page)

S10 






(mg/kg/day) 

Maximum 

skin level b 

Isophytol 

C20H40O 

CAS# 505-32-8 1-Hexadecen-3-ol,3,7,11,15- 

tetramethyl- 


3,7,11,15-Tetramethyl-1- 

25 °C e hexadecen-3-ol 

LogK ow : 8.23 e 


Vapor pressure:

a 

b 

c 

d 

e 




(mg/kg/day) 

Maximum 

skin level b 

Nerolidol (cis) c 

C 15 H 26 O 

CAS# 142-50-7 1,6,10-Dodecatrien-3-ol, 3,7,11-trimethyl-, 

[S-(Z)]- 

Henry’s law: 0.000181 atm m 3 /mol 25 °C e (+)-cis-Nerolidol HO 

0.01–0.1 0.01 0.02 

LogK ow 5.68 e d-Nerolidol 




Z 

Nerolidol (isomer unspecified) c 

C15H26O 

CAS# 7212-44-4 1,6,10-Dodecatrien-3-ol, 3,7,11-trimethyl- 

Henry’s law: 0.000181 atm m 3 /mol 25 °C e Melaleucol 10–100 0.03 2.02 

LogK ow 5.0 at 35 °C Methylvinyl homogeranyl carbinol 

HO 

Molecular weight: 222.72 Peruviol 

Vapor pressure: 0.1 mm Hg 20 °C e 3,7,11-Trimethyl-1,6,10-dodecatrien-3-ol 

Water solubility: 1.532 mg/l at 25 °C e 3,7,11-Trimethyldodeca-1,6,10- trien-3- 

ol,mixed isomers 

2007 Volume of use survey (IFRA, 2007a). 

Skin levels were based on the assumption that the fragrance mixture is used at 20% in a fine fragrance. 

Materials have been previously reviewed by in RIFM’s safety assessment of terpene alcohols (Belsito et al., 2008). 

Maximum concentration for IFRA QRA category 4 (eg. Hydroalcoholics for unshaved skin). 

Physical properties have been calculated. 

A default value of 0.02% was used to calculate dermal systemic exposure. 

f 

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S42 S11

S12 


dergo oxidation to hydroperoxides. Such compounds can take part 

in a range of nucleophilic and electrophilic addition reactions with 

biological material. The respective parent compounds that are not 

well studied (2-isopropyl-5-methyl-2-hexene-1-ol, 2-methyl-2- 

buten1-ol, phytol, 3,7,11,15-tetramethyl-2-hexadecen1-ol, 6,10- 

dimethylundeca-1,5,9-trien-4-ol, 4-methyl-3-decen-5-ol, 2,2,8- 

trimethylnonen-3-ol) should undergo a more in-depth toxicity 

assessment. However, the primary allylic alcohol, 3-methyl-2-buten-1-ol, 

did not show a higher toxicity than nonallylic alcohols 

in the available studies (McGinty et al., submitted for publication). 

The presence of a double bond may give rise to the metabolic 

formation of reactive and genotoxic epoxides although Ames tests 

did not indicate mutagenic activity, which would be expected if 

epoxides were formed in appreciable amounts, for any of the seven 

compounds tested (phytol; 3-methyl-2buten-1-ol; 7-nonen-2- 

ol,4,5-dimethyl-; 4-methyl-3-decen-5-ol; 3-7-dimethyl-1,6-nonadien-3-ol; 

2-methyl-3-buten-2-ol; or isophytol). 

1.2. Occurrence and use 

The alcohols under review are used as fragrance and flavor 

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 to be the primary exposure route for fragrance materials. 

When relevant, toxicity, metabolism and biological fate data 

from other routes of exposure have also been considered. 

The selected data from published and unpublished reports were 

deemed to be relevant based on the nature of the protocols, quality 

of the data and appropriate exposure. These data are presented below 

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-methyl-3-buten-2-ol and 2-methyl-2-hepten-6-ol 

have been approved for use as flavors by the Food and 

Drug Administration (FDA) in accordance with 21 CFR 172.515. 

3-Methyl-2-buten-1-ol, 2-methyl-2-buten-1-ol and phytol are 

listed as food additives (FDA, 2007). 

As judged by the International Joint FAO/WHO Expert Committee 

on Food Additives (JECFA), 3-methyl-2-buten-1-ol does not 

present a safety concern at current estimated intake levels (JECFA, 

2004). 

The annual worldwide use of the individual alcohols varies 

greatly and ranges from less than 0.1 to greater than 1000 metric 

tons. Compounds with use volumes greater than 100 metric tons 

are: 4-methyl-3-decen-5-ol, 3,7-dimethyl-1,6-nonadien-3-ol and 

dihydromyrcenol (IFRA, 2007c; Table 1). 

1.3. Estimated consumer exposure 

Potential consumer exposure to fragrance ingredients may occur 

mainly through the dermal and inhalation routes of exposure. 

For some of the substances under review, consumer exposure 

from use of fragranced products was estimated by two methods 

(IFRA, 2007c): 

(1) Assumed or reported maximum concentrations of the alcohols 

in fine fragrances coming into contact with skin were 

provided by RIFM for all alcohols, assuming that 20% of the 

fragrance oil is used in the final product. The highest maximum 

skin level concentration for all alcohols reported was 

dihydromyrcenol at 6.8%. The concentrations for the other 

three alcohols with use volumes of more than 10 metric tons 

per year were greater than 1% (Table 1). 

(2) From a survey of the use of fragrance mixtures (including 11 

of the substances under review) in 10 types of cosmetic products 

(body lotion, face cream, eau de toilette, fragrance cream, 

antiperspirant, shampoo, bath products, shower gels, toilet 

soap and hairspray), the daily systemic dose for consumers 

was calculated from the amount of applied cosmetic product, 

its application frequency, a retention factor to account for the 

length of time a product remains on the skin or for the likelihood 

of being washed off, the concentration of fragrance mixture 

in the product, the reported or assumed 97.5‰ of the 

concentration of the substance in the mixture and the consumer 

body weight of 60 kg. The daily systemic dose from 

each cosmetic product was calculated assuming 100% dermal 

uptake. To be conservative, it was assumed that a consumer is 

exposed simultaneously to all 10 cosmetic products. An 

explanation of how the data are obtained and how exposure 

was determined has been reported by Cadby et al. (2002) 

and Ford et al. (2000). The systemic doses from all 10 cosmetic 

products were summed and the sum for each substance 

is shown in Table 1. Maximum daily calculated exposures for 

these 11 substances range from 0.0003 to 0.33 mg/kg body 

weight/day for individual substances in users with high consumption 

of cosmetic products containing these materials. 

The highest exposures calculated were for dihydromyrcenol 

and 3,7-dimethyl-1,6-nonadien-3-ol (see Table 1). 

Data on inhalation exposure during use of the substances are 

lacking. Estimations for systemic exposure to the materials under 

review are only available for the dermal exposure route. 

2. Toxicokinetics 

2.1. Dermal route of exposure 

No data on dermal penetration of the compounds under review 

are available. Limited in vivo data and in vitro percutaneous studies 

in human skin preparations demonstrate that the terpene alcohols 

citronellol and linalool penetrate dermal tissues (Belsito et al., 

2008). Due to the structural similarity it is expected that the materials 

considered in this review can also be absorbed through the 

skin. Interaction of skin components with perfume can slow its 

evaporation substantially compared with relatively free evaporation 

from an inert surface. The quantities of perfume ingredients 

available for absorption may be higher than expected based on 

their volatility (Belsito et al., 2008). Results from a study by Behan 

et al. (1996) show that after application of 75 ll of a model cologne 

perfume with a ten-ingredient mixture (each at 1% w/w), residual 

quantities on the skin after 60 min of free evaporation were 293 

and 427 ng for 7-octen-2-ol, 2-methyl-6-methylene-, dihydro 

derivative and linalool, respectively. For the calculation of systemic 

exposure a worst-case assumption of 100% dermal absorption is 

used (see Section 1.3). 

2.1.1. Human studies 

Studies on the percutaneous absorption of citronellol and linalool 

in human skin in vitro and that of linalool in vivo have been described 

by Belsito et al. (2008). 

Linalool was absorbed from a 1500 mg massage oil containing 

2% lavender oil with approximately 25% linalool and 30% linalyl 

acetate through the skin of a male volunteer. Nineteen minutes 

after the massage, the peak concentration of 100 ng linalool/ml


plasma was reached. A biological half-life of 14 min was determined 

(Jäger et al., 1992; Belsito et al., 2008). 

A series of in vitro human skin penetration studies were conducted 

RIFM, 2006c,d,e, 2007c,d,e with 4% linalool under in-use 

(unoccluded) and occluded conditions in diethyl phthalate (DEP), 

dipropylene glycol (DPG), ethanol/water, petrolatum, ethanol/DEP 

or ethanol/DPG vehicles. Twelve active dosed diffusion cells were 

prepared from seven donors for each application condition (unoccluded, 

occluded, and an unoccluded control cell). Epidermal membranes 

were used, and their integrity was assessed by measuring 

the permeation rate of tritiated water over a period of 1 h. Permeation 

of linalool from a 5 ll/cm 2 dose was then measured at 12 

time-points over 24 h. Occluded conditions reduced the loss of volatile 

application vehicles and test compounds but may have also increased 

skin hydration, factors which caused a significant increase 

in the permeation of linalool. Under unoccluded experimental conditions, 

there was a gradual but comprehensive evaporative loss. 

Total absorbed dose values from an unoccluded application ranged 

from 1.8% to 3.57% (DPG < ethanol/DPG < ethanol/DEP < DEP < petrolatum 

< ethanol/water). Total absorbed dose values from an 

occluded application ranged from 5.73% to 14.4% (DEP < ethanol/ 

DEP < DPG < petrolatum < ethanol/DPG < ethanol/water). 

A similar study was conducted with dihydromyrcenol, an in vitro 

human skin absorption study with both in-use (unoccluded) and 

occluded conditions. The absorption of each dihydromyrcenol 

component (A and B) was measured via GC–MS and used to calculate 

the total dihydromyrcenol absorption. Skin permeation and 

distribution was determined using epidermal membranes from 

cosmetic surgery donors. Skin membranes were mounted into 

Franz-type diffusion cells with the stratum corneum facing the 

donor chamber. The average area available for diffusion was 

1.2 cm 2 . Dihydromyrcenol was applied, at the maximum in-use 

concentration of 6%, in 70/30 (v/v) ethanol/water to the skin surface 

at a dose of 5 ll/cm 2 . At 24 h, 3.85 ± 0.29 lg/cm 2 (unoccluded) 

and 15.0 ± 1.6 lg/cm 2 (occluded) (mean ± standard error, SE) of 

dihydromyrcenol had permeated, corresponding to 1.30 ± 0.10% 

(unoccluded) and 5.06 ± 0.53% (occluded) of the applied dose of 

296.2 lg/cm 2 . Levels of dihydromyrcenol in the epidermis (plus 

any remaining stratum corneum after tape stripping), filter paper 

membrane support and receptor fluid were combined (as per SCCFP 

guidelines) to result in a total absorbed dose value of 1.45 ± 0.10% 

(unoccluded) and 5.67 ± 0.58% (occluded). Differential absorption 

of the two components was observed, with greater levels of 

dihydromyrcenol A being absorbed under both unoccluded and occluded 

conditions. Overall recovery of dihydromyrcenol at 24 h was 

2.36 ± 0.24% (unoccluded) and 22.5 ± 2.1% (occluded). Low recoveries 

were attributed due to rapid evaporative loss of dihydromyrcenol. 

Under occluded conditions dihydromyrcenol may have 

undergone evaporation from the skin surface and subsequent loss 

through donor chamber sealing grease (RIFM, 2007g,h). 

In human skin,in vitro penetration into all skin layers was demonstrated 

for citronellol and linalool after 1 h of exposure. Total 

penetration amounts of linalool and citronellol were 827 and 

954 lg/cm 2 , respectively. Elimination from the skin was observed 

only for citronellol while the total skin content of linalool did not 

change, although diffusion from the stratum corneum into the epidermis/dermis 

occurred (Cal and Sznitowska, 2003; Belsito et al., 

2008). 

2.1.2. Animal studies 

Undiluted farnesol applied in vitro at 20% and 50% on pig skin 

stayed in the lipids of stratum corneum, and diluted farnesol in 

DMSO penetrated the epidermis and dermis of pigs (Bobin et al., 

1997; Belsito et al., 2008). 

2.2. Oral route of exposure 

When tritium labeled phytol was given to rats, the highest specific 

activity was found in the liver. The total activity remaining in 

the body was of the same order of magnitude as the levels of phytol 

metabolites, phytanic and phytenic acid, in the liver, as determined 

by gas chromatography. When phytol was fed in the diet, 

both metabolites were found in the liver (Bernhard et al., 1967). 

In rats, 72 h after a single oral dose of 500 mg 14 C-labelled linalool/kg 

body weight, about 55% of the dose was excreted in the urine, 

15% in the feces, and 23% as 14 CO 2 in the expired air. Only 3–4% 

residual activity was found in tissues (Parke et al., 1974; Belsito 

et al., 2008). 

2.3. Respiratory route of exposure 

For the compounds under review, no data on inhalation uptake 

were found. In studies with non-cyclic terpene alcohols, uptake via 

inhalation in mice was demonstrated (Belsito et al., 2008). 

After a 1 h inhalation exposure of mice to 5 mg/l linalool, serum 

levels were 7–9 ng/ml; they increased to 12 ng/ml linalool after 

addition of beta-glucuronidase to the blood assay (Jirovetz et al., 

1991; Buchbauer et al., 1991; Belsito et al., 2008). 

After a 1 h inhalation exposure to an atmosphere generated 

from 20–50 mg of essential oils or the pure materials (no data on 

air concentrations provided), the amounts detected in the plasma 

of mice at the end of the exposure period were 1.70 ng geraniol/ 

ml, 2.90 ng citronellol/ml, 4.22 ng linalool/ml and 5.70 ng nerol/ 

ml. Farnesol was not detected (Buchbauer et al., 1993; Belsito 

et al., 2008). 

3. Metabolism 

There are only limited data on metabolism of the alcohols under 

study. Data on terpene alcohols are available and applicable to 

these alcohols (Belsito et al., 2008). 

The main metabolism routes identified for the terpene alcohols 

include conjugation with glucuronic acid and oxidation of the primary 

alcohol group via the aldehyde to the acid and eventually to 

carbon dioxide. Alcohols with alkyl or alkenyl substituents may be 

oxidized at the allylic position to yield polar diol metabolites. 

Hydrogenation of the double bonds has also been demonstrated. 

Due to the structural similarities, similar metabolism pathways 

are expected for the alcohols under review. 

3.1. Conjugation 

Glucuronic acid conjugation and excretion is the primary route 

of metabolism of linalool, citronellol, nerol, and geraniol which are 

substrates of UDPGTs (UDP-glucuronosyltransferases). They show 

typical phenobarbital-like P450 induction behavior in Wistar rat liver 

(Boutin et al., 1985; Belsito et al., 2008). 

3.2. Oxidation of the carbon chain 

2-Methyl-3-buten-2-ol, a member of the group of tertiary allylic 

branched chain alcohols, induced cytochrome P450 3 A in mice 

after application of 1% or 2% via the drinking water for 3 days. It 

did not induce CYP450 2E and moderately induced CYP450 1 A 

(Mannering and Shoeman, 1996). 

Oxidation of the carbon chain, i.e. omega-hydroxylation or 

methyl side-chain oxidation was demonstrated for geraniol and 

linalool in rats. It is mediated by cytochrome P450 mainly in the 

liver but was also shown with rat lung and kidney microsomes 

for citronellol, geraniol, linalool and nerol. Further metabolism of

S14 


the diol metabolites of geraniol and linalool to aldehydes by alcohol 

dehydrogenase (ADH) is inhibited due to the bulky neighboring 

alkyl substituents and the substrate specificity of the enzyme (Chadha 

and Madyastha, 1982, 1984; Parke et al., 1974; JECFA, 1999; 

Eder et al., 1982a; Belsito et al., 2008). 

3.3. Oxidation of the alcohol group 

Primary alcohols: The oxidation of primary and primary allylic 

alcohols by alcohol dehydrogenase was investigated. Allylic alcohols 

were better substrates for human liver alcohol dehydrogenase 

than the corresponding saturated alcohols. A K m value of 

0.0045 mM was measured in vitro for 3-methyl-2-buten-1-ol. The 

reactivity of allylic alcohols increased with chain length (C3–C6 

investigated) (Pietruszko et al., 1973). 

Further oxidation of the aldehydes produces acids. The oxidation 

of the primary allylic alcohol phytol to the corresponding 

acids, phytanic acid (with reduced double bond; hexadecanoic 

acid, 3,7,11,15-tetramethyl-) and phytenic acid (2-hexadecenoic 

acid, 3,7,11,15-tetramethyl-), was shown in rats (Bernhard et al., 

1967). 

Especially short chained alcohols (e.g., 3-methyl-2-buten-1-ol) 

are primarily oxidized to the corresponding carboxylic acid that 

may enter the beta-oxidation pathway yielding shorter chain carboxylic 

acids that are subsequently metabolized to CO 2 via the tricarboxylic 

acid pathway (JECFA, 2004). 

Secondary alcohols: Secondary alcohols are expected to be excreted 

via conjugation or oxidation to ketones, which cannot be 

further oxidized. Additionally, they can be excreted unchanged or 

undergo hydroxylation of the carbon chain, which in turn may give 

rise to a metabolite that can be excreted. Generally all the metabolites 

show a low reactivity. 

Tertiary alcohols: Tertiary alcohols cannot be oxidized. They are 

expected to be excreted via conjugation, to be excreted unchanged, 

or to undergo hydroxylation of the carbon chain, which in turn 

may give rise to a metabolite that can be excreted. 

3.4. Hydrogenation of double bonds 

After a single oral dose of linalool to rats, reduced metabolites 

such as dihydro- and tetrahydrolinalool (metabolites D and E in 

Fig. 2) have been identified in the urine either free or in the conjugated 

form (Chadha and Madyastha, 1984; Parke et al., 1974a; Belsito 

et al., 2008). 

All of these reactions can occur to a varying degree, and they 

generally lead to polar metabolites. These metabolites can then 

be excreted by the kidneys or with the feces. As examples, the 

metabolisms of geraniol, a primary allylic alcohol, and linalool, a 

tertiary alcohol, are shown in Figs. 1 and 2: 

4. Toxicological studies 

4.1. Acute toxicity 

The dermal LD 50 values in rats, rabbits and guinea pigs are 

greater than 2000 mg/kg body weight and even greater than 

5000 mg/kg body weight in some cases, indicating that these compounds 

are of low acute toxicity or are practically non-toxic via the 

dermal route (Table 2a). 

The oral LD 50 values in rats and mice are greater than 2000 mg/ 

kg body weight except for 3-methyl-2-buten-1-ol and 2-methyl-3- 

buten-2-ol which show LD 50 values in the range of 800–2300 mg/ 

kg body weight (Table 2b). 

The most reported clinical sign was lethargy after oral or dermal 

application, diarrhea and gastrointestinal tract irritation after oral 

Fig. 1. Metabolism of geraniol in rats (Belsito et al., 2008). 

application, and irritation of the skin after dermal application. 

Acute toxicity data obtained from studies with other than oral or 

dermal exposure are summarized in Table 2c. 

4.2. Repeated dose toxicity 

There is little information available on toxicity after repeated 

dermal application for the alcohols included in this summary 

(see Table 3). Only linalool was tested in a repeated dose dermal 

toxicity study (RIFM, 1980b). 

Several of the alcohols under study were tested for toxicity after 

repeated oral application with histopathological evaluation. 

Ninety-day studies were conducted with isophytol, 3-methyl-2- 

buten-1-ol and dihydromyrcenol. Twenty-eight-day studies with 

2-methyl-3-buten-2-ol and isophytol and a one-generation study 

with isophytol (see Section 4.5 and Table 5) were performed. Furthermore, 

linalool was tested in a 28-day study (Belsito et al., 

2008), which is also included in this evaluation to increase the 

database. Only studies with histopathological examination were 

included. The results of these studies are summarized in Table 3. 

4.2.1. Dermal studies 

4.2.1.1. Primary and secondary alcohols. No studies are available for 

the members of these subgroups. 

4.2.1.2. Tertiary alcohols. SD rats (20/sex/dose) were dosed dermally 

by open application with 0, 250, 1000 or 4000 mg/kg body 

weight/day of linalool for 13 weeks (RIFM, 1980b; Belsito et al., 

2008). In order to minimize dermal irritation, the application sites 

were regularly changed. Slight erythema during the first three 

study weeks and slightly decreased activity were the only effects 

noted at the lowest dose level of 250 mg/kg body weight/day. 

One thousand mg/kg body weight/day caused slight erythema during 

the first six study weeks and a reduction in body weight in females. 

At 4000 mg/kg body weight/day, nine females and two 

males died. The food consumption in males was reduced early in 

the study, and a reduced body weight was found. Sporadic and 

transient lethargy was observed at the two lowest dose levels. Extreme 

lethargy was observed at the highest dose level. Liver 

weights were increased in both sexes; while kidney weight was 

elevated in females only. Slight erythema and slight to moderate 

epithelial hyperplasia were noted. No pathological findings were 

reported from hematology, clinical chemistry or urinalysis. The 

histopathological examination of skin, adrenals, brain, heart, 

kidneys, liver, thyroids, mesenteric lymph node, spinal cord, testes, 

ovaries, spleen, urinary bladder, sternal bone marrow, pituitaries 

and sciatic nerve did not show adverse effects. The no observed 

adverse effect level (NOAEL) was 250 mg/kg body weight/day;


and water consumption in males and females was reduced. In 

males, the mean absolute liver weights (but not the relative liver 

weights) were significantly decreased (high dose: 14.9%, mid 

dose: 7.9%) when compared to controls. At the high dose, in 

males and females, the urine volume was decreased with increased 

specific gravity, related to reduced water consumption. In males 

and females of the 5000 ppm group (243.8 and 307.2 mg/kg body 

weight/day), body weight and body weight gain were significantly 

reduced. The reduced absolute liver weight in high dose males can 

be explained by the reduced body weight, as the relative liver 

weight was not reduced. The NOAEL was assessed to be 

1000 ppm (65.4 and 82.1 mg/kg body weight/day) based on significant 

decrease of body weight as a consequence of reduced food 

and water consumption at 5000 ppm (243.8 and 307.2 mg/kg body 

weight/day) (RIFM, 2002c). 

4.2.2.3. Secondary and secondary allylic alcohols. No studies are 

available for members of these subgroups. 

Fig. 2. Metabolism of linalool in rats (Belsito et al., 2008). 

the lowest observed adverse effect level (LOAEL) was 1000 mg/kg 

body weight/day (based on body weight reduction in females). 

4.2.2. Oral studies 

4.2.2.1. Primary alcohols. No studies are available for members of 

this subgroup. Also, in the RIFM group summary of terpene alcohols 

(Belsito et al., 2008), no information on histopathological 

changes of primary non-cyclic terpene alcohols after repeated oral 

administration is contained. 

4.2.2.2. Primary allylic alcohols. In a 90-day study according to 

OECD test guideline 408, 3-methyl-2-buten-1-ol was administered 

in the drinking water in concentrations of 0, 200, 1000 or 

5000 ppm (14.4 and 21.0 mg/kg body weight/day, 65.4 and 

82.1 mg/kg body weight/day or 243.8 and 307.2 mg/kg body 

weight/day for males and females). In the mid dose groups, feed 

4.2.2.4. Tertiary alcohols. An oral 28-day study according to OECD 

test guideline 407 was conducted with 2-methyl-3-buten-2-ol 

(Roche, 1994 as cited in OECD/SIDS, 2005b). Ten to fourteen Wistar 

rats per sex and dose group were exposed to 0, 50, 200 or 600 mg/ 

kg body weight/day by gavage. No toxicologically relevant changes 

were noted in the low dose group. In mid dose (200 mg/kg body 

weight/day) female rats, minimally increased (not stated whether 

relative or absolute) liver weights and hypertrophy of hepatocytes 

were observed. In males, minimally increased (not stated whether 

relative or absolute) kidney weights and a slight to moderate accumulation 

of renal hyaline droplets were noted. At 600 mg/kg body 

weight/day, two animals died spontaneously and without a known 

cause. The LOEL was reported as 200 mg/kg body weight/day based 

on increased liver weight and hypertrophy of hepatocytes (probably 

enzyme induction). The NOEL of this study was 50 mg/kg body 

weight/day. 

Isophytol was tested in a 28-day repeated oral dose test according 

to OECD test guideline 407 in male and female Sprague–Dawley 

rats with an additional 14-day treatment-free observation 

Table 2a 

Acute dermal toxicity studies. 

Material Species No. animals/dose LD 50 (mg/kg body weight) a References c 


2-Isopropenyl-5-methyl-4-hexene-1-ol b Guinea pig 10 >5000 RIFM (1982a) 


2-Isopropyl-5-methyl-2-hexene-1-ol b Rabbit 8 >5000 RIFM (1973a) 

3-Methyl-2-buten-1-ol Rabbit 4 3900 (95% C.I. 2500–6000) RIFM (1977a) 

Rat 6 (3/sex) >4000 RIFM (1979i) 

Phytol Rabbit 10 >5000 RIFM (1977a) 


Methylheptenol Rabbit 10 >5000 RIFM (1976a) 

7-Nonen-2-ol,4,8-dimethyl- Rabbit 10 >2000 RIFM (1979d) 


7-Octen-2-ol, 2-methyl-6-methylene-, dihydro derivative Rabbit 10 >5000 RIFM (1973a) 

2,6-Dimethyl-2-hepten-6-ol b Rabbit 10 >5000 RIFM (1974a) 

3,7-Dimethyl-1,6-nonandien-3-ol Rabbit 10 >5000 RIFM (1975a) 

Dihydromyrcenol Rabbit 10 >5000 RIFM (1977a) 

Isophytol Rabbit 10 >5000 RIFM (1982a) 

2-Methyl-3-buten-2-ol Rabbit Not reported >2000 RIFM (1972e) 

3-Methyl-1-octen-3-ol b Rabbit 10 >5000 RIFM (1978a) 

3-Methyl-1-octyn-3-ol b Rabbit 4 (2/sex) 5600 (95% C.I. 4000–8000) RIFM (1979a) 

Nerolidol (isomer unspecified) d Rabbit 10 >5000 RIFM (1973b) 

3,7,9-Trimethyl-1,6-dicadien-3-ol b Rabbit 10 >5000 RIFM (1977a) 

a 

b 

c 

Units have been converted to make easier comparisons; original units are in the fragrance material reviews. 

No relevant use was reported, therefore the available data are mentioned only in the table but not in the text. 

Not all of the original reports in the OECD/SIDS assessment were made available to RIFM. 

d Materials have been previously reviewed by in RIFM’s safety assessment of terpene alcohols (Belsito et al., 2008).

S16 


Table 2b 

Acute oral toxicity studies. 

Material Species No. animals/dose LD 50 (mg/kg body weight) a References c 


2-Isopropenyl-5-methyl-4-hexene-1-ol b Mouse 10 (males) >5000 RIFM (1982a) 


2-Isopropyl-5-methyl-2-hexene-1-ol b Rat 10 >5000 RIFM (1973a) 

3-Methyl-2-buten-1-ol Rat 10 810 (95% C.I. 550–1180) RIFM (1977a) 

Rat 20 (10/sex) 1591 RIFM (1970e) 

RIFM (2003a) 

Phytol Rat 10 >5000 RIFM (1977a) 

Rat Not reported >10,000 (50% in olive oil) RIFM (1978b) 


7-Nonen-2-ol,4,8-dimethyl- Rat 10 >5000 RIFM (1979c) 

Rat 10 >2000 RIFM (2004a) 

Methylheptenol Rat 10 >5000 RIFM (1976a) 

Mouse 5 3903 ± 297 RIFM (1967a) 

Subgroup: secondary allylic 

4-Methyl-3-decen-5-ol Mouse 10 >8000 RIFM (1980a) 


7-Octen-2-ol, 2-methyl-6-methylene-, dihydro derivative Rat 10 3600 (95% C.I. 3000–4200) RIFM (1973a) 

Rat 10 (5/sex) 4150 (95% C.I. 2990–6060) RIFM (1977b) 

2,6-Dimethyl-2-hepten-6-ol b Rat 10 >5000 RIFM (1974a) 

3,7-Dimethyl-1,6-nonadien-3-ol Rat 10 5000 RIFM (1975a) 

Mouse 5 5283 ± 383 RIFM (1967a) 

Dihydromyrcenol Rat 10 4100 (95% C.I. 3500–4800) RIFM (1977a) 

Isophytol Rat 10 >5000 RIFM (1982a) 

Rat Not reported 5400 RIFM (1969) 

RIFM (1970a) 

Rat 5 or 10 >8000 Bächtold (1973) as cited in OECD/SIDS (2006) 

Mouse 5 or 10 >8000 Bächtold (1980) as cited in OECD/SIDS (2006) 

Isophytol (crude) Rat 5 or 10 >12,000 Bächtold (1980) as cited in OECD/SIDS (2006) 

Mouse 5 or 10 >8000 Bächtold (1980) as cited in OECD/SIDS (2006) 

2-Methyl-3-buten-2-ol Rat Not reported 1800 RIFM (1991) 

Rat Not reported 2280 Roche (1990) as cited in OECD/SIDS (2005b) 

3-Methyl-1-octen-3-ol b Rat 10 1800 (95% C.I. 1300–2500) RIFM (1978a) 

3-Methyl-1-octyn-3-ol b Rat 5 (male) 860 (95% C.I. 610–1200) RIFM (1979a) 

Nerolidol (isomer unspecified) d Rat 10 >5000 RIFM (1973b) 

Mouse 5 (male) 9976 ± 350 RIFM (1967a) 

3,7,9-Trimethyl-1,6-dicadien-3-ol b Rat 10 >5000 RIFM (1977a) 

Mouse 5 (male) 5892 ± 555 RIFM (1967a) 

a 

b 

c 




d Materials have been previously reviewed by in RIFM’s safety assessment of terpene alcohols (Belsito et al., 2008). 

period for half of the control and high dose animals (Strobel and 

Lambert, 1998, as cited in OECD/SIDS, 2006). In control and high 

dose groups, 12 animals per sex were exposed, and the remaining 

two groups used six per sex. Doses administered were 0, 250, 500 

or 1000 mg/kg body weight/day per gavage. No obvious treatmentrelated 

abnormalities were observed at necropsy or during histopathological 

examination. Hunched posture, weight loss and pallor, 

increased body weight in males, a number of clinical 

chemistry changes in males and females, increased liver weights 

in both sexes, and increased kidney and spleen weights in females 

were associated with the 1000 mg/kg body weight/day dosage 

group. The majority of clinical findings, although statistically different 

from the vehicle control group, were within the ranges of 

historical background data quoted for control animals. After a 

14-day treatment-free period, the majority of changes were no 

longer apparent. The NOAEL was 500 mg/kg body weight/day 

while the LOAEL, based on minor and reversible changes, was set 

at 1000 mg/kg body weight/day. 

Coriander oil containing 72.9% linalool was tested in a 28-day 

study on rats. The oil was administered by gavage to male and female 

rats at dose levels of 160, 400 or 1000 mg/kg body weight/day 

(117, 290, and 729 mg linalool/kg body weight/day) (RIFM, 1990; 

Belsito et al., 2008). Absolute liver weights were increased in mid 

and high dose animals. In the high dose group, degenerative lesions 

were found in the renal cortex of males, and hepatocellular cytoplasmic 

vacuolization was seen in females. Based on these effects, 

the NOAEL was 160 mg/kg body weight/day (117 mg linalool/kg 

body weight/day). 

Dihydromyrcenol was tested in a 90-day toxicity study in rats 

according to OECD test guideline 408 (RIFM, 2007a,b,c,d,e,f,g,h). 

The test substance was administered by gavage to male and female 

rats at dose levels of 0, 10, 50, 500 or 1000 mg/kg body weight/day 

in corn oil, with 10 animals per sex and group. Incidents of increased 

salivation were evident in all dose groups, indicative of local 

irritation but not of a systemic effect. No toxicologically 

relevant changes were noted in females of the low dose group. In 

males of all dose groups, a greater incidence and severity of basophilic 

tubules or globular accumulations of eosinophilic material 

consistent with an accumulation of a 2u -globulin within the proximal 

tubular epithelium were observed. Males treated with doses of 

50 mg/kg body weight/day and higher showed reduced platelet 

counts and elevated plasma urea and creatinine levels. Absolute 

and relative liver weights were elevated in males as well. Animals 

of the two higher dose groups revealed reduced body weight gain 

and feed consumption, increased water consumption, elevated 

cholesterol levels and increased relative and absolute kidney 

weights. Animals of either sex treated with 500 and 1000 mg/kg 

body weight showed statistically significant increases in liver


Table 2c 

Acute miscellaneous toxicity studies. 

Material Dosing route Species No. animals/dose LD 50 References b 


LC 50 extrapolated to 4 h according to Haber’s 

rule: > 7.7 mg/l (4 h) 

RIFM (1970e, 2003e) 

Rat 3 h: 12 (6/sex) 

8 h: 6 (3/sex) 

3-Methyl-2-buten-1-ol Inhalation, exposure to a saturated vapor (20 °C) for 3 h 

and 8 h 

>16.8 mg/l (4 h) 

Reduced post observation time (7 days instead of 14 

days) 

i.p. injection (water emulsion in gum tragacanth) Mouse 10 (5/sex) 413 mg/kg body weight RIFM (2003b) 

RIFM (1980a) 


4-Methyl-3-decen-5-ol i.p. injection (Gummi arabicum emulsion) Mouse 10 1000–2000 mg/kg body weight (10/10 died at 2000 mg/ 

kg body weight, No mortality at 1000 mg/kg body 

weight) 


Isophytol i.p. injection (1–30% water emulsion in gum tragacanth) Mouse Not reported Approx. 0.2 ml/kg body weight RIFM (1969, 1970a) 

Inhalation, exposure to isophytol-saturated air (20 °C Rat 12 No deaths and no lesions at necropsy, RIFM (1969, 1970a) 

and 100 °C) for 8 h 

2-Methyl-3-buten-2-ol 4 h inhalation Rat 5/sex LC 50 > 21.2 mg/l RIFM (1989e) 

i.p. injection Rat Not reported 1315 mg/kg body weight Wohlfahrt et al. (1993) 

i.p. injection Mouse Not reported (only males) 1117 mg/kg body weight Wohlfahrt et al. (1993) 

3-Methyl-1-octyn-3-ol a 1 h inhalation Rat 10 (5/sex) LC 50 > 20 mg/l RIFM (1979a) 

No relevant use was reported; therefore the available data are mentioned only in the table but not in the text. 


a 

b 

weights, both absolute and relative to terminal body weights. 

Both sexes also had centrilobular hepatocyte enlargement, occasionally 

with associated centrilobular lipid-type vacuolation of 

hepatocytes. 

Renal tubular necrosis was noted in males of the 500 and 

1000 mg/kg body weight/day group. Also, reductions in haemoglobin, 

haematocrit, albumin/globulin ratio, and erythrocyte counts 

were found in females treated with 1000 mg/kg body weight/day, 

and the reductions on erythrocyte count extended into the females 

treated with 500 mg/kg body weight/day. In high dose animals, 

noisy respiration, increased salivation, hunched posture and tiptoe 

gait were observed throughout the treatment period. In males, 

higher grades of severity of adipose infiltration of the bone marrow 

were observed, which was interpreted by the authors as indication 

of hypoplasia. The a 2u -globulin nephropathy is a male rat-specific 

renal syndrome and has no relevance for humans. The authors concluded 

that the histopathologically identified kidney changes could 

be regarded as male rat-specific effects. The NOAEL was 10 mg/kg 

body weight/day in males because of elevated liver weight and elevated 

plasma levels of urea and creatinine at 50 mg/kg body 

weight/day. However, in female rats at this dose, no treatment-related 

changes were noted and a NOEL of 50 mg/kg body weight/ 

day was established. 

In a one-generation study according OECD test guideline 415 

(Beekhuijzen, 2002, as cited in OECD/SIDS, 2006), female and male 

Wistar Crl: (WI) BR (outbred, SPF) rats were orally administered 

isophytol in vegetable oil per gavage at doses of 0, 250, 500 or 

1000 mg/kg body weight/day. Exposure duration in males ranged 

from 91 to 134 days (average 98 days) while in females exposure 

ranged from 52 to 108 days (average 64 days). The following toxicologically 

relevant findings were noted for the parental animals: 

Dilated renal tubules and general mineralization were consistently 

observed in all treatment groups and in both males and females. In 

addition, in males of all treatment groups, a decrease in the incidence 

of hyaline droplets was found. In the two higher dose 

groups, absolute and relative kidney weights were significantly increased 

in females; in the kidneys of males and females basophilic 

aggregates and increased basophilic tubules were noted. In the 

high dose group a significant increase in the relative kidney weight 

was observed in males, however, body weight was depressed. In 

high dose females there was an increase in lethargy, hunched posture, 

piloerection, and body weight loss during lactation. The animals 

showed minimal to moderate periportal hepatocyte 

vacuolation. Based on the kidney effects, no NOAEL can be derived. 

The LOAEL is 250 mg/kg body weight/day. 

No effects on kidneys were observed (Strobel and Lambert, 

1998, as cited in OECD/SIDS, 2006) in the isophytol 28-day repeated 

dose toxicity test discussed above, which might be due to 

the shorter exposure time in comparison to the one-generation 

study or to differences in the strain of rat and diet. 

4.2.3. Inhalation studies 

No repeated-dose inhalation toxicity studies are available. 

4.3. Genotoxicity 

Genotoxicity testing with the alcohols under study has been 

performed mostly in vitro, with only a few substances (the primary 

allylic alcohol 3-methyl-2-buten-1-ol and the tertiary alcohols isophytol 

and 2-methyl-3-buten-2-ol) tested in vivo. To supplement 

the database, studies with the primary allylic alcohols, farnesol 

and geraniol, and the tertiary alcohol, linalool, which have already 

been assessed (Belsito et al., 2008), were used for the evaluation of 

the genotoxic potential of alcohols with unsaturated branched 

chain. The results of these tests are summarized in Tables 4a and 

4b.

S18 


4.3.1. In vitro genotoxicity studies 

The in vitro genotoxicity studies contained in Belsito et al., 2008 

have been checked for whether the substances were tested up to 

cytotoxic levels to ensure the validity of negative test results. 

In an assay for sister chromatid exchange, up to 150 lg linalool/ 

ml gave negative results in Chinese Hamster Ovary (CHO) cells 

(Sasaki et al., 1989). A test for induction of unscheduled DNA synthesis 

with linalool was negative in rat primary hepatocytes in 

concentrations up to 43.6 lg/ml (Heck et al., 1989; RIFM, 1986a). 

The positive and equivocal results observed in two rec-assays with 

linalool ‘‘may have been caused by unspecific cytotoxicity, and are 

therefore of limited relevance for the evaluation of the genotoxicity 

of linalool” (Belsito et al., 2008). Citronellol was negative in a recassay 

(Belsito et al., 2008). 

The primary alcohol, citronellol; the primary allylic alcohols, 

farnesol, geraniol, and 3-methyl-2-buten-1-ol; the secondary 

allylic alcohol, 4-methyl-3-decen-5-ol; and the tertiary alcohols, 

3,7-dimethyl-1,6-nonadien-3-ol, isophytol, 2-methyl-3-buten-2- 

ol, dehydrolinalool and linalool were inactive in bacterial mutagenicity 

assays (Ames tests). Linalool was also inactive in mammalian 

cell systems (mouse lymphoma cells). The weak positive result 

with linalool in one mouse lymphoma assay (Heck et al., 1989) 

was probably associated with unphysiological changes in the culture 

medium, as a second test under normal osmolality and pH 

was negative (Belsito et al., 2008). 

In a host-mediated assay the urine of rats given citronellol or 

linalool showed no mutagenic activity in Salmonella typhimuriumstrains 

TA98 and TA100 without S9 activation (Rockwell and 

Raw, 1979; Belsito et al., 2008). 

The primary allylic alcohols, farnesol and geraniol, as well as the 

tertiary alcohol, linalool, did not induce chromosome aberrations 

in vitro when incubated with Chinese hamster ovary or Chinese 

hamster fibroblast cells (Ishidate et al., 1984; RIFM, 1983b; Rupa 

et al., 2003). 

When geraniol was tested up to toxic levels (78.1–156.3 lg/ml) 

the results were inconclusive in vitro (Rupa et al., 2003). However, 

in a micronucleus test in vivo by the same authors, geraniol was not 

mutagenic (see in vivo genotoxicity studies below). Therefore, the 

inconsistency observed in vitro genotoxicity is not expressed 

in vivo and not of concern (Belsito et al., 2008). 

4.3.2. In vivo genotoxicity studies 

The primary allylic alcohols, farnesol, geraniol and 3-methyl-2- 

buten-1-ol; and the tertiary alcohols, isophytol, 2-methyl-3-buten- 

2-ol and linalool, were non-genotoxic in the mouse bone marrow 

micronucleus test (RIFM, 1992; RIFM, 2001b; Meerts, 2002 as cited 

in OECD/SIDS, 2006; RIFM, 2001; Rupa et al., 2003). 

4.4. Carcinogenicity 

No valid bioassays on carcinogenicity are available for the alcohols 

with unsaturated branched chain or for closely structurally related 

substances. 

4.5. Reproductive and developmental toxicity 

4.5.1. Fertility 

4.5.1.1. Primary alcohols. No studies are available for the members 

this subgroup or for closely structurally related substances. 

4.5.1.2. Primary allylic alcohols. Histopathological examinations of 

the reproduction organs of male and female rats in the 90-day repeated 

dose study with 3-methyl-2-buten-1-ol (RIFM, 2002c) 

administered by drinking water showed no adverse effects on 

males and females up to the highest concentration tested (243.8 

and 307.2 mg/kg body weight/day). No treatment-related changes 

in sperm analysis were observed (see Table 3). 

4.5.1.3. Secondary alcohols. No studies are available for the members 

of these subgroups. 

4.5.1.4. Tertiary alcohols. No gross or histopathological effects on 

the primary reproduction organs (ovaries, uterus, testes and epididymis) 

were noted in rats after administration of coriander oil 

containing 72.9% of linalool for 28 days. The oil was given by gavage 

to male and female rats at dose levels of 160, 400 or 

1000 mg/kg body weight/day (117, 292 or 729 mg linalool/kg body 

weight/day) (RIFM, 1989d; Belsito et al., 2008) (see Table 3). 

Dihydromyrcenol was tested in a 90-day toxicity study in rats. 

The test substance was administered by gavage to male and female 

rats at dose levels of 0, 10, 50, 500, or 1000 mg/kg body weight/ 

day. Histopathological examinations of the reproduction organs 

showed no adverse effects. No treatment-related effects on female 

estrous cycles or proportion of females with anomalous estrous cycles 

were observed. In males, sperm motility values, morphological 

assessments, or homogenization-resistant spermatid counts were 

unaffected (RIFM, 2007a) (see Table 3). 

In a screening test for reproductive and developmental toxicity 

according to OECD test guideline 421 (draft), 2-methyl-3-buten-2- 

ol was administered to 10 male and 10 female Fü–Albino (RORO) 

rats per sex and group at doses of 0, 12.5, 50 or 200 mg/kg body 

weight/day (Roche, 1995b as cited in OECD/SIDS, 2005b). The test 

material was given by gavage once daily, starting 14 days premating. 

The exposure duration was 22 days and the duration of the 

study 54 days. At the high dose, parental effects reported include 

reduced body weight in males and a slight compound-related decrease 

of the food consumption of females. The parental NOAEL 

was 50 mg/kg body weight/day. The reproduction parameters were 

unaffected (mean number of: corpora lutea, implantations, pups 

per litter; resorption rates, mean gestation lengths, mean pup 

weights, pup sex ratios). Administration of 2-methyl-3-buten-1- 

ol at levels up to 200 mg/kg body weight/day was without effect 

on the general reproductive performance of the test animals. 

In a one-generation study according to OECD test guideline 415, 

isophytol in doses of 0, 250, 500 or 1000 mg/kg body weight/day 

was administered by gavage to 24 male and 24 female rats per 

dose group (Beekhuijzen, 2002 as cited in OECD/SIDS, 2006). The 

parental effects were described above in Section 4.2.2. Reproductive 

parameters were affected in the highest dose group. Females 

showed a slightly increased mean pre-coital time and decreases 

in fertility index and conception rate. The numbers of dead pups 

at first litter check, postnatal losses and breeding losses were significantly 

increased, resulting in a decreased weaning index. In 

conclusion, 250 mg/kg body weight/day was the LOAEL for parental 

systemic toxicity based on effects in kidneys in males and females 

(dilated renal tubule, renal mineralization). Five hundred 

mg/kg body weight/day was the NOAEL for parental effects on 

reproduction based on slightly increased mean pre-coital time, decreased 

fertility index and conception rate in females. 

The reproductive toxicity of linalool was investigated in four 

groups of 10 virgin Crl CD rats administered 0, 250, 500 or 

1000 mg/kg body weight/day of an essential oil (coriander oil) containing 

72.9% linalool by mass (182, 365 or 729 mg linalool/kg 

body weight/day) (RIFM, 1989d). The test material was given by 

gavage once daily; seven days prior to cohabitation; through 

cohabitation (maximum of seven days), gestation, and delivery; 

and for a 4-day post-parturition period. The duration of the study 

was 39 days. Maternal indices monitored included observation, 

body weights, feed consumption, duration of gestation, and reproductive 

parameters (mating and fertility index, gestation index, 

number of offspring per litter). In the dams, all dosages caused ex-


Table 3 

Repeated dose toxicity studies. 

Material Method Dose (mg/kg body Species (no./dose 

weight/day) a group) 

Results (mg/kg body weight/day) a References b 


3-Methyl-2- Oral (drinking 

buten-1-ol water), 14 days 

Oral (drinking 

water), 14 days 

Oral (drinking 

water), 90 days, 

OECD 408 

0.25, 0.5, 0.75 rat (3/sex/dose) No effects RIFM (2003c) 

250, 500, 750, 

1500 

m: 14.4, 65.4, 

243.8 f: 21, 82.1, 

307.2 

Rat (3/sex/dose) Decreased food and water consumption at 250 mg/kg 

Rat (Wistar) (10/ 

sex/dose) 

Slight to moderate salivation at 500 and 750 mg/kg RIFM (2003c) 

Significant decreases in food and water consumption at 1500 mg/kg (treatment stopped after day 5) RIFM (2003d) 

NOAEL = 65.4 (m) or 82.1 (f) 

LOAEL = 243.8 (m) or 307.2 (f) 

14.4 or 21: no effects 

P65.4 or 82.1: food consumption decreased (f), water consumption decreased (m,f); abs. liver weight decreased (m) RIFM (2002c) 

243.8 or 307.2: food consumption decreased (m), body weight decreased (m,f), body weight gain decreased (m,f); 

urinary volume decreased (m,f), urine specific gravity increased (m,f) 


2-Methyl-3- 

buten-2-ol 

Oral (gavage) 

28 day 

Oral (gavage), 28 

days, OECD 407 

Dihydromyrcenol Oral (gavage), 90 

days OECD 408 

Isophytol Oral (gavage), 28 

days plus 14 days 

post-treatment 

observation 

(control and high 

dose group) OECD 

407 

30, 150, and 750 Rat (Wistar) (5/ 

sex/dose) 

0, 50, 200, 600 

(vehicle not 

mentioned) 

0 (corn oil), 10, 50, 

500 or 1000 

0 (maize/corn oil), 

250, 500, 1000 

Rat (Wistar) (10– 

14/sex/dose) 

Rat (crl:CD (SD) 

IGS BR) (10/sex/ 

dose) 

Rat (Crl:CD (SD)BR 

(VAF plus) (6 or 12 

(control, high 

dose) animals/sex/ 

group) 

NOAEL = 150 

750: ataxia (m,f), decrease in chloride (m,f) triglycerides (m) and potassium (f), increase in cholesterol (m,f) and 

magnesium (m). 

No substance-related findings 30, or 150 

NOEL = 50 

NOAEL = 50 

LOAEL = 200 

P200: liver weight increased (f), hypertrophy of hepatocytes (1f); kidney weight increased (m), slight to moderate 

accumulation of renal hyaline droplets (m) 600: sedation, ataxia, uncoordinated gait during first days of application 

(m,f); salivation increased (m,f); 2 animals died (1m, 1f); liver weight increased (m), periacinar hypertrophy of 

hepatocytes (m,f), transaminases increased (m,f) 

NOEL females = 50 

NOAEL males = 10 

P10: overall activity increased (f); plasma urea decreased (f), ; rel. and abs. adrenal weight increased (m), rel. and 

abs. thymus weight increased (m); incidence and/or severity of groups of basophilic tubules increased (m), 

accumulation of a2u-globulin in renal proximal tubular epithelium (m) 

P50: platelet count decreased (m); plasma urea increased (m), creatinine increased (m); rel. and abs. liver weight 

increased (m) 

P500: body weight gain decreased, food consumption decreased (m, f), water consumption increased (m,f); 

cholesterol increased (m,f);, erythrocyte count decreased (f),, rel. and abs. kidney weight increased (m,f), rel. and 

abs. liver weight increased (f); centrilobular hepatocyte enlargement, occasionally with associated centrilobular 

lipid-type vacuolation of hepatocytes (2m,2f), tubular necrosis (m) 

1000: last 20% of recorded mobile activity increased (m); increased salivation, noisy respiration, hunched posture, 

tiptoe gait (m,f);, haemoglobin, haematocrit decreased (f), higher grades of severity of adipose infiltration of the 

bone marrow increased (m);albumin/globulin ratio decreased (f); urine volume increased (m,f), specific gravity 

decreased (m,f); rel. and abs. adrenal weight increased (f); centrilobular hepatocyte enlargement, occasionally with 

associated centrilobular lipid-type vacuolation of hepatocytes (stat. sign.) (m,f) 

NOAEL = 500 

LOAEL = 1000 

P250: blood Ca increased (f) (reversible); abs. kidney weight increased (f), abs. spleen weight increased (m,f); 

terminal body weight increased (m) 

RIFM (1994d) 

Roche (1994) as 

cited in OECD/SIDS 

(2005b) 

RIFM (2007a) 


S20 



Material Method Dose (mg/kg body Species (no./dose 

weight/day) a group) 

Results (mg/kg body weight/day) a References b 

Oral (gavage), one 

generation study, 

males average 

98 day (91–134), 

females average 

64 day (52-108), 

OECD 415 

Linalool c dermal, open 

application, 13 

weeks 

Linalool (72.9% in Oral (gavage), 

coriander oil) c 28 day study 

0 (maize/corn oil), 

250, 500, 1000 

0 (saline), 250, 

1000 or 4000 

0 (vehicle), 160, 

400 or 1000 mg 

coriander oil/kg 

body weight/day 

in 1% 

methylcellulose 

(117, 290, 729 mg 

linalool/kg body 

weight/day) 

Rat (Wistar, 

Crl:WI (BR) 

outbred, SPF) (24/ 

sex/dose) 

SD rat (20/sex/ 

dose) 

SD rat (10/sex/ 

dose) 

P500: blood Ca increased (m), alanine aminotransferase increased (m) (both reversible); urine volume increased, 

specific gravity decreased (m) 

1000: fur-staining (f), hypoactivity, hunched posture, weight loss, pallor (in 1 f); alanine aminotransferase increased 

(f) (reversible); white blood cell counts increased (f), mean prothrombin time decreased (m) (both reversible); urine 

volume increased, specific gravity decreased (f) (no recovery); abs. and rel. liver weight increased (m,f) (reversible), 

rel. kidney weight increased (f), rel. spleen weight increased (f), rel. brain weight decreased (m,f) 

LOAEL = 250 

P 250: dilated renal tubules (m,f), renal mineralization (m,f), renal hyaline droplets decreased (m) 

P 500: abs. kidneys weight increased (m,f), rel. kidney weight increased (f), incidence and severity of renal 

basophilic aggregates increased (m,f), incidence and severity of renal basophilic tubules increased (m,f) 

1000: lethargy, hunched posture, piloerection (f); body weight, terminal body weight decreased (m), body weight 

loss during lactation (f), food consumption during lactation decreased (f); abs. and rel. prostate weight decreased, 

abs. seminal vesicles weight decreased, rel. kidneys weight increased (m), abs. and rel. uterus weight increased (f); 

periportal hepatocyte vacuolation decreased(f) 

NOAEL: 250 

P250: slightly decreased activity, slight erythema during the first 3 weeks 

P1000: slight erythema during the first 6 weeks, body weight decreased (f) 

4000: 9 females and 2 males died; lethargy in females; slight erythema; food consumption in males decreased early 

in study, body weight decreased (m); liver weight increased, kidney weight (f) increased, slight to moderate 

epithelial hyperplasia; histology, hematology, clinical chemistry and urinalysis findings normal 

NOAEL: 117 

117 mg/kg body weight/day: no adverse effects 

P290 mg/kg body weight/day: abs. and rel. kidney weight increased (m), abs. and rel. liver weight increased, total 

protein and serum albumin increased (m), histopathology: lesions in the nonglandular region of the stomach (f) 

729 mg/kg body weight/day: abs. and rel. kidney weight increased (f), total protein and serum albumin increased (f), 

serum calcium increased (m), histopathology: degenerative lesions in renal cortex (m); hepatocellular vacuolization 

(f) 

Strobel and Lamber 

(1998) as cited in 

OECD/SIDS (2006) 

Beekhuijzen (2002) 

as cited in OECD/ 

SIDS (2006) 

RIFM (1980b) 

RIFM (1990) and 

Belsito et al. (2008) 

NOEL: no observed effect level. 

NOAEL: no observed adverse effect level. 

LOAEL: lowest observed adverse effect level. 

m: male, f: female. 

rel: relative, abs.: absolute. 

a 

b 

c 



Materials have been previously reviewed by in RIFM’s safety assessment of terpene alcohols (Belsito et al., 2008).


cess salivation, a sign of local irritation. At 729 mg/kg body weight/ 

day, there were statistically significant decreases in gestation index, 

length of gestation, body weight during premating, feed consumption, 

and litter size. The NOAEL for systemic maternal 

toxicity and fertility was 365 mg/kg body weight/day based on decreased 

body weight and gestation index at 729 mg/kg body 

weight/day. 

4.5.2. Developmental toxicity 

4.5.2.1. Primary and primary allylic alcohols. The developmental 

toxicity of 3-methyl-2-buten-1-ol was investigated according to 

OECD test guideline 414. Time-mated female Wistar rats (n = 25) 

were dosed via gavage on gestational days 7–19 post coitum with 

an aqueous suspension of 3-methyl-2-buten-1-ol at 0, 50, 200 or 

600 mg/kg body weight/day (RIFM, 2002d). In the high dose group, 

clinical signs including salivation, lacrimation, abdominal position 

and piloerection were observed throughout the treatment period. 

One dam in the high dose group died before scheduled sacrifice. 

It is likely that the death of this dam is substance related because 

high dose rats showed signs of maternal toxicity. However, no 

other clinical or necropsy findings were observed that would help 

explain this unscheduled death. Feed consumption, body weight, 

and body weight gain were statistically significantly reduced. No 

signs of substance-induced maternal toxicity occurred at the low 

and the mid dose levels. The maternal NOAEL was 200 mg/kg body 

weight/day based on clinical signs and effected body weights at the 

highest dose. At 600 mg/kg body weight/day, developmental toxicity 

was not observed. 

4.5.2.2. Secondary alcohols. No studies are available for the members 

of these subgroups or for closely structurally related 

substances. 

4.5.2.3. Tertiary alcohols. In a one-generation study according to 

OECD test guideline 415, 0, 250, 500 or 1000 mg of isophytol/kg 

body weight/day was administered by gavage to 24 male and 24 

female rats per dose group (Beekhuijzen, 2002 as cited in OECD/ 

SIDS, 2006; see above). A parental NOAEL was not obtained (see 

Section 4.5.1). In the highest dose group, the survival and general 

fitness of pups was reduced. Growth retardation, little or no milk 

uptake and mortality were observed. Mean body weights of both 

female and male pups of the high dose group were significantly decreased 

on days 4–7 of lactation in comparison with controls. The 

NOAEL for postnatal developmental toxicity was 500 mg/kg body 

weight/day. 

In a screening test for reproduction and developmental toxicity 

according to OECD test guideline 421 (draft), 2-methyl-3-buten-2- 

ol was administered by gavage to 10 male and 10 female Fü–Albino 

(RORO) rats per sex and group at doses of 0, 12.5, 50 or 200 mg/kg 

body weight/day (Roche, 1995b as cited in OECD/SIDS, 2005b; see 

above). The pup viability index was reduced at the highest dose level. 

The NOAEL for developmental toxicity was 50 mg/kg body 

weight/day. 

An essential oil (coriander oil) containing 72.9% linalool by mass 

was tested in a one-generation study in four groups of 10 virgin Crl 

CD rats. The estimated doses of linalool were 0, 250, 500 or 

1000 mg/kg body weight/day (RIFM, 1989d). The authors concluded 

that there were no effects observed in the dams at 

250 mg/kg body weight/day or in the offspring at the 250 and 

500 mg/kg body weight/day levels of coriander oil. They concluded 

that the maternal NOAEL was 250 mg/kg body weight/day and the 

developmental NOAEL was 500 mg/kg body weight/day. These values 

correspond to 183 mg/kg body weight/day and 365 mg/kg 

body weight/day of linalool. 

The developmental toxicity of linalool was investigated in Sprague–Dawley 

rats. Twenty-five presumed pregnant rats were dosed 

via gavage on gestational days 7–17 with linalool in corn oil at 0, 

250, 500, or 1000 mg/kg body weight/day (Politano et al., 2008). 

There were no test substance-related clinical signs or gross lesions. 

Body weight gains were slightly but not significantly reduced (11%) 

in the 1000 mg/kg body weight/day group during the dosage period. 

During the post-dosage period, body weight gains in the 

1000 mg/kg body weight/day group were increased over the vehicle 

control. Pregnancy occurred in 22, 23, 20, and 22 dams in the 0, 

250, 500, or 1000 mg/kg body weight/day groups, respectively. No 

litter parameters were affected by doses of linalool as high as 

1000 mg/kg body weight/day. No gross external, soft tissue, or 

skeletal fetal alterations were observed. The maternal NOAEL is 

500 mg/kg body weight/day. No developmental toxicity was observed 

at the highest tested dose of 1000 mg/kg body weight/day. 

Dihydromyrcenol was also tested for developmental toxicity in 

rats. One hundred pregnant Crl:CD(SD) rats (25/group) were orally 

administered via gavage 10 ml/kg of dihydromyrcenol at 0 (corn 

oil), 250, 500 or 1000 mg/kg/day on days 7–17 of gestation. Dams 

were observed for viability, clinical signs, abortions, premature 

deliveries, deaths, body weights, and feed consumption. On gestation 

day 21, all dams were Caesarean-sectioned and a gross necropsy 

was performed on the thoracic, abdominal and pelvic 

viscera. Uteri were examined for implantations, fetuses, and 

resorptions. Number of corpora lutea were recorded. Fetuses were 

weighed and examined for gender and gross external changes. 

One-half of the fetuses in each litter were examined for soft tissue 

alterations and the remaining for skeletal alterations. No deaths or 

treatment-related clinical signs were observed. The 1000 mg/kg 

body weight/day dosage group had maternal body weight losses 

in the first two days of dosing which persisted for the entire dosage 

period. These reductions were associated with significant reductions 

in feed consumption. Fetal body weights in the 1000 mg/kg 

body weight/day groups were reduced 3% compared to vehicle 

controls and were associated with retardation in the ossification 

of the metatarsal bones. These observations were within the historical 

range of the testing facility and are not considered toxicologically 

important. Fetal body weights in the 1000 mg/kg body 

weight/day group were reduced 3% compared to vehicle controls; 

the reduction in female fetuses was statistically significant. 

Although these observations were within the historical control values 

for the testing facility, the reduction correlated with a maternally 

toxic dosage in which reduced maternal body weight gains 

and feed consumption occurred at 1000 mg/kg/day early in the 

dosage period. A small but statistically significant reversible retardation 

in the ossification of the metatarsal bones in the hind paws 

was observed in the 1000 mg/kg/day dosage group. This is not considered 

to be of toxicological importance because the value is within 

the historical range of the testing facility and other ossification 

sites in the fetuses were not affected. An increase in supernumerary 

thoracic ribs and associated increases and decreases in thoracic 

and lumbar vertebrae, respectively, were also observed in fetuses 

from the 1000 mg/kg body weight/day group. This minor variation 

is reversible and often observed at maternally toxic doses. Due to 

maternal body weight and feed consumption effects as well as fetal 

body weight reductions and increases in reversible variations in 

skeletal ossification, the maternal and developmental NOELs of 

500 mg/kg body weight/day and NOAELs of 1000 mg/kg bodyweight/day 

were established for dihydromyrcenol (Politano et al., 

2009). 

4.6. Skin irritation 


Nine alcohols with unsaturated branched chains and worldwide 

uses of >0.01 metric tons/year have been well studied for their potential 

to produce skin irritation in humans (see Table 6a).

S22 


Table 4a 

Genotoxicity: in vitro studies. 

Material Test system Concentrations Results References a 


Citronellol b Rec-assay Bacillus subtilis strains H 17 

(rec+) and M 45 (rec ) 

Ames assay with S9 

activation 

Host mediated assay, with 

and without betaglucuronidase 

Salmonella typhimurium 

TA98, TA100 


TA98, TA100 

17 lg/disc publication in 

Japanese, not clear whether 

tested up to cytotoxic 

concentrations 

100 ll cytotoxicity: not 

reported 

50–300 ll of 24 h direct 

urine sample or aqueous 

fractions of ether extracts 

from urine of two rats given 

0.5 ml undiluted test 

material p.o.cytotoxicity: 

not reported 

Not mutagenic Oda et al. (1979) 

Not mutagenic Rockwell and Raw 

(1979) 


(1979) 


Farnesol b Ames assay with and 

without S9 activation 

Ames assay with and 


Chromosome aberration 

test with and without S9 

activation 

Geraniol b Ames assay with and 


(liquid suspension test) 







activation 



activation 

Phytol Ames assay with and 

without S9 activation (plate 

incorporation test and preincubation 

test) 

3-Methyl-2-buten-1-ol Ames assay with and 



test) OECD 471 


TA98, TA100, TA1535, 

TA1537 

Up to 5000 lg/plate not 

cytotoxic 

Not mutagenic RIFM (1989a) 

Salmonella typhimurium, 

To the level of toxicity Not mutagenic Rupa et al. (2003) 

E. coli 

Chinese hamster ovary cells To the level of toxicity Not clastogenic Rupa et al. (2003) 


TA100 


TA92, TA94, TA98, TA100, 

TA1535, TA1537 

Salmonella typhimurium, 

E. coli 

Chinese hamster lung 

fibroblasts (CHL) 

Chinese hamster ovary cells 

(CHO) 

Salmonella typhimurium TA 

100 

Drosophila wing spot test Transheterozygous larvae 

(mwh+/+flrI) Drosophila 

melanogaster 

Modified Ames test (liquid 

suspension pre-incubation 

assay) 


TA98, TA100, TA1535, 

TA1537 


TA98, TA100 

10–3000 lg per 2 ml 

incubation volume 

cytotoxicity: not reported 

Up to 500 lg/plate in DMSO 

(highest non-toxic dose) 

Not mutagenic Eder et al. (1980, 

1982a,b) and Lutz et al. 

(1980) 

Not mutagenic Ishidate et al. (1984) 

To the level of toxicity Not mutagenic Rupa et al. (2003) 

Up to 0.125 mg/ml in DMSO 

for 48h (highest non-toxic 

dose) 

8.0% cells with polyploidy, structural 

aberrations (4%) not increased over 

control; judged as equivocal result 

with regard to polyploidy 

To the level of toxicity Inconclusive (increase in number of 

cells with structural aberrations in 1 

of 2 experiments with metabolic 

activation 

Ishidate et al. (1984) 

Rupa et al. (2003) 

0.5%, 1.0%, 2.5%, and 5.0% Not mutagenic Choi et al. (1993) 

50, 10, or 200 ll/plate Phytol did not induce any mutation 

including gene mutations, deletions, 

or mitotic recombinations 

20–5000 lg/plate 

cytotoxicity: P100 lg/plate 

(TA100) 

20–5000 lg/plate not 

cytotoxic 

Choi et al. (1993) 

Not mutagenic RIFM (1989h) 

Not mutagenic RIFM (1991c)


Table 4a (continued) 



7-Nonen-2-ol,4,8- 

dimethyl- 




test) 


TA98, TA100, TA1535, 

TA1537 E. coli WP2uvrA 

Up to 313 lg/plate Not mutagenic RIFM (1979e) 


4-Methyl-3-decen-5-ol Ames assay with and 



test) 


TA98, TA100, TA102, 

TA1535, TA1537 

Plate incorporation test: 1– 

1000 or 100–2000ll/plate 

(TA102/-S9) toxic P33 ll/ 

plate ( S9) or P333 ll/ 

plate (+S9) P1000 ll/plate 

(TA102/ S9) preincubation 

test: 0.3–333 ll/ 

plate cytotoxicity: P33 ll/ 

plate 



Dehydrolinalool b Ames assay with and 


(standard plate and 

preincubation assay) 

3,7-Dimethyl-1,6- 

nonadien-3-ol 




test) 

Isophytol Ames assay with and 







test) 

Modified Ames test (liquid 

suspension pre-incubation 

assay) 

Linalool b Ames assay with and 


(liquid suspension test) 



Ames assay with S9 

activation 




TA98, TA100, TA1535, 

TA1537 


TA98, TA100, TA102, 

TA1535, TA1537 


TA97, TA98, TA100, TA1535 


TA97, TA98, TA100, TA102, 

TA104, TA1535 


TA98, TA100, TA1535, 

TA1537 


TA98, TA100 


TA100 


TA92, TA94, TA98, TA100, 

TA1535, TA1537 


TA98, TA100 


TA98, TA100, TA1535, 

TA1537, TA1538 

20–5000 lg/plate (standard 

plate assay) to the level of 

toxicity 4–2500 lg/plate 

(preincubation assay) 

cytotoxicity: P100–500 lg/ 

plate 

Plate incorporation test: 

10–1000 ll/plate or 500– 

3000 ll/plate (+S9) 

cytotoxicity: 1000 ll/plate 

or P2000 ll/plate (+S9) 

pre-incubation test: 3– 

1000 ll/plate toxic 

P100 ll/plate 

Not reported cytotoxicity: 

not reported 

Up to 10,000 lg/plate 

10,000 lg/plate were close 

to the toxic concentration 


cytotoxic 


cytotoxic 

10–3000 lg per 2 ml 

incubation volume 


Up to 1000 lg/plate in 

DMSO (highest non-toxic 

dose) 

100 ll (87,000 lg) 


5–10,000 lg/plate 

cytotoxicity: 10,000 lg/ 

plate 

Mutation assay E. coli WP2uvrA 125–1000 lg/plate to the 

level of toxicity 

Not mutagenic RIFM (1989b) 


Equivocal Zeiger and Margolin 

(2000) 

Not mutagenic US National Toxicology 

Program (1993, 2000) 

Not mutagenic RIFM (1989g) 


Not mutagenic Eder et al. (1980, 

1982a,b) and Lutz et al. 

(1980) 

Not mutagenic Ishidate et al. (1984) 


(1979) 


Not mutagenic Yoo (1986) 


S24 


Table 4a (continued) 


Host mediated assay, with 

and without betaglucuronidase 

Rec assay (spore plate 

method) 


TA98, TA100 

Bacillus subtilis strains H 17 


Rec-assay Bacillus subtilis strains H 17 


Rec-assay (spore plate 

assay) 

Mammalian cell mutation 

with and without S9 

activation 

Mammalian cell mutation 

with and without S9 

activation 



activation 

Chromosomal aberration 


activation 

2-Methyl-3-buten-2-ol Ames assay with and 



test) 

Bacillus subtilis strains H 17 


Mouse lymphoma L5178Y 

TK+/ 

Mouse lymphoma L5178Y 

TK+/ 

Chinese hamster lung 

fibroblasts (CHL) 

50–300 ll of 24 h direct 

urine sample or aqueous 

fractions of ether extracts 

from urine of 2 rats given 

0.5 ml undiluted linalool 

p.o. 


(1979) 

630–10,000 lg/disc Questionable effect Kuroda et al. (1984) 

17 lg/disc publication in 

Japanese, not clear whether 

tested to cytotoxic 

concentrations 

Not mutagenic Oda et al. (1979) 

10,000 lg/disc Positive Yoo (1986) 

3.9–300 nl/ml (3.4–261 lg/ 

ml highly toxic P 200 nl/ml 

(174 lg/ml) ( S9) resp. 300 

nl/ml (261 lg/ml) (+S9) 

12.5–274 lg/ml highly toxic 

P200 lg/ml 

Up to 0.25 mg/ml in DMSO 

for 48h (highest non-toxic 

dose) 

Chinese hamster ovary cells 16.7–500 lg/ml toxic 

P350 lg/ml 

Not genotoxic in one experiment and 

weakly positive in the other 

RIFM (1982b) 35826 

and Heck et al. (1989) 

Not genotoxic RIFM (1994a) 

Not genotoxic Ishidate et al. (1984) 

Not genotoxic RIFM (1983b) 

Sister chromatid exchange Chinese hamster ovary cells 5–150 lg/ml not toxic Not genotoxic Sasaki et al. (1989) 

Unscheduled DNA synthesis primary rat hepatocytes 0.5–43.6 lg/ml cytotoxic 

P0.1 ll/ml (87 lg/ml) 


TA98, TA100, TA1535, 

TA1537 

20–5000 lg/plate 


Not genotoxic RIFM (1986a) and Heck 

et al. (1989) 

Not mutagenic RIFM (1989f) 

a 

b 




Table 4b 

Mutagenicity and genotoxicity: in vivo studies. 

Material Test system Species Dose or concentration Results References b 


Farnesol a Bone marrow micronucleus assay Mouse To the level of toxicity Not genotoxic Rupa et al. (2003) 

Geraniol a Bone marrow micronucleus assay Mouse To the level of toxicity Not genotoxic Rupa et al. (2003) 

RIFM (2001b) 

Not genotoxic; PCE/NCE reduced at 

P250 mg/kg body weight 500 mg/kg body 

weight led to evident signs of toxicity 

0, 125, 250, 500 mg/kg body weight in olive oil 

by two i.p. injections at a 24 h interval positive 

control: cyclophosphamid, vincristine 

NMRI mouse (five males per 

dose) 

Bone marrow micronucleus assay sampling time: 

24 h after last dosing 

3-Methyl-2- 

buten-1- 

ol 

Not genotoxic; PCE/NCE not affected Meerts (2002) as cited in 

OECD/SIDS (2006) 

0, 2000 mg/kg body weight in maize/corn oil 

by single gavage positive control 

cyclophosphamid 

NMRI BR mouse (5 males 

per group) 


Isophytol Bone marrow micronucleus assay; sampling 

times: 24, 48 h after dosing OECD 474 

Not genotoxic RIFM (2001) 

Linalool a Bone marrow micronucleus assay Mouse 500, 1000, 1500 mg/kg body weight by single 

gavage 

Not genotoxic; PCE/NCE not affected RIFM (1992) 

0, 500, 1000, 1500 mg/kg body weight in water 

by single gavage positive control: 

cyclophosphamid, vincristine 

Bone marrow micronucleus assay NMRI mouse (male and 

female), n not reported 

2-Methyl-3- 

buten-2- 

ol 



a 

b 

No irritation was observed in predictive tests (e.g. in pre-tests 

for maximization studies with single occlusive applications for 

48 h) with the highest concentrations tested: 30% 3,7-dimethyl- 

1,6-nonadien-3-ol (RIFM, 1975b), 10% 3-methyl-2-buten-1-ol 

(RIFM, 1977c), 10% phytol (RIFM, 1977d), 10% isophytol (RIFM, 

1982a), 4% nerolidol (RIFM, 1973c), 4% 7-octen-2-ol, 2-methyl-6- 

methylene-, dihydro derivative (RIFM, 1973c), 4% dihydromyrcenol 

(RIFM, 1977d), 2% methylheptenol (RIFM, 1976b). 

Neat 7-octen-2-ol, 2-methyl-6-methylene-, dihydro derivative 

led to moderate skin reactions in two out of 99 volunteers during 

the induction phase of a human repeat insult patch test (HRIPT) 

(RIFM, 2006b). No irritation was observed with up to 20% 7-octen-2-ol, 

2-methyl-6-methylene-, dihydro derivative during the 

induction phase of two other HRIPTs (RIFM, 1973c, 1995). The repeated 

application of 10% 4-methyl-3-decen-5-ol during the 

induction phase of an HRIPT yielded little or no irritation (RIFM, 

1981b). A moderate skin reaction appeared in only 1 of 41 subjects 

under repeated application of 7.5% dihydromyrcenol (RIFM, 

1977d). 

Further details on studies of dermal irritation in humans are 

provided in Table 6a. 


Ten of the alcohols under review with worldwide uses of 

>0.01 metric tons/year have been tested in animal models of skin 

irritation using rabbits or guinea pigs (see Table 6b). 

If applied undiluted, phytol, methylheptenol, 3,7-dimethyl-1,6- 

nonandien-3-ol, 2-methyl-3-buten-2-ol and nerolidol produced no 

irritation to moderate irritation in almost all studies with rabbits or 

guinea pigs regardless of the method used with the exception of 

undiluted 3-methyl-2-buten-1-ol, which was corrosive after 1h 

occlusive application (RIFM, 1979j) and undiluted isophytol, which 

produced severe irritation after 1 min application (RIFM, 1970a). 

Tests performed in accordance with current test guidelines (4 h, 

semi-occlusive) with 4-methyl-3-decen-1-ol, 7-octen-2-ol, 2- 

methyl-6-methylene-, dihydro derivative and dihydromyrcenol 

showed slight to moderate irritation. 

No effects or only slight effects were observed in rabbits or guinea 

pigs with diluted compounds: 50% dihydromyrcenol and 5% 

methylheptenol, slight reactions; 5% nerolidol, very slight reaction. 

Moderate skin effects were observed in rabbits with 5% 3,7-dimethyl-1,6-nonandien-3-ol 

after a 24 h application. 

Further details on studies of dermal irritation in animals are 

provided in Table 6b. 

4.7. Mucous membrane irritation 

No human studies on mucous membrane irritation are 

available. 

The potential to induce eye irritation has been studied in animals 

for 10 alcohols under review with worldwide uses of 

>0.01 metric tons/year (see Table 7). 

Some alcohols, phytol (RIFM, 1978b), isophytol (RIFM, 1970a), 

nerolidol (RIFM, 1968), and methylheptenol (RIFM, 1968), elicited 

no irritation or only slight eye irritation in rabbits when tested 

undiluted. 2-Methyl-3-buten-2-ol was irritating to the rabbit eye 

after 8 h but eventually returning to normal when tested undiluted 

(no further information available; RIFM, 1972e). 

Undiluted 7-octen-2-ol, 2-methyl-6-methylene-, dihydro derivative 

(RIFM, 1980d), 3,7-dimethyl-1,6-nonadien-3-ol (RIFM, 1968), 

dihydromyrcenol (RIFM, 1977e) and 4-methyl-3-decen-5-ol showed 

moderate irritation. The effects noted were reversible after up to 

10 days. Thirty percent and 10% 4-methyl-3-decen-5-ol were only 

slightly irritating and without corneal effects. Moderate conjunctival 

irritation with corneal involvement was reported for undiluted 

3-methyl-2-buten-1-ol. The effects did not clear completely after

S26 


Table 5 

Reproductive and developmental toxicity studies. 

Material Method Concentration(s)/dose (mg/kg body Species Results (mg/kg body weight/day) a References b 

weight/day) a 


3-Methyl-2-buten-1-ol Pre-test for maternal toxicity 10 

pregnant females/dose via gavage on 

days 6–19 p.c. 

100, 300, or 1000 as an aqueous 

suspension 

OECD TG 414 25 pregnant females/ 

dose were dosed via gavage on 

gestational days 6–19 p.c. 

0, 50, 200, 600 as aqueous suspension 

(0.5% carboxymethylcellulose CB 

30,000 in doubly distilled water) 


Isophytol OECD TG 415, one-generation study 

24 male and female rats were dosed 

via gavage exposure duration: males: 

10 weeks prior to mating till 

termination (mean: 98) females: 2 

weeks prior to mating till termination 

(mean: 64 day) 

0 (vehicle), 250, 500 or 1000 in maize/ 

corn oil 

Dihydromyrcenol OECD and ICH Harmonized Tripartite 

Guideline Stages C + D 100 (25/ 

group) female rats were dosed via 

gavage on GD 7–17 p.c. 

10 ml/kg of 0, 250, 500 or 1000 in 

maize/corn oil 

Rats 

(Wistar) 

Rat 

(Wistar) 

Rat 

(Wistar) 

Crl:CD (SD) 

rats 

100: no effects 300: transient salivation 1000: three dams died prematurely 

and remaining seven were sacrificed early. Clinical observations included 

unsteady gait, abdominal position, salivation, ataxia, tremor, urine smeared 

fur, piloerection, fluid filled stomach, and ulceration. Reduction (35%) in 

food consumption 

NOAEL maternal = 200 

NOAEL developmental = 600 

Maternal: 

600: salivation, lacrimation, abdominal position, piloerection; 1 died; mean 

food consumption, mean body weight, mean body weight gain decreased, 

corrected body weight gain, mean carcass weight decreased 

Offspring: 

No effects 

LOAEL parental toxicity = 250 

NOAEL fertility: 500 

NOAEL developmental toxicity = 500 

Maternal: 

P250: dilated renal tubules (m,f), renal mineralization (m, f), renal hyaline 

droplets decreased (m) 

P500: abs. kidneys weight increased (m,f), rel. kidney weight increased (f), 

incidence and severity of renal basophilic aggregates increased (m,f), 

incidence and severity of renal basophilic tubules increased (m,f) 

1000: lethargy, hunched posture, piloerection (f); body weight, terminal 

body weight decreased (m), body weight loss during lactation (f), food 

consumption during lactation decreased (f); abs. and rel. prostate weight 

decreased, abs. seminal vesicles weight decreased, rel. kidneys weight 

increased (m), abs. and rel. uterus weight increased (f); periportal 

hepatocyte vacuolation decreased (f) pre-coital time increased, fertility 

index decreased, conception rate decreased 

Offspring: 

1000: survival decreased, general fitness decreased, mean body weights 

during lactation period (m,f) decreased 

NOAEL maternal 500 mg/kg body weight/day 

NOAEL developmental 500 mg/kg body weight/day 

Maternal: 

Absolute and relative feed consumption values decreased 

Offspring: 

Statistically significant reduction in fetal bodyweights at 1000 mg/kg body 

weight/day (but within historical controls of facility). Skeletal variations 

were limited reversible changes at 1000 mg/kg body weight/day 

RIFM (2003h) 

RIFM (2002d) 

Beekhuijzen 

(2002) as cited 

in OECD/SIDS 

(2006) 

RIFM (2007d)



Material Method Concentration(s)/dose (mg/kg body Species Results (mg/kg body weight/day) a References b 

weight/day) a 

Linalool (72.9% in coriander oil) c Coriander oil, dissolved in corn oil 

was administered daily by gavage to 

female CD virgin rats (10/dose) 7 

days prior to a 7-day cohabitation 

period with male rats, and continued 

through day 25 of presumed 

gestation (for rats that did not deliver 

a litter), or until day 4 of lactation. 

0 (vehicle), 250, 500 or 1000 mg 

coriander oil/kg body weight/day (182, 

365, 729 mg linalool/kg body weight/ 

day) 

Rat NOAEL maternal and fertility = 365 mg linalool/kg body weight/day 

NOAEL developmental: 365 mg linalool/kg body weight/day 

Maternal 

365: salivation, statistically non significant: food consumption decreased, 

body weight decreased, gestation index decreased, length of gestation 

decreased 

729: salivation, urine-stained abdominal fur, ataxia and/or decreased motor 

function, statistically significant: average maternal body weight gain during 

the premating period decreased, litter size decreased, gestation index 

decreased, length of gestation decreased 

Offspring 

729: a 16.3% decrease in delivered live litter size, indicative of in utero 

deaths, and a statistically significant increase in pup mortality on day 1, 

with associated pup morbidity were observed 

RIFM (1989d) 

and Belsito 

et al. (2008) 

Linalool c 25 presumed pregnant rats were 

daily dosed via gavage on gestational 

days 7–17 

2-Methyl-3-buten-2-ol OECD TG 421 (screening test) male 

and female rats (10/sex/group) were 

dosed via gavage premating exposure 

period (both sexes): 2 weeks 

exposure period: 22 days 

0 (vehicle), 250, 500 or 1000 in corn oil Crl:CD Ò 

(SD) IGS BR 

VAF/PLUS Ò 

rats 

0 (vehicle), 12.5, 50 or 200 Rat (Fü- 

Albino 

(RORO)) 

NOAEL maternal = 500 

LOAEL maternal = 1000 (reduction in body weight gain, reduced feed 

consumption) 

NOAEL developmental toxicity = 1000 

Maternal Politano et al. 

Pregnancy occurred in 22, 23, 20, and 22 dams in the 0, 250, 500, or 1000 (2008) 

respectively. 

There were no test substance-related clinical signs or gross lesions. 

1000: body weight gains reduced (11%) during the dosage period (increased 

during post-dosage period). Absolute and relative feed consumption values 

significantly reduced (7%) for the dosage period. 

Offspring 

No litter parameters affected. No gross external, soft tissue, or skeletal fetal 

alterations. 

NOAEL parental and offspring: 50 mg/kg body weight/day 

Parental: 

200 mg/kg body weight/day: body weights (m) decreased; food 

consumption during lactation period (f) decreased pasty feces (m,f) 

Offspring 

200 mg/kg body weight/day: pup viability index decreased 

Roche (1995b) 

as cited in 

OECD/SIDS 

(2005b) 

p.c. = post coitum. 

a 


b 


c 


S28 


eight days. The authors concluded that the substance has a risk of 

serious damage to the eyes (RIFM, 1970e). 

4.8. Skin sensitization 


Nine of the alcohols under review with worldwide uses of 

>0.01 metric tons/year have been evaluated for their potential to 

induce sensitization in humans (see Tables 8a and 8b). 

In the subgroup of primary allylic alcohols, no evidence of sensitizing 

effects in a maximization test with volunteers was observed 

with 3-methyl-2-buten-1-ol (10%, RIFM, 1977c). Phytol 

was considered to be a marginal sensitizer when 1 in 25 volunteers 

showed a positive reaction (10%, RIFM, 1977d). 

Methylheptenol (2%, RIFM, 1976b) from the subgroup of secondary 

alcohols, 4-methyl-3-decen-5-ol (10%, RIFM, 1981b) from 

the subgroup of secondary allylic alcohols, and 7-octen-2-ol, 2- 

methyl-6-methylene-, dihydro derivative (neat or 20%, RIFM, 

1995, 2006b), 3,7-dimethyl-1,6-nonadien-3-ol (30%, RIFM, 

1975b), dihydromyrcenol (7.5%, RIFM, 1972c), isophytol (10%, 

RIFM, 1981a) and nerolidol (4%, RIFM, 1973c) from the subgroup 

of tertiary alcohols did not induce positive reactions in maximization 

tests or repeated insult patch tests. 

From the previously reviewed terpene alcohol groups (Belsito 

et al., 2008), sensitization reactions were observed in human predictive 

tests with geraniol (6% in petrolatum), farnesol (undiluted) 

and rhodinol (3,7-dimethyl-7-octen-1-ol; 5% in petrolatum). 

Restrictions for use apply to farnesol, geraniol (considered weak 

sensitizers), rhodinol, and citronellol (considered extremely week 

sensitizers) (IFRA, 2006, 2007b,c; Api et al., 2006). 

4.8.1.1. Elicitation studies. In Belsito et al. (2008), the diagnostic 

patch test data was summarized for several materials in this group. 

Positive reactions in the diagnostic patch tests on dermatitis patients 

were reported for geraniol, nerol, nerolidol, citronellol, and 

in very few cases for linalool and rhodinol. 

Benke and Larsen (1984) studied the dose response relationships 

of geraniol in product use by testing 12 pre-sensitized subjects. 

Patch test thresholds were initially determined using 48 h 

patches of 0.5–5% in petrolatum. Four patients reacted to geraniol 

at concentrations greater than 2.5%, and no reactions were seen in 

control subjects. Eight to 10 weeks after threshold levels had been 

determined, 48 h patch tests were conducted on the same 12 patients 

with a mixture of hydroxycitronellal, geraniol, and 3 and 

4-(4-hydroxy-4-methylpentyl)-. Individual materials were not 

tested alone, and the dose was not reported. One patient who previously 

reacted to geraniol also reacted to a mixture of hydroxycitronellal 

and geraniol as well as a mixture of all three. Three 

patients who had not previously reacted to geraniol reacted to a 

mixture of geraniol and hydroxycitronellal. One patient who had 

not previously reacted to geraniol reacted to a mixture of geraniol 

and hydroxycitronellal, as well as to a mixture of all three. The 12 

dermatitis patients determined from confirmed sensitivity in 48 h 

closed patch tests were then supplied with shampoos containing 

the fragrance mixture with overall concentrations of 0.03%, 

0.09%, 0.3%, 0.9%, 3%, 9% or 15%. Reactions were reported in two 

dermatitis patients and one control patient with the shampoo containing 

5% of each material (the highest dose, an overall concentration 

of 15%). 

Johansen et al. (1998) investigated the ability of deodorants, 

which had previously caused axillary dermatitis in fragrance mix 

sensitive eczema patients, to provoke reactions on repeated open 

application tests (ROATs) to the upper arm and in the axillae. Trials 

of 20 deodorants were tested among 14 patients where two applications 

were made per day in the axilla and simultaneously on a 

25 cm 2 area of the upper arm. Geraniol was present in 15 of the 

deodorants analyzed. Nine of the deodorants containing geraniol 

(mean concentration of 0.023%) resulted in use test positive reactions 

and five deodorants (mean concentration of 0.018%) were 

negative in the use test. In general the mean concentration of fragrance 

mix constituents was higher in deodorants causing a positive 

use test. 

A ROAT was conducted with farnesol in a patient who reacted 

positively to fragrance mix II (which contains farnesol). The patient 

reacted to 2.8% farnesol on day 8 (Frosch et al., 2005). 


Information on the individual animal studies is provided in 

Table 8c. In comparison to humans, sensitization in animals has 

been less studied. Only tertiary alcohols were tested. 

7-Octen-2-ol, 2-methyl-6-methylene-, dihydro derivative 

(RIFM, 1994b,c, 1996), dihydromyrcenol (RIFM, 2007b) and isophytol 

(RIFM, 1970a) were negative in guinea pig sensitization 

tests. 

Weak reactions were found in guinea pig tests with nerolidol. 

Nerolidol was weakly positive in two adjuvant tests with challenge 

concentrations of 3% and 10% (Hausen et al., 1995). An open epicutaneous 

test (OET) (Klecak, 1979, 1985) and a Draize sensitization 

test (Sharp, 1978) were negative. To evaluate cross-sensitization, 

guinea pigs induced with farnesyl acetate were cross-challenged 

with nerolidol and no cross-reactions were observed (RIFM, 1977f). 

Certain oxidation products of alcohols (hydroperoxides) may 

give rise to skin sensitization, as was shown for linalool (Belsito 

et al., 2008). There is an IFRA standard on linalool which limits 

the peroxide level to 20 mmol/l in the raw material (IFRA, 2004). 

Oxidation has to be avoided and it has to be ensured that only pure 

materials are used in fragrances. 

4.9. Phototoxicity and photoallergenicity 

Limited data were available with regard to the phototoxicity 

and photoallergenicity of alcohols with unsaturated chains (see Table 

9). From human or animal studies, reliable data were available 

on the phototoxicity of the secondary allylic alcohol, 4-methyl-3- 

decen-5-ol, and the tertiary alcohols, 7-octen-2-ol, 2-methyl-6- 

methylene-, dihydro derivative and dihydromyrcenol. 4-Methyl- 

3-decen-5-ol was the only compound tested for its photoallergenic 

potential. 

No phototoxic reactions were seen in groups of 10 human volunteers 

exposed to 1–8% 7-octen-2-ol, 2-methyl-6-methylene-, 

dihydro derivative and 12% dihydromyrcenol, followed by irradiation 

with UVA (RIFM, 1981c). 

Only one reliable phototoxicity animal study was performed. In 

guinea pigs, 10% 4-methyl-3-decen-5-ol in ethanol elicited no 

reactions (RIFM, 1980g). Isophytol was tested in a non-valid study 

with guinea pigs (RIFM, 1999). The study was performed without 

control animals. No conclusion regarding phototoxicity potential 

can be made because all the test doses were irritating without 

UV irradiation. 

Results obtained in non-validated in vitro yeast assays with 7- 

octen-2-ol, 2-methyl-6-methylene-, dihydro derivative and 

dihydromyrcenol are not considered to be reliable or relevant 

(Bagley et al., 1988; RIFM, 1980i; Tenenbaum et al., 1984). 

There are no studies investigating the photoallergic potential in 

humans. 

Only 4-methyl-3-decen-5-ol was tested for its photoallergenicity 

in a reliable test with guinea pigs (RIFM, 1989c). No photoallergenicity 

was observed in guinea pigs induced with 10% in 

petrolatum and 10 J/cm 2 UVA (after injection of FCA before the first 

induction) then challenged three weeks after initiation of induction 

with up to 30% (in acetone:ethanol 1:1) and irradiation.


Table 6a 

Skin irritation studies in humans. 

Material Method Concentration Subjects Results References 


2-Isopropenyl-5-methyl-4- 

hexene-1-ol a 


2-Isopropenyl-5-methyl-2- 

hexene-1-ol a 

48 h, occlusive (pre-test for a 

maximization study) 



Induction phase of HRIPT 

5% in petrolatum 26 volunteers No irritation RIFM 

(1981a) 

10% in petrolatum 5 male 

volunteers 

vehicle and concentration not 16 female 

reported 

volunteers 

3-Methyl-2-buten-1-ol 



10% in petrolatum 26 healthy 

volunteers 

Phytol 

48 h, occlusive (pre-test for a 10% in petrolatum 25 healthy 


volunteers 

(Z)-2-Penten-1-ol Induction phase of HRIPT 0.25% in alcohol SDA 40 38 healthy 

volunteers 


5,9-Dimethyl-8-decen-3-ol a Induction phase of HRIPT 1% in ethanol 39 healthy 

(semi-occlusive) 

volunteers 


48 h, occlusive (pre-test for a 2% in petrolatum 25 healthy 


volunteers 

7-Nonen-2-ol,4,8-dimethyl- Induction phase of HRIPT 20% in white petrolatum 50 healthy 

(semi-occlusive) 

volunteers 


4-Methyl-3-decen-5-ol 

Induction phase of HRIPT 10% in dimethyl phthalate 50 healthy 

(occlusive) 

volunteers 

6,10-Dimethylundeca-1,5,9- 

trien-4-ol a 


7-Octen-2-ol, 2-methyl-6- 

methylene-, dihydro 

derivative 

a 

2,6-Dimethyl-2-hepten-6-ol a 

3,7-Dimethyl-1,6-nonadien-3-ol 


Isophytol 

3-Methyl-1-octen-3-ol a 

3-Methyl-1-octyn-3-ol a 

Nerolidol (mixed isomers) b 

3,7,9-Trimethyl-1,6-decadien-3- 

ol a 

Induction phase of HRIPT 

(occlusive) 

No irritation 

Little or no irritation 

No irritation 

No irritation 

No irritation 

No irritation 

No irritation 

No irritation 

RIFM 

(1972a) 

RIFM 

(1972b) 

RIFM 

(1977c) 

RIFM 

(1977d) 

RIFM 

(1971) 

RIFM 

(1965) 

RIFM 

(1976b) 

RIFM 

(1979e) 

No irritation 

RIFM 

(1981b) 

0.5% in Alcohol SDA 39 C 38 volunteers No irritation RIFM 

(1973d) 

Induction phase of HRIPT 5% (vehicle not provided) 42 healthy 

volunteers 

Induction phase of HRIPT 20% in diethyl phthalate (DEP) 109 healthy 

volunteers 

Induction phase of HRIPT 20% in 1:3 diethyl 

99 healthy 

phthalate:Ethanol (DEP:EtOH) volunteers 










volunteers 


volunteers 


volunteers 


volunteers 

Induction phase of HRIPT 7.5% in alcohol SDA 39 C 41 healthy 

volunteers 












volunteers 


volunteers 


volunteers 


volunteers 


volunteers 


b Materials have been previously areviewed by in RIFM’s safety assessment of terpene alcohols (Belsito et al., 2008). 

No irritation 

No irritation 

Barely perceptible to mild 

irritation with equivalent or less 

irritation produced by saline, 2/ 

99 barely perceptible to 

moderate and marked erythema 

No irritation 

No irritation 

No irritation 

No irritation 

Moderate irritation in 1/41 

No irritation 

No irritation 

No irritation 

No irritation 

No irritation 

RIFM 

(1964b) 

RIFM 

(1995) 

RIFM 

(2006b) 

RIFM 

(1973c) 

RIFM 

(1974b) 

RIFM 

(1975b) 

RIFM 

(1977d) 

RIFM 

(1972c) 

RIFM 

(1981a) 

RIFM 

(1978c) 

RIFM 

(1979b) 

RIFM 

(1973c) 

RIFM 

(1977c) 

UV spectra have been obtained for 13 materialsa (6-ethyl-3- 

methyloct-6-en-1-ol; (Z)-2-penten-1-ol; methylheptenol; 4- 

methyl-3-decen-5-ol; 7-octen-2-ol, 2-methyl-6-methylene-, dihydro 

derivative; 3,7-dimethyl-1,6-nonadien-3-ol; dihydromyrcenol; 

isophytol; 2-methyl-3-buten-2-ol; (E)-nerolidol; nerolidol (isomer 

unspecified); 3-methyl-2-buten-1-ol; (2E,6Z)-nona-2,6-dien-1-ol). 

In general, they did not absorb UVB light (290-320 nm). They all absorbed 

UV light peaking in the UVC range (

S30 


Table 6b 

Skin irritation studies in animals. 

Material Method Concentration Species Results References b ) 


2-Isopropenyl-5-methyl-4- 4 h, semi-occlusive, 0.5 ml as a single application Undiluted Guinea pig 

hexene-1-ol a (n = 10) 

Slight to absent skin reactions RIFM (1982a) 


2-Isopropyl-5-methyl-2- 

24 h, occlusive, 0.5 ml as a single application on 

hexene-1-ol a intact and abraded skin, readings: 24 h, 72 h 

n.f.i Rabbit (n = 6) Not irritating (Primary Irritation Index: 1.5) RIFM (1972d) 

3-Methyl-2-buten-1-ol 1, 5, 15 min and 20 h, occlusive, 0.5 ml, single 

application on intact skin, observation: 24 h, 8 days 

24 h, occlusive, 0.5 ml as a single application on 

intact and abraded skin 

Undiluted Rabbit (n =8,2 

per exposure 

time) 

Corrosive: 1 and 5 min: slight erythema (at 24 h), 

slight scaling (at 8 days) 15 min: moderate 

erythema, slight edema (at 24 h), moderate scaling 

(at 8 days) 20 h: moderate erythema, slight edema, 

necrosis (at 24 h), necrosis (at 8 days) 

RIFM (1970a, 

2003g) 

Undiluted Rabbit (n = 6) Extremely irritating RIFM (1979j) 

4 h, occlusive, 0.5 ml as a single application Undiluted Rabbit (n = 4) Corrosive (Primary Irritation Index: 6.13, 

calculation not done in the original report, done by 

OECD) 

SCAT (1992) as 

cited in OECD/ 

SIDS (2005a) 

4 h, semi-occlusive, 0.5 ml as a single application Undiluted Rabbit (n = 4) Moderate to severe erythema mild to severe edema RIFM (1977a) 

4 h, semi-occlusive, 0.5 ml as a single application Undiluted Rat (n = 6) Slight local skin irritation RIFM (1979j) 

1 h, occlusive, 0.5 ml as a single application Undiluted Rabbit (n = 4) Corrosive in 2 out of 4 animals after 1 h of occlusive 

exposure 

Phytol 4h, semi-occlusive, 0.5 ml as a single application undiluted rabbit (n = 10) Mild to moderate erythema and edema RIFM (1977a) 

RIFM (1978b) 

1, 5 and 120 min, no information if semi-occlusive, 

single application on intact skin 

2 h, single application on intact and abraded skin, 

readings at 24 h, 72 h, 8 days, according to Federal 

Register 38, No 187, §1500.41, 27.09.1973 

(Z)-2-penten-1-ol 24 h, occlusive, 0.5 ml as a single application on 

intact and abraded skin 

n.f.i Rabbit (n = 2) 1 min: mild erythema (1/2) 5 min: mild erythema 

(2/2), at 8 days questionable erythema; 

questionable (1/2) to mild edema (1/2), reversible 

at 8 days 120 min: mild erythema (2/2), persisted 

until 8 days, questionable or mild edema, reversible 

at 8 days moderately irritating 

n.f.i Rabbit (n = 6) Moderately irritating (Primary irritation index: 5.0), 

effects persisted until 8 days 

0.25% in alcohol 

SDA 40 

Rabbit (n = 3) Erythema and Eschar formation was observed on 

the abraded skin at 24 h. Produced a primary 

irritation index of 1 

RIFM (1978b) 

RIFM (1970b) 


Methylheptenol 4 h, semi-occlusive, 0.5 ml as a single application Undiluted Rabbit (n = 10) Moderate to marked erythema slight to moderate 

edema 

24 h, occlusive, single application on intact and 

abraded skin,, readings at patch removal and at 48 h 

Undiluted and 5% 

in 

diethylphthalate 

Rabbit (n = 3) 100%: Very slight erythema (3/3, at 24 h), very 

slight (1/3) to well-defined (2/3) erythema (at 48 h), 

without edema 5%: very slight erythema (at 24 h), 

reversible at 48 h 

RIFM (1967b, 

1976d) 

RIFM (1968) 

7-Nonen-2-ol,4,8-dimethyl- 24 h, single application on intact and abraded skin, 

readings at 24 h, and 72 h 

24 h, single application on intact and abraded skin, 

readings at 24 h, and 72 h 

48 h, occlusive, 0.3 ml as a single application 1%, 10%, or 100% in 

petrolatum 

Cumulative open application of 0.3 ml once daily 

for two weeks 

Maximization (Induction: six intradermal injections 

and an occluded 48 h patch) 

Undiluted Rabbit (n = 10) Very slight to well-defined erythema very slight to 

slight edema at 24 h 

Undiluted Rabbit (n = 6) Very slight to well-defined erythema which 

increased from 24 to 72 h very slight to slight 

edema 

Guinea pig (3/ 

dose) 

10% or 100% Guinea pig (3/ 

dose) 

0.05% in 1:3 

dipropylene 

glycol:aqueous 

propylene glycol 

10% in 

dipropylene glycol 

Guinea pig 

(n = 10) 

1% mild irritation 10% moderate irritation 100% 

severe irritation 

10% weak irritation 100% severe irritation 

(discontinued) 

Irritation reactions were observed with intradermal 

injections of Freund’s complete adjuvant alone and 

mixed in solution. 

RIFM (1979a) 

RIFM (1979f) 

RIFM (2004a) 

RIFM (2004a) 

RIFM (1976c)


Table 6b (continued) 



4-Methyl-3-decen-5-ol 4 h, semi-occlusive, 0.5 ml as a single application Undiluted Rabbit (n = 3) Slightly irritating (mean score for erythema 1.33 

and for edema 0.56), effects reversible (erythema by 

7 days, edema by 4 days, scaling by 21 days) 

48 h, 0.1 ml as a dermal application 10% in acetone/ 

ethanol (1:1) 

Guinea pig 

(n =8) 

At 4 h slight irritation observed in 2/8 reversible by 

48 h 

RIFM (2000) 

RIFM (1980g) 

6,10-Dimethylundeca- 

24 h, occlusive, 0.5 ml as a dermal application 0.5% in alcohol 

1,5,9-trien-4-ol a SDA 39 C 

Rabbit (n = 3) No irritation observed to the intact and abraded 

skin 

RIFM (1973f) 


7-Octen-2-ol, 2-methyl-6- 


derivative 

Buehler (pre-test), 6 h, occluded 0.4 ml as 3 

applications 

5, 12.5, 25,50, 

100% 

Guinea pig 

(n =2) 

24 h, occluded, 5 g/kg as a single application Undiluted Rabbit 

(n = 10) 

No irritation reactions were observed RIFM (1994c) 

Slight (6/10) to moderate (1/10) erythema and 

Slight (5/10) to moderate (1/10) edema 

4 h, semi-occlusive, 0.5 ml as a single application Undiluted Rabbit (n = 3) Irritating (mean score for erythema 2.0 and for 

edema 1.7) 

4 h, semi-occlusive, 0.5 ml as a single application Undiluted Rabbit (n = 4) Slightly irritating (mean score for erythema 1.5 and 

for edema 0.5) 

RIFM (1973a) 

RIFM (1984a) 

RIFM (1985) 

2,6-Dimethyl-2-hepten-6- 4 h, semi-occlusive, 0.5 ml as a single application Undiluted Rabbit 

ol a (n = 10) 


nonandien-3-ol 

24 h, no information if semi-occlusive, 0.5 ml, single 

application on intact and abraded skin, observations 

24 and 72 h 


in DEP 

4 h, semi-occlusive, 0.5 ml as a single application Undiluted Rabbit 

n = 10) 

Marked redness in 10, moderate edema in 7 and 

marked edema in 3 

Rabbit (n = 3) Undiluted: well-defined erythema, still present at 

study end as slight erythema, 5% in DEP: very slight 

(2/3) to well-defined erythema (1/3) cleared by 72 h 

RIFM (1974a) 

RIFM (1968) 

Slight to moderate erythema and edema RIFM (1975a) 

Dihydromyrcenol 4 h, semi-occlusive, 0.5 ml as a single application Undiluted Rabbit (n = 3) Irritating according to EEC classification (mean 

erythema score of 2.0 in 2 animals, 0.3 in one 

animal): very slight erythema (2/3), marked 

desquamation (3/3), very slight edema (1/3) at 

160 h 

4 h, semi-occlusive, 0.5 ml as a single application Undiluted Rabbit (n = 4) Irritating (mean score for erythema 2.0 and for 

4 h, semi-occlusive, 0.5 ml as a single application Undiluted Rabbit 

(n = 10) 

4 h, semi-occlusive, 0.5 ml as a single application Undiluted and 50% 

in DEP 

edema 1.6), at 168 h very slight (1/4) to welldefined 

RIFM (1984a) 

RIFM (1985) 

Moderate to sever erythema and edema RIFM (1977a) 

Rabbit (n = 4) Undiluted: irritating (mean score for erythema 2.0 

and for edema 1.9) 50%: non-irritating (mean score 

for erythema 1.8 and for edema 1.7) 

RIFM (1986b) 

Isophytol 4 h, semi-occlusive, 0.5 ml as a single application Undiluted Rabbit 

(n = 10) 

single application (n.f.i.) back: 1, 5, 15 min and 20 h 

ear: 20 (observation after 24 h and 8 day) 

phototoxicity study: occlusive without UV 

irradiation, duration of application not reported, 

invalid study, observations at 24 and 48 h 

Undiluted Rabbit 

5, 10%, 30% and 

50% in acetone, no 

control 

(number not 

reported) 

Guinea pig 

(Hartley; 

female) (5) 

moderate to severe erythema and edema RIFM (1982c) 

Back: all durations: very severe erythema (at 24 h), 

severe flaking (at day 8) 20 h: additional severe 

edema (at 24 h), severe flaking and severe erythema 

(at day 8) ear: 20 h: very severe at 8 day: severe 

flaking 

5%, 10%, 30%, 50%: dose dependently irritating (with 

and without UV irradiation), PII (irradiated and 

non-irradiated): 0.4, 0.9, 1.6, 1.8 (5%, 10%, 30%, 50%) 

RIFM (1969, 

1970a) 

RIFM (1999) 

3-Methyl-1-octen-3-ol a 4 h, semi-occlusive, 0.5 ml as a single application Undiluted Rabbit 

(n = 10) 

Slight redness in 2/10 animals, moderate redness in 

1/10 animals and severe redness in 7/10 animals. 

Moderate edema in 10/10 animals. Limited mobility 

due to eschar formation 

RIFM (1978a) 


S32 


Table 6b (continued) 


n.f.i Rabbit (n = 6) No irritation (Primary irritation score: 1.09) RIFM (1979a) 

3-Methyl-1-octyn-3-ol a 24 h, occlusive, 0.5 g, single application on intact 

and abraded skin, readings at patch removal and at 

72 h 

RIFM (1968) 

Rabbit (n = 3) Undiluted: well-defined erythema, still present at 

study end, slight edema; 5% in DEP: very slight 

edema in one animal, cleared by 48 h 


in DEP 

application on intact and abraded skin, readings at 

24 and 48 h 

Nerolidol (isomer 

24 h, no information if semi-occlusive, 0.5 ml, single 

unspecified) c 

RIFM (1968) 

Rabbit (n = 3) Undiluted: very slight to well-defined erythema, 

still present as very slight at study end 5% in DEP: 

very slight to well-defined erythema, cleared by 

72 h 

undiluted and 5% 

in DEP 

3,7,9-Trimethyl-1,6- 

24 h, occlusive, 0.5 ml, single application on intact 

dicadien-3-ol a and abraded skin, readings at 24 and 48 h 

RIFM (1977a) 

4 h, semi-occlusive, 0.5 ml as a single application Undiluted Rabbit (n = 10) Moderate redness in 10, mild edema in 3 and 

moderate edema in 7. Skin hairless at exposure site 

in 6 at necropsy 

DEP = diethylphthalate. 

n.f.i. = no further information. 




a 

b 

c 

branching of the carbon chain. Unsaturated alcohols in general decreased 

the content of reduced glutathione and ATP in the liver to a 

greater extent than saturated alcohols. However, this was not the 

case for 3-methyl-2-buten-1-ol. Lipid peroxidation was observed 

with unsaturated alcohols including 3-methyl-2-buten-1-ol. The 

mechanism(s) of hepatic injury by unsaturated alcohols may include 

oxidation to a reactive metabolite (allylic aldehyde) which 

depresses the glutathione content (Strubelt et al., 1999). 

4.10.2. Effects on nervous system 

2-Methyl-3-buten-2-ol seems to contribute to the sedative action 

of hops. Administration of 206.5 mg 2-methyl-3-buten-2-ol/ 

kg body weight i.p. to Wistar rats caused a decline of motility by 

50% within two minutes. A maximum response was reached within 

2 h (Wohlfahrt et al., 1993). 

Neurophysiological stimulation of jasmine absolute oil and certain 

identified components thereof, e.g. phytol and isophytol, was 

tested in a mouse model (Tsuchiya et al., 1992). Mice were anaesthetised 

using sodium pentobarbital i.p. and exposed to atmospheric 

concentrations of jasmine absolute or its components. 

Jasmine absolute and phytol significantly reduced the pentobarbital 

sleep time; whereas isophytol had no effect on sleeping time. 

Nerolidol and phytol had sedative (50 and 100 mg/kg body 

weight, respectively.) and spasmolytic effects (EC 50 1.5 and 

20 lg/ml, respectively) in mice (Binet et al., 1972). 

5. Summary 

The compounds assessed in this group summary are structurally 

related and have similar metabolism and toxicity profiles. 

5.1. Exposure summary 

Calculated maximum daily systemic exposures for 15 of the 

compounds under review when applied dermally were estimated 

to range from 0.0003 to 0.33 mg/kg body weight/day for the individual 

substances in users with high consumption of cosmetic 

products containing these materials (see Table 1). The highest 

maximum skin level concentration for the alcohols in fine fragrances 

has been reported to be 6.8% for dihydromyrcenol. Data 

on inhalation exposure during use of the substances are lacking. 

5.2. Toxicokinetics summary 

Although data on pharmacokinetics are scarce, the alcohols under 

review are expected to be taken up via the skin and the lung as 

demonstrated by structurally related terpene alcohols. Uptake via 

the oral route was demonstrated for phytol and linalool as well as 

for other materials by toxicity after acute oral application in animal 

experiments (see Section 4.2). Quantitative data on uptake and 

elimination are lacking for the compounds under review. For linalool 

a rapid uptake and elimination from blood was shown in a volunteer 

after application to the skin. Urine followed by expired air 

and feces are the main excretion pathways for linalool in rats. 

5.3. Metabolism summary 

Data on metabolism for the compounds under review are available 

only for phytol. 

Data from structurally similar non-cyclic terpene alcohols that 

contain all key structural elements (a hydroxy group, methyl 

substituents, and double bonds including allylic alcohols) and 

potential sites of metabolism as the members of this group demonstrate 

that the major pathways of metabolism and fate are:


Table 7 

Mucous membrane irritation studies in rabbits. 

Material Method Results References b 


2-Isopropyl-5-methyl- 0.1 ml, used as received (n.f.i.), 

2-hexene-1-ol a observations at 24, 48, 72 h, 6 animals 

3-Methyl-2-buten-1-ol 0.1 ml, undiluted, observations at 24, 48, 

72 h, 3 animals 

Slight to moderate conjunctivitis in 4/6 (24 h), reversible 

Highly irritating (Irritation score (24, 48 and 78 h): 28.7, max. score = 110): 

slight to moderate corneal opacity, moderate conjunctival redness and 

chemosis, not completely reversible within 8 days 

0.05 ml, undiluted, 2 animals Irritating: slight corneal opacity, moderate redness and edema, reversible 

after 8 days except a slight conjunctival redness 

Phytol 

n = 6, according to Federal Register 38, No. 

187, §1500.42, 27019 (27.9.73) 

Slight to moderate conjunctival erythema and slight secretion, primary 

irritation index: 3.2 authors: not irritating 

(Z)-2-penten-1-ol 0.1 ml, 0.25% in alcohol SDA 40, 3 animals Produced a moderate irritation involving the conjunctivae of the treated eyes 

eyes returned to normal by 7th day 


5,9-Dimethyl-8-decen- 

3-ol a 0.1 ml, 5%, observations at 24, 48, 72, 96 h, 

7 day, 3 animals 


0.1 ml, undiluted and 5% in 

diethylphthalate, observations 

immediately and at 1, 2, 4, 24 and 48 h, 3 

animals 

0.1 ml, undiluted, observations up to 3 

days, 6 animals 


4-Methyl-3-decen-5-ol 0.1 ml, undiluted, 30% and 10% in 

diethylphthalate observations 

immediately and at 1, 24, 48, 72 h, 7 and 

14 days, 3 animals 

No corneal or iris effects, mild vessel injection (1/3) or more diffuse redness 

(2/3) of palpebral conjunctivae, with slight (2/3) or obvious chemosis (1/3) 

and very slight (2/3) to slight discharge (1/3), all effects cleared by the 7th day 

100%: very slight corneal opacity (3/3, tested with fluorescein at 48 h), very 

slight erythema in 3/3 (4 h), 2/3 (24 h), 1/3 (48 h), very slight chemosis (2/3), 

cleared by 24 h, discharge: well-defined in 3/3 (4 h), very slight in 1/3 (24 h, 

48 h) 5%: very slight erythema at instillation, normalized after 1 h, very slight 

discharge in 1/3 (1 and 2 h), normalized by 4 h 

Irritation observed. Corneal and conjunctival irritation persisted until day 3 

100%: moderate redness, very slight edema, accompanied by corneal opacity, 

all effects cleared by the 7th day 30% and 10%: slight erythema without 

cornea effects, cleared after 4 days and 72 h resp. 

7-Nonen-2-ol,4,8- 

dimethyl- 

6,10-Dimethylundeca- 

1,5,9-trien-4-ol a 0.1 ml, 0.5% in alcohol SDA 39 C, 3 animals Mild conjunctival irritation which lasted seven days in one animal with that 

animal showing corneal involvement 

0.1 ml, 0.5% in alcohol SDA 39 C, 3 animals Conjunctival irritation which did not clear on the 10th day of observation 

with corneal involvement 

0.1 ml, 0.1% in alcohol SDA 39 C, 3 animals Conjuctival irritation which cleared on the 10th day of observation with 

corneal involvement clearing on the 4th day 


7-Octen-2-ol, 2- 

methyl-6- 


derivative 


nonadien-3-ol 

0.1 ml, undiluted, 6 animals Conjunctival irritation and corneal opacity was observed in all rabbits. All 

eyes had normalized by day 10 

0.1 ml, 7% in propylene glycol, 6 animals Conjunctival irritation (6/6), corneal opacity (3/6); vascularization on day 7 in 

one rabbit. All eyes had normalized by day 7 

0.1 ml, 5% (vehicle not provided), 3 Mild vessel injection of palpebral conjunctivae was observed. The treated 

animals 

eyes were normal on the third day 

0.1 ml, undiluted and 5% in 

100%: very slight to well-defined erythema, still present at 72 h, very slight to 

diethylphthalate, observations 

well-defined chemosis, cleared by 72 h, very slight cornea opacity (3/3), still 

immediately and at 1, 2, 4, 24, 48 and 72 h, present at 72 h, discharge: well-defined to moderate till 4 h, at 72 h very 

3 animals 

slight discharge still present in 1/3 5%: very slight erythema at instillation, 

normalized by 1 h, very slight discharge in 2/3 (1 and 2 h), normalized by 4 h 

Dihydromyrcenol 0.1 ml, 7.5% in alcohol SDA 39 C, 3 animals Conjunctival irritation (moderate redness, slight to moderate edema and 

slight to severe discharge), with corneal involvement, effects still present 

after 7 days. Effects in control rabbits (0.1 ml alcohol SDA 39 C) more severe 

0.1 ml, undiluted, 6 animals Irritating: conjunctival irritation (6/6), iris involvement (4/6) and opacity (2/ 

6) was observed, all eyes had normalized by day 7 (Draize scores of 16.9, 9.0 

and 8.4 at days 1, 2, and 3) 

RIFM (1972d) 

RIFM (1979k) 

RIFM (1970e, 

2003f) 

RIFM (1978b) 

RIFM (1970c) 

RIFM (1964a) 

RIFM (1968) 

RIFM 

(1979g,h) 

RIFM (1980c) 

RIFM (1973e) 

RIFM (1975c) 

RIFM (1975d) 

RIFM (1980d) 

RIFM (1980e) 

RIFM (1980f) 

RIFM (1968) 

RIFM (1977e) 

RIFM (1984b) 

Isophytol 0.05 ml, undiluted, (n.f.i.) Slight redness by 1 h and 24 h, slight corneal clouding by 24 h; cleared after 8 RIFM (1969, 

days 

1970a) 

2-Methyl-3-buten-2-ol ‘‘internal method BASF”, rabbit (n.f.i.) irritating (n.f.i.) RIFM (1972e) 

3-Methyl-1-octyn-3- 

ol a 0.1 g, undiluted, observations at 1 h and 1, 

2, 3, 5, 7 and 14 days, 6 animals 0.1 g, 

undiluted, washout after 5 sec, 

observations at 1 h and 1, 2, 3, 5, 7 days, 3 

animals 

Conjunctival erythema, chemosis and discharge and opacity was observed in 

all rabbits. In 2/6 effects still present after 14 days conjunctival erthema, 

chemosis and discharge and opacity were observed in all rabbits, chemosis 

(3/3) and discharge (1/3) still present after 7 days 

RIFM (1979a) 

Nerolidol (isomer 0.1 ml undiluted and 5% in DEP, 3 animals Undiluted: very slight redness, cleared by 2 h 5%: no effects RIFM (1968) 

unspecified) c 

3,7,9-Trimethyl-1,6- 

dicadien-3-ol a 0.1 ml undiluted and 5% in DEP, 3 animals Undiluted: very slight to well-defined redness and chemosis, very slight to 

moderate discharge, redness and discharge still present at the end of study 

(72 h) 5%: very slight redness at instillation, very slight discharge till 2 h 

RIFM (1968) 

DEP = diethylphthalate 

n.f.i.: no further information 

a No relevant use was reported, therefore the available data are mentioned only in the table but not in the text. 

b Not all of the original reports in the OECD/SIDS assessment were made available to RIFM. 

c Materials have been previously reviewed by in RIFM’s safety assessment of terpene alcohols (Belsito et al., 2008).

S34 


Table 8a 

Skin sensitization studies in humans. 

Material Method Concentration(s) Subjects Results References 


2-Isopropenyl-5-methyl-4-hexene-1-ol a Maximization test 5% in petrolatum 26 volunteers No sensitization reactions RIFM (1981a) 


2-Isopropenyl-5-methyl-2-hexene-1-ol a Maximization test 10% in petrolatum 25 male volunteers No sensitization reactions RIFM (1972a) 

HRIPT concentration and vehicle not reported 16 female volunteers No sensitization reactions RIFM (1972b) 

3-Methyl-2-buten-1-ol Maximization test 10% in petrolatum 26 volunteers No sensitization reactions RIFM (1977c) 

Phytol Maximization test 10% in petrolatum 25 volunteers 1 positive reaction RIFM (1977d) 

(Z)-2-Penten-1-ol HRIPT 0.25% in alcohol SDA 40 38 healthy volunteers No sensitization reactions RIFM (1971) 


5,9-Dimethyl-8-decen-3-ol a HRIPT 1% in ethanol 39 volunteers No sensitization reactions RIFM (1965) 

Methylheptenol Maximization test 2% in petrolatum 25 volunteers No sensitization reactions RIFM (1976b) 

7-Nonen-2-ol,4,8-dimethyl- HRIPT 20% in white petrolatum 50 healthy volunteers No sensitization reactions RIFM (1979e) 


4-Methyl-3-decen-5-ol HRIPT (occlusive) 10% in dimethyl phthalate 50 volunteers No sensitization reactions RIFM (1981b) 

6,10-Dimethylundeca-1,5,9-trien-4-ol a HRIPT 0.5% in alcohol SDA 39 C 38 volunteers No sensitization reactions RIFM (1973d) 


7-Octen-2-ol, 2-methyl-6-methylene-, dihydro derivative Maximization test 4% in petrolatum 25 volunteers No sensitization reactions RIFM (1973c) 

HRIPT 5% in ethanol 42 volunteers No sensitization reactions RIFM (1964b) 

HRIPT 20% in diethyl phthalate 109 volunteers No sensitization reactions RIFM (1995) 

HRIPT 20% in 1:3 EtOH:DEP 99 volunteers No sensitization reactions RIFM (2006b) 

2,6-Dimethyl-2-hepten-6-ol a Maximization test 10% in petrolatum 25 volunteers No sensitization reactions RIFM (1974b) 

3,7-Dimethyl-1,6-nonadien-3-ol Maximization test 30% in petrolatum 25 volunteers No sensitization reactions RIFM (1975b) 

Dihydromyrcenol Maximization test 4%, vehicle not mentioned 25 volunteers No sensitization reactions RIFM (1977d) 

HRIPT 7.5% in alcohol SDA 39 C 41 volunteers No sensitization reactions RIFM (1972c) 

Isophytol Maximization test 10% in petrolatum 27 volunteers No sensitization reactions RIFM (1981a) 

3-Methyl-1-octen-3-ol a Maximization test 10% in petrolatum 25 volunteers No sensitization reactions RIFM (1979b) 

Maximization test 10% in petrolatum 25 volunteers 2 positive reactions at induction 

RIFM (1978c) 

(mild to moderate reaction), 

1 positive reaction at challenge (moderate) 

3-Methyl-1-octyn-3-ol a Maximization test 2% in petrolatum 25 volunteers No sensitization reactions RIFM (1979b) 

Nerolidol (isomers unspecified) b Maximization test 4% in petrolatum 25 volunteers No sensitization reactions RIFM (1973c) 

3,7,9-Trimethyl-1,6-decadien-3-ol a Maximization test 20% in petrolatum 26 volunteers No sensitization reactions RIFM (1977c) 

HRIPT: human repeat insult patch test. 

a 


b 



Table 8b 

Elicitation studies in humans. 

Material Method Concentration(s) Subjects Results References 

Three positive reactions Hausen (2001) 


Nerolidol (isomers unspecified) a Patch test 1% in petrolatum 2273 dermatosis patients were tested 

with balsam of Peru, 445 reacted, 102 

of these were tested with nerolidol 

(constituent of balsam of Peru) 

Two reactions at 2.5% or greater 2 reactions at 4% or greater Benke and Larsen 

(1984) 

0.5–5% in petrolatum 1 male and 11 female patients with a 

history of dermatitis 

Geraniol a 48 h Patch 

test 

Two patients who previously reacted to geraniol did not react to any of the mixtures Benke and Larsen 

One patient who previously reacted to geraniol reacted to mixtures of geraniol with 

hyroxycitronellal as well as a mixture of geraniol, hydroxycitronellal, and 3 and 4-(4- 

Hydroxy-4-methylpentyl)- 

Three patients who had not previously reacted to geraniol reacted to a mixture of 

geraniol and hydroxycitronellal 

One patient who had not previously reacted to geraniol reacted to a mixture of all 

three materials 

1 male and 11 female patients with a 


No dose reported in mixture of 

geraniol, hydroxycitronellal, or 3 

and 4-(4-Hydroxy-4- 

methylpentyl)- 

Geraniol a 48 h Patch 

test 

Benke and Larsen 

(1984) 

One patient reacted with visible skin reaction to 15% mixture 

Second patient reported burning sensation to 15% mixture 

Two control subjects reported stinging sensation to 15% mixture 

1 male and 11 female patients with a 


Overall concentrations of 0.03%, 

0.09%, 0.3%, 0.9%, 0.3%, 0.9%, 3%, 

9% and 15% in geraniol, 

hydroxycitronellal, and 3 and 4- 

(4-Hydroxy-4-methylpentyl)- 

mixture (1:1:1) 

Geraniol a Use test with 

shampoos 


a 

– conjugation of the alcohol group with glucuronic acid, 

– oxidation of the alcohol group, 

– carbon chain oxidation yielding polar metabolites which may be 

conjugated and excreted – or further oxidation to an aldehyde, a 

carboxylic acid, and to CO 2 , 

– hydrogenation of the double bonds, 

– excretion of the unchanged parent compound. 

The same metabolism pathways are expected for the members 

of this group of alcohols due to the structural similarity. 

These metabolism pathways are common for primary and secondary 

and except for oxidation for tertiary alcohols. In most cases, 

metabolism yields innocuous metabolites that are excreted in the 

urine and feces. Some substances of this assessment, however, 

may generate alpha, beta-unsaturated compounds or be oxidized 

to hydroperoxides which can undergo nucleophilic and electrophilic 

addition reactions with biological material (Belsito et al., 

2008). The respective parent compounds, for which no data on toxicity 

after repeated application exist, are 2-isopropyl-5-methyl-2- 

hexene-1-ol, 2-methyl-2-buten1-ol, phytol, 3,7,11,15-tetramethyl-2-hexadecen1-ol, 

6,10-dimethylundeca-1,5,9-trien-4-ol, 

4-methyl-3-decen-5-ol and 2,2,8-trimethylnonen-3-ol. 

5.4. Acute toxicity summary 

LD 50 values indicate a low oral and dermal toxicity. Most dermal 

(rabbit, rat, guinea pig) and oral (mouse, rat) LD 50 values exceed 

2000 mg/kg body weight with the majority of values being 

greater than 5000 mg/kg body weight. 3-Methyl-2-buten-1-ol 

and 2-methyl-3-buten-2-ol show LD 50 values in the range of 

800–2300 mg/kg body weight. 

Clinical signs after dermal application were lethargy and irritation 

of the skin. After oral administration, lethargy and diarrhea 

were observed. 

5.5. Repeated dose toxicity summary 

The database on repeated dose toxicity for the members of this 

group is limited. Therefore, studies with linalool, a terpene alcohol 

with unsaturated branched chain, were included (Belsito et al., 

2008). The repeated dermal exposure to SD rats with linalool for 13 

weeks induced only a slight lethargy in two of the lower dose levels, 

and a reduction in female body weight. The NOAEL was 250 mg/kg 

body weight/day and the LOAEL was 1000 mg/kg body weight/day. 

The target organs of the tested alcohols after repeated oral 

application are kidneys and liver. Some alcohols have the potential 

to induce a 2u -nephropathy in male rats. This is a male rat-specific 

effect and has no relevance for humans. In rats, NOELs and NOAELs 

ranged from 10 (dihydromyrcenol) to 65 mg/kg body weight/day 

(3-methyl-2-buten-1-ol) in oral 90-day studies. Higher doses increased 

liver weight (probably due to enzyme induction) without 

histopathological alterations or induced kidney effects (dilated renal 

tubules and general mineralization of basophilic tubules) in females 

and males. The NOAEL for dihydromyrcenol is 50 mg/kg 

body weight/day whereas the primary allylic alcohol, 3-methyl- 

2-buten-1-ol, which would be expected to yield a reactive aldehyde 

intermediate, was 65 mg/kg body weight/day. From the few 

studies available, no consistent differences in toxicity between 

the subgroups are seen. 

5.6. Genotoxicity summary 

The five tested primary allylic, secondary allylic and tertiary alcohols 

(3-methyl-2-buten-1-ol, 4-methyl-3-decen-5-ol, 3,7-dimethyl-1,6-nonadien-3-ol, 

isophytol and 2-methyl-3-buten-2-ol) 

along with the five terpene alcohols (citronellol, dehydrolinalool,

S36 


Table 8c 

Skin sensitization studies in animals. 

Material Method Concentration(s) Subjects Results References a 


7-Nonen-2- Maximization 

ol,4,8- 

test 

dimethyl- 

Maximization 

test 


4-Methyl-3- Photoallergy 

decen-5-ol test 

(Controls) 



methyl-6- 

methylene-, 

dihydro 

derivative 


Isophytol 

Nerolidol (isomers 

unspecified) b 

Local Lymph 

Node assay 

Maximization 

test 

Buehler test 

Local Lymph 

Node assay 

Maximization 

test 

Skin painting 

test, open 

epicutaneous 

Modified FCA 

method 

Modified FCA 

method 

Modified 

Draize 

method 

Induction: 10% i.d. injections & 100% 

dermal application challenge: 100% 

dermal application 

Induction: 30% i.d. injections & 100% 

dermal application challenge: 0.1%, 1%, 

3%, 5%, or 30% dermal application 

Induction (topical): 10% challenge 

(topical) 30%, 10%, 3%, 1% vehicle: 

acetone/ethanol (1:1) 

Guinea pig No sensitization RIFM (1976c) 

Guinea pig No sensitization RIFM (2004a) 

Guinea pig, 

injected with 

FCA 

No sensitization 

RIFM (1989c) 

1%, 10% and 30% (w/v) in acetone CBA mice No sensitization RIFM (1996) 

Induction with 5% in oleum arachidis 

(intradermal) and undiluted 

(percutaneous), challenge: undiluted 

Induction with closed patch topical 

application of undiluted material for 6 h 

once a week for three weeks; challenge: 

undiluted 

0.5%, 1%, 2.5%, 10%, 25% (w/v) in ethanol/ 

diethylphthalate (1:3) 

Induction with 1% in light paraffin 

(intradermal) and 50% (percutaneous) in 

ethanol, challenge: 25% in ethanol, rechallenge: 

12.5% in ethanol 

Induction: 10% in acetone (1/10) or 1% (9/ 

10) challenge: 0.5% in acetone (control 

group: 0.5% (3/6) or 1% (3/6) 

Challenge: 3% 

Challenge: 10% 

Induction: 1%, challenge: 1% and 20% 

Guinea pig 

(20 in test 

group, 10 in 

control group) 

Guinea pig 

(20 in test 

group, 10 in 


CBA female 

mice 

Guinea pig 

(20 in test 

group, 10 in 


Guinea pig 

(10 in test 

group, 6 in 


Guinea pig 

(10) 

Guinea pig 

(number not 

reported) 

Guinea pig 

(10) 



No sensitization (EC3 value not determined, 

estimated to be >25%) 

Challenge: 15/20 of test group and 6/10 of control 

group showed skin reactions (discrete or patchy 

erythema to moderate and confluent 

erythema) = irritating concentration rechallenge: 

7/20 and 2/10 resp. showed skin 

reactions effects observed were interpreted as 

signs of irritation 

questionable erythema in 5/10 test animals and 

2/3 control animals (1%), no erythema in control 

group (0.5%); effects were interpreted as signs of 

irritation 

Weak sensitizing capacity (mean response 0.28) 

Weak sensitizing capacity (mean response 0.28) 

RIFM (1994b) 

RIFM (1994c) 

RIFM (2007b) 

Csato and 

Chubb (1996) 

as cited in 

OECD/SIDS 

(2006) 

RIFM (1970a,d) 

Hausen et al. 

(1992) 

Hausen et al. 

(1995) 

No sensitization Sharp (1978) 

OET Challenge: 4% Guinea pig No sensitization Klecak (1979, 

1985) 

Intradermal 

injection test 

Induction: 0.25% or 25% farnesyl acetate 

cross-challenge: 0.2% nerolidol 

Guinea pig 

(10 in test 

group, 6 in 


No cross-sensitization 

RIFM (1977f) 

FCA: Freund’s complete adjuvant. 

OET: open epicutaneous test. 

n.i.: no information. 

a Not all of the original reports in the OECD/SIDS assessment were made available to RIFM. 

b Materials have been previously reviewed by in RIFM’s safety assessment of terpene alcohols (Belsito et al., 2008). 

farnesol, geraniol and linalool) were inactive in bacterial tests. Linalool 

was inactive in mammalian cell systems (mouse lymphoma 

cells). Farnesol, geraniol and linalool showed no clastogenic activity 

in Chinese hamster ovary or Chinese hamster fibroblast cells. Linalool 

did not induce unscheduled DNA synthesis in fibroblasts or sister 

chromatid exchange in CHO cells. All six alcohols that were tested in 

the in vivo mouse micronucleus test were not genotoxic. 

Overall, the alcohols tested were not genotoxic in vitro and 

in vivo. 

5.7. Carcinogenicity summary 

No valid bioassays on carcinogenicity are available for the alcohols 

with unsaturated branched chains or closely structurally related 

substances. 

5.8. Reproductive and developmental toxicity summary 

Reproductive and developmental toxicity data are limited to 

studies with primary allylic and tertiary alcohols in rats. 

5.8.1. Fertility 

Histopathological examinations of the reproductive organs of 

male and female rats in 90-day studies showed no adverse effects 

up to 243.8 and 307.2 mg/kg body weight/day 3-methyl-2-buten- 

1-ol and 1000 mg/kg body weight/day dihydromyrcenol , the highest 

dose tested. No effects on male or female fertility were noted 

for linalool in coriander oil at 365 mg/kg body weight/day, for linalool 

alone at 500–1000 mg/kg, for 2-methyl-3-buten-2-ol at 

200 mg/kg body weight/day, or for isophytol (female fertility only) 

at 500 mg/kg body weight/day.


Table 9 

Phototoxicity and photoallergenicity. 

Material Method Concentration Species Results References 

As part of an HRIPT 20 volunteers were treated 

with a nine semi-occlusive patches over a three 

week period. Sites were irradiated (365 nm) for 

15 min at a distance of 15 in. 

Open applicationto two sites on the dorsal skin 

with a 0.02 ml on 1.5 cm 1.5 cm area. Then 

subsequently irradiated with 320–400 nm of UV 

light from a distance of 10 cm for 60 min. 


7-Nonen-2- 

ol,4,8- 

dimethyl- 


4-Methyl-3- 8 animals per group; patch applied 48 h; 4 h after 

decen-5-ol removal of patches left flank of two groups of 

experimental animals was radiated: Group A: 

with UVA (320–400 nm), 30 min Group B: with 

UVB (280-370 nm), 15 min Group C (control): no 

radiation Group D (control): not pretreated, 

radiated from both light sources; observations 4, 

24 and 48 h after radiation 

Photoallergy test induction: FCA injection 

followed by topical administration of test 

substance, 30 min later irradiation with UVA 

(320–400 nm, 10 J/cm 2 ) and UVB (280-320 nm, 

1.8 J/cm 2 ), induction repeated on days 3, 5, 8, 10 

without FCA injection challenge: three weeks 

after initiation of induction ± UVA irradiation 



methyl-6- 

methylene-, 

dihydro 

derivative 


Isophytol 

0.2 g of 20% in white petrolatum human Not phototoxic not 

photoallergic 

3%, 10%, or 30% in ethanol guinea pig Weak phototoxic 

reactions at 30% only 

10% in ethanol Guinea 

pig 

induction (topical): 

10% + UVA + UVB challenge 

(topical) 30%, 10%, 3%, 

1% ± UVA; vehicle: acetone/ 

ethanol (1:1) 

Guinea 

pig, 

injected 

with FCA 

semi-occlusive patch for 24 h, followed by 

irradiation for 12 min (150 W, 290–400 nm, 

covered by a UVB filter to block transmission of 

290–320 nm), readings at 24 and 48 h, 10 healthy 

adults 

In vitro 5%, 10% S. 

cerevisiae 

Not phototoxic 

No photoallergenicity 

RIFM (1979e) 

RIFM (2004a) 

RIFM (1980g) 

RIFM (1989c) 

1% Human Not phototoxic RIFM (1981c) 

In vitro 0.1%, 1%, 10% S. 

cerevisiae 

Semi-occlusive patch for 24 h, followed by 

irradiation for 12 min (150 W, 290–400 nm, 

covered by a UVB filter to block transmission of 

290–320 nm), readings at 24 and 48 h, 10 healthy 

adults 

In vitro 0.1%, 1%, 10% S. 

cerevisiae 

Five animals, UV irradiation at 320–400 nm for 

70 min; observations at 24 and 48 h 

Not phototoxic 

0.1%: not phototoxic 

1%, 10%: phototoxic 

Bagley et al. 

(1988) and 

Tenenbaum 

et al. (1984) 

RIFM (1980i) 

12% Human Not phototoxic RIFM (1981c) 

5%, 10%, 30% and 50% in 

acetone, no control 

a Materials have been previously reviewed by in RIFM’s Safety Assessment of Terpene Alcohols (Belsito et al., 2008). 

FCA: Freund’s complete adjuvant. 

Guinea 

pig 

(Hartley; 

female) 

0.1%, 1%: not 

phototoxic 10%: 

phototoxic 

RIFM (1980h) 

Not phototoxic RIFM (1999) 

5.8.2. Developmental toxicity 

3-Methyl-2-buten-1-ol showed no developmental effects in 

rats exposed at doses up to the maternally toxic dose of 

600 mg/kg body weight/day. In a one-generation study with isophytol, 

growth retardation and reduced survival occurred at 

1000 mg/kg body weight/day, and a NOAEL of 500 mg/kg body 

weight/day was derived. A LOAEL for maternal toxicity of isophytol 

was set at 250 mg/kg body weight/day. The NOAEL for linalool 

(72.9% in coriander oil) in a one-generation study is 183 mg/kg 

body weight/day for maternal and 365 mg/kg body weight/day 

for developmental. In a developmental toxicity study, the highest 

tested maternally toxic dose of linalool, 1000 mg/kg body weight/ 

day, showed no developmental toxicity. In an OECD TG 421 test 

with 2-methyl-3-buten-2-ol, the NOAEL was 50 mg/kg body 

weight/day, a dose which was maternally non-toxic. The next 

higher dose of 200 mg/kg body weight/day reduced the viability 

of the pups. 

No specific teratogenic effect was observed in any study. 

5.8.3. Estrogenic activity 

Nerolidol showed no ability to bind to the rat uterine estrogen 

receptor (Blair et al., 2000). 

In the RIFM group summary of terpene alcohols (Belsito et al., 

2008), a study to investigate the potential estrogenic activity of a 

number of essential oil constituents is described. Estrogenic activity 

was detected for high concentrations of geraniol in a bioassay 

using recombinant yeast cells expressing the human estrogen 

receptor. Geraniol and nerol did not show estrogenic or anti-estrogenic 

activity in the human cell line lshikawa Var 1 and no androgenic 

or anti-androgenic activity in yeast. In ovariectomized mice, 

geraniol did not induce estrogenic responses. 

5.9. Skin irritation summary 

The potential for skin irritation of most of the alcohols assessed 

in this report has been well characterized in humans and in experimental 

animals.

S38 


Table 10 

Summary of UV spectra data. 

Material 

UV spectra range of 

absorption (nm) 

6-Ethyl-3-methyloct-6-en-1-ol Peaked at 210–215 

3-Methyl-2-buten-1-ol Peaked at 200–205 

(Z)-2-Penten-1-ol Peaked at 210–215 

(2E,6Z)-Nona-2,6-dien-1-ol Peaked at 200–210 

Methylheptenol Peaked at 200–210 

4-Methyl-3-decen-5-ol Peaked at 200–210 

7-Octen-2-ol, 2-methyl-6-methylene-, 

Peaked at 200–210 

dihydro derivative 

3,7-Dimethyl-1,6-nonadien-3-ol Peaked at 200–210 

Dihydromyrcenol Peaked at 200–210 

Isophytol Peaked at 200–205 

2-Methyl-3-buten-2-ol Peaked at 200–205 

(E)-Nerolidol Peaked at 200–210 

Nerolidol (isomer unspecified) Peaked at 200–220 

Phytol, methylheptenol, 3,7-dimethyl-1,6-nonandien-3-ol, 2- 

methyl-3-buten-2-ol, and nerolidol, when tested undiluted in rabbits, 

induced no irritation to moderate skin irritation with the 

exception of 3-methyl-2-buten-1-ol, which was corrosive, and isophytol, 

which produced severe irritation. When tested in humans, 

no evidence of irritation at concentrations of 2–30% for 3,7-dimethyl-1,6-nonadien-3-ol, 

7-octen-2-ol, 2-methyl-6-methylene-, 

dihydro derivative, dihydromyrcenol, isophytol, 3-methyl-2-buten-1-ol, 

4-methyl-3-decen-5-ol, methylheptenol, nerolidol and 

phytol was noted. It can be concluded that at current concentrations 

of use (Table 1), the alcohols under review are not irritating 

to the skin. For dihydromyrcenol a maximum skin level of 6.8%, 

which is slightly above the human NOAEL for irritation, was 

reported. 

5.10. Mucous membrane summary 

Undiluted phytol, isophytol, nerolidol and methylheptenol 

showed no irritation or only slight eye irritation in rabbits. Moderate 

eye irritation was noted for undiluted 2-methyl-3-buten-2-ol, 

7-octen-2-ol, 2-methyl-6-methylene-, dihydro derivative, 3,7-dimethyl-1,6-nonadien-3-ol, 

dihydromyrcenol and 4-methyl-3-decen-5-ol. 

Undiluted 3-methyl-2-buten-1-ol was highly irritating. 

5.11. Skin sensitization summary 

The sensitization potential for nine of the alcohols with worldwide 

uses of >0.01 metric tons/year has been well characterized in 

humans. Supporting data from animal experiments exist for four of 

these nine alcohols. IFRA Standards (IFRA, 2006, 2007b,c) restricting 

the use of geraniol, dl-citronellol, rhodinol (3,7-dimethyl-7-octen-1-ol) 

and farnesol are based on the dermal sensitization QRA 

approach (Api et al., 2006). 

No sensitizing potential has been demonstrated in human tests 

in concentrations from 4 to 100% of the following alcohols: 3- 

methyl-2-buten-1-ol, methylheptenol, 4-methyl-3-decen-5-ol, 7- 

octen-2-ol, 2-methyl-6-methylene-, dihydro derivative, 3,7-dimethyl-1,6-nonadien-3-ol, 

dihydromyrcenol, isophytol, and nerolidol. 

For phytol, a sensitization potential cannot be excluded due to 

one human reaction at 10% in petrolatum. 

In animal experiments no sensitization potential for 7-octen-2- 

ol, 2-methyl-6-methylene-, dihydro derivative, dihydromyrcenol, 

isophytol and nerolidol was demonstrated. 

Oxidation products of alcohols (hydroperoxides) may give rise 

to skin sensitization, as was shown for linalool (Belsito et al., 

2008). There is an IFRA standard on linalool which limits the peroxide 

level to 20 mmol/l in the raw material (IFRA, 2004). Oxidation 

has to be avoided and it has to be ensured that only pure 

materials are used in fragrances. 

5.12. Phototoxicity and photoallergenicity summary 

Based on the UV spectra and review of phototoxic/photoallergy 

data, the alcohols with unsaturated chains would not be expected 

to elicit phototoxicity or photoallergy under the current conditions 

of use as fragrance ingredients. 

6. Conclusion 

Because there is insufficient information for many of the 40 

compounds under review, the database is supplemented with 

studies from previously assessed materials that share similar 

structural features and metabolic patterns. It is expected that these 

would share similar systemic toxicity profiles. 

The RIFM Expert Panel is of the opinion that there are no safety 

concerns regarding the branched chain unsaturated alcohols 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 opinion was based on the following reasons: 

No evidence or only minimal evidence of skin irritation in 

humans was associated with current levels of use at 2–30% for 

individual compounds considered. Therefore, due to the structural 

similarities, the compounds in the present assessment 

not tested for skin irritation in humans are expected to be of 

no concern provided concentrations in end products are in the 

range of 2–10%. 

Sensitizing hydroperoxides may be formed by contact with air. It 

should be ensured that oxidation reactions are prevented in the 

end product. There is an IFRA standard on linalool which limits 

the peroxide level to 20 mmol/l in the raw material (IFRA, 

2004b). 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. 

Available data for eight of the substances show that there is no 

sensitization potential. However, for phytol, a single positive 

reaction in a human maximization test has been detected, which 

indicates weak sensitization potential. There are IFRA Standards 

(IFRA, 2006, 2007b,c) restricting the use of geraniol, citronellol, 

rhodinol (3,7-dimethyl-7-octen-1-ol) and farnesol. They are 

based on the dermal sensitization QRA approach (Api et al., 2006). 

From the limited data available there is no indication for a relevant 

phototoxic activity of this group of materials. 

The compounds have a low order of acute toxicity. 

The branched chain, unsaturated alcohols tested were of low systemic 

toxicity after repeated application. Changes indicative of 

enzyme induction in the liver (liver enlargement) and a 2u - 

nephropathy in male rats have been observed at doses from 

P200 mg/kg body weight/day. From the subacute and subchronic 

oral studies available, no consistent differences in 

toxicity between the subgroups are seen. The NOAEL for 

dihydromyrcenol (from the least reactive tertiary alcohols) is 

50 mg/kg body weight/day whereas the primary allylic alcohol, 

3-methyl-2-buten-1-ol, which would be expected to yield a reactive 

aldehyde intermediate (and thus display greater toxicity), 

was 65 mg/kg body weight/day. 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, linalool had a higher systemic 

NOAEL of 250 mg/kg body weight/day in a subchronic dermal 

study compared to the lowest oral NOAEL of 50 mg/kg body 

weight/day (dihydromyrcenol).Compared to the conservative 

estimated daily uptake of about 0.49 mg/kg body weight/day of 

7-octen-2-ol, 2-methyl-6-methylene-, dihydro derivative (100% 

dermal resorption assumed), the margin of safety for this compound 

is 100 (100% oral resorption is assumed on the basis of a 

study with linalool and is also used in Belsito et al., 2008). For 

the other compounds with estimated daily doses (Table 1), the 

margin of safety is between 150 and 160,000. There is an adequate 

margin of safety for the alcohols under review when used 

in consumer products at the current concentrations. 

The three group members tested, 3-methyl-2-buten-1-ol, isophytol 

and 2-methyl-3-buten-2-ol, and the non-cyclic terpene 

alcohol, linalool, did not show specific adverse effects in relation 

to fertility and developmental toxicity. For dihydromyrcenol, no 

effects on the reproductive organs, sperm parameters and 

estrous cycle in rats were noted. 

Apart from the double bonds, especially those in conjugation 

with primary and secondary alcohol groups, the substances of 

this group evaluation do not posses further reactive structures 

that may give rise to genotoxic potential. Available in vitro and 

in vivo studies from five compounds of this group or the structurally 

related non-cyclic terpene materials do not show genotoxic 

potential. Therefore, the remaining compounds are not 

expected to be genotoxic. 

Valid data on carcinogenicity of the compounds or for closely 

structurally related substances are not available, but in view of 

the negative mutagenicity tests so far obtained, they are not of 

primary concern. 

Conflict of interest statement 

The authors are member of the Expert Panel of the Research 

Institute for Fragrance Materials, an independent group of experts 

who evaluate the safety of fragrance materials that is supported by 

the manufacturers of fragrances and consumer products containing 

fragrances. 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. 

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International Flavors and Fragrances. Report number 54718, 20 November. 


Research Institute for Fragrance Materials, Inc. (RIFM), 1970c. Eye irritation study 

with (Z)-2-penten-1-ol (cis-2-pentenol) in rabbits. Unpublished report from 



Research Institute for Fragrance Materials, Inc. (RIFM), 1970d. Report on the 

examination of isophytol for any skin sensitizing effect. Unpublished report 

from BASF, 17 August. Report number 55382. RIFM, Woodcliff Lake, NJ, 

USA. 

Research Institute for Fragrance Materials, Inc. (RIFM), 1970e. Analytical toxicology 

of 3-methyl-2-buten-1-ol. Unpublished report from BASF. Report number 

55393, 20 June. RIFM, Woodcliff Lake, NJ, USA. 


test with (Z)-2-penten-1-ol (cis-2-pentenol) humans. Unpublished report from 

International Flavors and Fragrances. Report number 54716, 23 October. RIFM, 


Research Institute for Fragrance Materials, Inc. (RIFM), 1972a. The contactsensitization 

potential of fragrance materials by maximization testing in 

humans. RIFM report number 1804, February–November. RIFM, Woodcliff 



test. Unpublished report from Fritzsche Dodge & Olcott Inc., Report number 

14605, 1 August. RIFM, Woodcliff Lake, NJ, USA. 

Research Institute for Fragrance Materials, Inc. (RIFM), 1972c. Repeated insult 

patch test with dimyrcetol. Unpublished report from International Flavors 

and Fragrances. Report number 50437, 6 July. RIFM, Woodcliff Lake, NJ, 

USA. 

Research Institute for Fragrance Materials, Inc. (RIFM), 1972d. Primary skin and 

acute eye irritation studies on a series of six samples. Unpublished report from 

Fritzsche Dodge & Olcott Inc. Report number 14607, 18 April. RIFM, Woodcliff 


Research Institute for Fragrance Materials, Inc. (RIFM), 1972e. Trade toxicology of 2- 

methyl-3-buten-2-ol. Unpublished report from BASF. Report number 55332, 13 

October. RIFM, Woodcliff Lake, NJ, USA. 


on rats and rabbits. RIFM report number 2021, February to November. RIFM, 


Research Institute for Fragrance Materials, Inc. (RIFM), 1973b. Acute oral and 

dermal toxicity studies. RIFM report number 2033, March 5. RIFM, Woodcliff 


Research Institute for Fragrance Materials, Inc. (RIFM), 1973c. Report on human 

maximization studies. RIFM report number 1802, February–December. RIFM, 


Research Institute for Fragrance Materials, Inc. (RIFM), 1973d. Repeated insult patch 

test of 6,10-dimethylundeca-1,5,9-trien-4-ol. Unpublished report from 

International Flavors and Fragrances. Report number 53319, October 26. 


Research Institute for Fragrance Materials, Inc. (RIFM), 1973e. Eye irritation with 

6,10-dimethylundeca-1,5,9-trien-4-ol in rabbits. Unpublished report from 

International Flavors and Fragrances. Report number 53320, 17 July. RIFM, 


Research Institute for Fragrance Materials, Inc. (RIFM), 1973f. Dermal irritation with 


International Flavors and Fragrances. Report number 53323, 10 July. RIFM, 


Research Institute for Fragrance Materials, Inc. (RIFM), 1974a. Acute oral and 

dermal toxicity studies. RIFM report number 1778, August 23. RIFM, Woodcliff 


Research Institute for Fragrance Materials, Inc. (RIFM), 1974b. Report on human 

maximization studies. RIFM report number 1779, June to November. RIFM, 



on rats, rabbits and guinea pigs. RIFM report number 2020, April 09. RIFM, 



maximization studies. RIFM report number 1798, June 03. RIFM, Woodcliff Lake, 

NJ, USA. 

Research Institute for Fragrance Materials, Inc. (RIFM), 1975c. Eye irritation with 


International Flavors and Fragrances. Report number 53321, 13 May. RIFM, 


Research Institute for Fragrance Materials, Inc. (RIFM), 1975d. Eye irritation with 


International Flavors and Fragrances. Report number 53322, 13 May. RIFM, 



on rats, rabbits and guinea pigs. RIFM report number 2019, January to 

September. RIFM, Woodcliff Lake, NJ, USA. 


maximization studies. RIFM report number 1797, February to December. RIFM, 


Research Institute for Fragrance Materials, Inc. (RIFM), 1976c. Screening test for 

delayed contact hypersensitivity with 7-nonen-2-ol, 4,8-dimethyl- in the albino 

guinea pig. Unpublished report from Firmenich Incorporated, 28 July. Report 

number 38741. RIFM, Woodcliff Lake, NJ, USA. 

Research Institute for Fragrance Materials, Inc. (RIFM), 1976d. Acute toxicity studies 

in rats, mice, rabbits and guinea pigs. RIFM report number 2019, September 07. 


Research Institute for Fragrance Materials, Inc. (RIFM), 1977a. Acute toxicity study 

in rats, rabbits and guinea pigs. RIFM report number 1695, January–October. 


Research Institute for Fragrance Materials, Inc. (RIFM), 1977b. Determination 

of the acute oral toxicity of dihydromyrcenol in rats. Unpublished report 

from Quest International. Report number 45928. RIFM, Woodcliff Lake, NJ, 

USA. 


maximization studies. RIFM report number 1691, February to October. RIFM, 

Woodcliff Lake, NJ, USA.


Research Institute for Fragrance Materials, Inc. (RIFM), 1977d. Report on human 

maximization studies. RIFM report number 1702, February to November. RIFM, 


Research Institute for Fragrance Materials, Inc. (RIFM), 1977e. Rabbit eye irritation 

study with dimyrcetol. Unpublished report from International Flavors and 

Fragrances, February. Report number 50434. RIFM, Woodcliff Lake, NJ, USA. 

Research Institute for Fragrance Materials, Inc. (RIFM), 1977f. Guinea pig skin 

sensitization test with farnesyl acetate. Unpublished report from Quest 

International, Report number 46005, March 29. RIFM, Woodcliff Lake, NJ, 

USA. 


in rats, mice, rabbits, and guinea pigs. RIFM report number 1699, October 4. 


Research Institute for Fragrance Materials, Inc. (RIFM), 1978b. Acute toxicity studies 

on phytol. Unpublished report from BASF, 20 July. Report number 4455. RIFM, 



maximization studies. RIFM report number 1787, February to December. RIFM, 


Research Institute for Fragrance Materials, Inc. (RIFM), 1979a. Toxicity studies on 

methyl octynol. Unpublished Report from Air Products & Chemicals, Inc. Report 

number 13486, 2 February. RIFM, Woodcliff Lake, NJ, USA. 


maximization studies. RIFM report number 1697, April to November. RIFM, 


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7-nonen-2-ol, 4,8-dimethyl- in rats. Unpublished report from Firmenich 

Incorporated, Report number 38735. RIFM, Woodcliff Lake, NJ, USA. 

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of 7-nonen-2-ol, 4,8-dimethyl- in rabbits. Unpublished report from Firmenich 

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insult patch test of 7-nonen-2-ol, 4,8-dimethyl. Unpublished report from 

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Research Institute for Fragrance Materials, Inc. (RIFM), 1979f. Primary dermal 

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Research Institute for Fragrance Materials, Inc. (RIFM), 1979g. Eye irritation study of 

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report from BASF. Report number 55385, 23 April. RIFM, Woodcliff Lake, NJ, 

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corrosive effect of 3-methyl-2-buten-1-ol in rabbits. Unpublished report from 

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primary eye irritant effect of 3-methyl-2-buten-1-ol in rabbits. Unpublished 

report from BASF. Report number 55399, 23 April. RIFM, Woodcliff Lake, NJ, 

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S42 


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Review 

Addendum to Fragrance material review on Nerolidol (isomer unspecified) 

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 

An addendum to the toxicologic and dermatologic review of Nerolidol (isomer unspecified) when used as 

a fragrance ingredient is presented. 

Ó 2009 Published by Elsevier Ltd. 

Contents 

Introduction . . . ...................................................................................................... S43 

1. Identification . . ...................................................................................................... S43 

2. Physical properties . . . . . . . . . . . . . . . . . ................................................................................... S44 

3. Usage. . . . . . . . . ...................................................................................................... S44 

4. Toxicology data ...................................................................................................... S44 

4.1. Absorption, distribution and metabolism . . . ......................................................................... S44 

4.1.1. Metabolism . . . . . . . . . . . . . . . .............................................................................. S44 


Conflict of interest statement . . . . . . . . ................................................................................... S45 

References . . . . ...................................................................................................... S45 

Introduction 

* Corresponding author. Tel.: +1 201 689 8089; fax: +1 201 689 8090. 

E-mail address: dmcginty@RIFM.org (D. McGinty). 

This document provides a comprehensive summary of the toxicologic 

review of Nerolidol when used as a fragrance ingredient 

including all human health endpoints. Nerolidol (see Fig. 1; CAS 

Number 7212-44-4) 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. 

Its worldwide use is greater than 10–100 metric tons per 

year (IFRA, 2004). It is a clear pale yellow to yellow liquid having 

a faint floral odor reminiscent of rose and apple (Arctander, 

1969). This material has been reported to occur in nature. 

In 2007, a complete literature search was conducted on Nerolidol. 

On-line databases that were surveyed included Chemical Abstract 

Services and the National Library of Medicine. In addition, 

fragrance companies were asked to submit all test data. 

The safety data on this material was last reviewed by Opdyke 

(1975). 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. 

Nerolidol is a member of the fragrance structural group Alcohols 

Branched Chain Unsaturated. Their common characteristic 

structural elements are one hydroxyl group per molecule, a C 4 – 

C 16 carbon chain with one or several methyl or ethyl side chains 

and up to four non-conjugated double bonds. This individual Fragrance 

Material Review is not intended as a stand-alone document. 

Please refer to A Safety Assessment of Alcohols with Unsaturated 

Branched Chain When Used as Fragrance Ingredients (Belsito 

et al., 2010) for an overall assessment of this material. 

1. Identification 

1.1. Synonyms: 1,6,10-dodecatrien-3-ol, 3,7,11-trimethyl-; melaleucol; 

methylvinyl homogeranyl carbinol; peruviol; 3,7, 

11-trimethyl-1,6,10-dodecatrien-3-ol; 3,7,11-trimethyldodeca-1,6,10-trien-3-ol,mixed 

isomers; 

1.2. CAS registry number: 7212-44-4; 

1.3. EINECS number: 230–597; 

1.4. Formula: C 15 H 26 O; 

1.5. Molecular weight: 222.37; 

0278-6915/$ - see front matter Ó 2009 Published by Elsevier Ltd. 

doi:10.1016/j.fct.2009.11.008

S44 

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S43–S45 

OH 

HO 

2.7. Refractive index @ 20 °C: 1.478–1.483; 

2.8. Specific gravity: 0.872–0.882 (20 °C); 

2.9. Specific gravity: 0.870–0.880 (25 °C); 

2.10. Vapor pressure (calculated): 0.1 mm Hg 20 °C; 

2.11. Water solubility (calculated): 1.532 mg/l @ 25 °C; 

2.12. UV spectra available at RIFM, peaks at 220–230 and returns 

to base line at 340. 

3. Usage 

E 

Z 

Nerolidol (isomer unspecified) 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 average maximum use level in formulae that go into fine 

fragrances has been reported to be 2.02% (IFRA, 2007), assuming 

use of the fragrance oil at levels up to 20% in the final product. 

The 97.5 percentile use level in formulae for use in cosmetics in 

general has been reported to be 1.15 (IFRA, 2007), which would result 

in a maximum daily exposure on the skin of 0.0293 mg/kg for 

high end users (see Table 1). 

1.6. Council of Europe (2000): Nerolidol (isomer unspecified) 

was included by the Council of Europe in the list of substances 

granted B – information required – 28 days oral 

study (COE No. 67); 

1.7. FDA: Nerolidol (isomer unspecified) was approved by the 

FDA as GRAS (21 CFR 172.515); 

1.8. FEMA (1970): Flavor and Extract Manufacturers’ Association 

states: generally recognized as safe as a flavor ingredient – 

GRAS 3. 

2. Physical properties 

OR 

Fig. 1. Nerolidol (isomer unspecified). 

2.1. Physical form: a clear pale yellow to yellow liquid having a 

faint floral odor reminiscent of rose and apple; 

2.2. Boiling point: 276 °C; 

2.3. Flash point:>212 °F; CC; 

2.4. Henry’s Law (calculated): 0.000181 atm m 3 /mol 25 °C; 

2.5. Log K ow (calculated): 5.68; 

2.6. Refractive index: 1.4799; 

4. Toxicology data 

4.1. Absorption, distribution and metabolism 

4.1.1. Metabolism 

In vivo studies. 

Rats were fed 20, and 40 mg of Nerolidol mixed with 1 mL of 

cottonseed oil and 30–35 mL of evaporated milk per day, for a 

period of 8 days. The average daily excretion on the 1st to 4th 

and 4th to 8th day was monitored. Respectively, 20 mg/day 

yielded 0.3 and 0.7 mg with a maximum average of 0.9 mg. From 

40 mg/day a maximum average of 2.1 mg was determined and the 

average daily excretions were 1.0 and 1.6 mg/day (Longenecker 

et al., 1939). 

In vitro studies. 

Saccharomyces cerevisiae of haploid IWD72 strain was grown in 

a medium comprised of yeast extract, bacteriolocial peptone, glucose, 

adenine, and uracil. Nerolidol (100 ug ml 1 ) in ethanol was 

added to the 50 ml bacteria culture in YEPD medium. After 24 h, 

the aerobic cultures were harvested and cells were collected. 

Residual Nerolidol recovered was 79.6 ug ml 1 (King and Dickenson, 

2003). 

Table 1 

Calculation of the total human skin exposure from the use of multiple cosmetic products containing Nerolidol. 

Product type Grams applied Applications per day Retention factor Mixture/product Ingredient/mixture a Ingredientmg/kg/day b 

Anti-perspirant 0.5 1 1 0.01 1.15 0.0010 

Bath products 17 0.29 0.001 0.02 1.15 0.0000 

Body lotion 8 0.71 1 0.004 1.15 0.0044 

Eau de toilette 0.75 1 1 0.08 1.15 0.0115 

Face cream 0.8 2 1 0.003 1.15 0.0009 

Fragrance cream 5 0.29 1 0.04 1.15 0.0111 

Hair spray 5 2 0.01 0.005 1.15 0.0001 

Shampoo 8 1 0.01 0.005 1.15 0.0001 

Shower gel 5 1.07 0.01 0.012 1.15 0.0001 

Toilet soap 0.8 6 0.01 0.015 1.15 0.0001 

Total 0.0293 

a 

b 

Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products. 

Based on a 60s-kg adult.

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S43–S45 S45 


To study the development of the fetal epidermal barrier, 

in vitro, activators of the receptors for vitamin D 3 , retinoids, peroxisome 

proliferators activated receptors (PPARs), and farnesoid X- 

activated receptors (FXR) were examined. Sprague Dawley rats 

were impregnated (plug date = day 0) so that 17 day fetuses could 

be used for an organ culture model and measurement of barrier 

function. Specifically, the effect of FXR activators, isoprenoid precursors 

and metabolites on the barrier development in vitro was 

observed. Explants were incubated for 2 days in the presence of 

100 uM Nerolidol. Full thickness flank skin from the fetal rats 

was excised and prepared. Skin samples were also analyzed with 

light and electron microscopy. Incubation of Nerolidol did not significantly 

affect barrier function or activate the FXR during skin 

development (Hanley et al., 1997). 

This individual Fragrance Material Review is not intended as a 

stand-alone document. Please refer to A Safety Assessment of Alcohols 

with Unsaturated Branched Chain When Used as Fragrance 

Ingredients (Belsito et al., 2010) for an overall assessment of this 

material. 


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 

Arctander, S., 1969. Perfume and Flavor Chemicals (Aroma Chemicals), vol. II, no. 

2316. Montclair, New Jersey. 


Sipes, I.G., Calow, P., Tagami, H., 2010. A safety assessment of alcohols with 

unsaturated branched chain when used as fragrance ingredients. Food and 

Chemical Toxicology 48 (S3), S151–S192. 

Council of Europe, 2000. Partial Agreement in the Social and Public Health Field. 

Chemically-defined Flavouring Substances. Group 2.1.4 Acyclic Terpene 

Alcohols. Council of Europe Publishing, Strasbourg, Number 67, p. 63. 

FDA (Food and Drug Administration), Code of Federal Regulations, 21 CFR 172.515. 

Title 21 – Food and Drugs, Volume 3, Chapter I – Food and Drug Administration, 

Department of Health and Human Services. Part 172 – Food Additives Permitted 

for Direct Addition to Food for Human Consumption. Subpart F – Flavoring 

Agents and Related Substances, 515 – Synthetic Flavoring Substances and 

Adjuvants. 

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 19(2, Part 2), 151–197. 

Hanley, K., Jiang, Y., Crumrine, D., Bass, N.M., Appel, R., Elias, P.M., Williams, M.L., 

Feingold, K.R., 1997. Activators of the nuclear hormone receptors PPAR alpha 

and FXR accelerate the development of the fetal epidermal permeability barrier. 

Journal of Clinical Investigation 100 (3), 705–712. 

IFRA (International Fragrance Association), 2004. Use Level Survey, August 2004. 

IFRA (International Fragrance Association), 2007. Volume of Use Survey, February 

2007. 

King, A.J., Dickenson, J.R., 2003. Biotransformation of hop aroma terpenoids by ale 

and lager yeasts. FEMS Yeast Research 3 (1), 53–62. 

Longenecker, H.E., Musulin, R.R., Tully I, R.H., King, C.G., 1939. An acceleration of 

vitamin C synthesis and excretion by feeding known organic compounds to rats. 

Journal of Biological Chemistry 129, 445–453. 

Opdyke, D., 1975. Fragrance raw materials monographs. Nerolidol. Food and 

Chemical Toxicology 13 (2), 887.





Review 

Fragrance material review on 7-octen-2-ol, 2-methyl-6-methylene-, 

dihydro derivative 

D. McGinty * , A. Lapczynski, S.P. Bhatia, C.S. Letizia, A.M. Api 

Research Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA 

article 

Keywords: 

Review 


info 

abstract 

A toxicologic and dermatologic review of 7-octen-2-ol, 2-methyl-6-methylene-, dihydro derivative when 

used as a fragrance ingredient is presented. 


Contents 

Introduction ......................................................................................................... S47 

1. Identification . . . . . . . . . . . . . . . ......................................................................................... S47 

2. Physical properties . . . . . . . . . . . ......................................................................................... S47 

3. Usage. . . . . . ......................................................................................................... S47 

4. Toxicology data . . . . . . . . . . . . . ......................................................................................... S48 

4.1. Acute toxicity . . . ............................................................................................... S48 

4.1.1. Oral studies (see Table 2). ................................................................................. S48 

4.1.2. Dermal studies . . . . . . . . . ................................................................................. S48 

4.2. Skin irritation . . . ............................................................................................... S48 

4.2.1. Human studies (see Table 3) . . . . . . . . . . . . . . ................................................................. S48 

4.2.2. Animal studies (see Table 4) . . . . . . . . . . . . . . ................................................................. S48 

4.3. Mucous membrane (eye) irritation (see Table 5) . . . . . . . . . . ............................................................ S49 




4.4.3. Other studies. . . . . . . . . . . ................................................................................. S49 

4.4.4. Local lymph node assay (LLNA) . . . . . . . . . . . . ................................................................. S50 

4.5. Phototoxicity and photoallergy . . . . . . . . ............................................................................ S50 

4.5.1. Phototoxicity. . . . . . . . . . . ................................................................................. S50 

4.5.2. Photoallergy . . . . . . . . . . . ................................................................................. S50 

4.6. Absorption, distribution, metabolism. . . . ............................................................................ S50 

4.6.1. Absorption. . . . . . . . . . . . . ................................................................................. S50 

4.6.2. Distribution. . . . . . . . . . . . ................................................................................. S50 

4.6.3. Metabolism . . . . . . . . . . . . ................................................................................. S50 

4.7. Repeated dose toxicity . . . . . . . . . . . . . . . ............................................................................ S50 

4.8. Reproductive and developmental toxicity ............................................................................ S50 

4.9. Genotoxicity . . . . ............................................................................................... S50 

4.10. Carcinogenicity . . ............................................................................................... S50 


References . . ......................................................................................................... S50 




doi:10.1016/j.fct.2009.11.009


Table 2 

Summary of acute toxicity studies. 

Route Species No. animals/dose group LD 50 (g/kg) a References 

Fig. 1. 7-Octen-2-ol, 2-methyl-6-methylene-, dihydro derivative. 

Oral Rats 10 3.6 RIFM (1973b) 

Oral Rats 6 4.15 RIFM (1977) 

Dermal Rabbits 10 >5.0 RIFM (1973b) 

a 

Some units have been converted to make easier comparisons. 

Introduction 


review of 7-octen-2-ol, 2-methyl-6-methylene-, dihydro 

derivative when used as a fragrance ingredient including all human 

health endpoints. 7-Octen-2-ol, 2-methyl-6-methylene-, dihydro 

derivative (see Fig. 1; CAS No. 53219-21-9) is a fragrance ingredient 

used in cosmetics, fine fragrances, shampoos, toilet soaps and 


cleaners and detergents. It is colorless, viscous oil with a fresh 

lime-like odor of considerable tenacity (Arctander, 1969). This 

material has been reported to occur in nature. 

In 2006, a complete literature search was conducted on 7-octen-2-ol, 

2-methyl-6-methylene-, dihydro derivative. On-line databases 

that were surveyed included Chemical Abstract Services 

and the National Library of Medicine. In addition, fragrance companies 

were asked to submit all test data. 







review. 

7-Octen-2-ol, 2-methyl-6-methylene-, dihydro derivative is a 

member of the fragrance structural group Alcohols Branched Chain 

Unsaturated. Their common characteristic structural elements are 

one hydroxyl group per molecule, a C 4 to C 16 carbon chain with one 

or several methyl or ethyl side chains and up to 4 non-conjugated 

double bonds. This individual Fragrance Material Review is not intended 

as a stand-alone document. Please refer to A Safety Assessment 

of Alcohols with Unsaturated Branched Chain When Used as 

Fragrance Ingredients (Belsito et al., 2010) for an overall assessment 

of this material. 


1.1 Synonyms: Dihydromyrcenol (isomer); 2-methyl-6-methyleneoctan-2-ol; 

2-methyl-6-methyleneoct-7-en-2-ol, dihydro 

derivative; myrcenol, dihydro-; 

1.2 CAS Registry No.: 53219-21-9; 

1.3 EINECS No.: 258-432-2; 

1.4 Formula: C 10 H 20 O; 

1.5 Molecular weight: 156.27. 


2.1 Physical form: colorless, viscous oil with a fresh lime-like 

odor; 

2.2 Boiling point: 85 °C at 3 mm Hg; 

2.3 Flash point: 165 F; CC; 

2.4 Henry’s Law (calculated): 0.0000481 atm m 3 /mol 25 °C; 

2.5 Log K ow (calculated): 3.6; 

2.6 Specific gravity: 0.831; 

2.7 Vapor pressure: 0.2270 torr; 

2.8 Water solubility: 869 mg/l (24 and 72 h stirring); 

2.9 UV spectra available at RIFM; peaks at 210 nm and returns 

to base line at: 330 nm. 

3. Usage 

7-Octen-2-ol, 2-methyl-6-methylene-, dihydro derivative 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. 

The worldwide volume of use for 7-octen-2-ol, 2-methyl-6-methylene-, 

dihydro derivative is in the region of 100–1000 metric tons 

per year (IFRA, 2004). The reported volume is for the use of a fragrance 

ingredient 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 average maximum use level in formulae that goes into fine 


use of the fragrance oil at levels up to 20% In the final product. 

Table 1 

Calculation of the total human skin exposure from the use of multiple cosmetic products containing 7-octen-2-ol, 2-methyl-6-methylene-, dihydro derivative. 

Product type Grams applied Applications per day Retention factor Mixture/product Ingredient/mixture a Ingredient (mg/kg/day) b 

Antiperspirant 0.5 1 1 0.01 19.23 0.0160 

Bath products 17 0.29 0.001 0.02 19.23 0.0003 

Body lotion 8 0.71 1 0.004 19.23 0.0728 


Face cream 0.8 2 1 0.003 19.23 0.0154 


Hair spray 5 2 0.01 0.005 19.23 0.0016 

Shampoo 8 1 0.01 0.005 19.23 0.0013 

Shower gel 5 1.07 0.01 0.012 19.23 0.0021 

Toilet soap 0.8 6 0.01 0.015 19.23 0.0023 

Total 0.4900 

a 

b 


Based on a 60 kg adult.

S48 


Table 3 

Summary of human irritation studies. 

Method Dose (%) Vehicle Results References 

Reactions Incidence (%) 

Induction phase (HRIPT) 20 1:3 DEP:EtOH 2/99 4 RIFM (2006) 

Induction phase (HRIPT) 20 DEP 0/109 0 RIFM (1995) 

Induction phase (HRIPT) 5 Vehicle not provided 0/42 0 RIFM (1964) 

Pre-test maximization 4 Petrolatum 0/5 0 RIFM (1973a) 

Table 4 

Summary of animal irritation studies. 

Method Dose (%) Species Reactions References 

Pre-test Buehler Sensitization 5, 12.5, 25, 50 or 100 Guinea pigs No irritation (0/2) RIFM (1994a) 

Dermal LD 50 100 Rabbits Slight to moderate Irritation observed RIFM (1973b) 

4 h Semi-occlusive test 100 Rabbits Irritation observed RIFM (1985) 

4 h Semi-occlusive test 100 Rabbits No irritation RIFM (1984) 

The 97.5 percentile use level in formulae for use in cosmetics in 

general has been reported to be 19.23 (IFRA, 2003), which would 

result in a maximum daily exposure on the skin of 0.49 mg/kg 

for high end users (see Table 1). 



4.1.1. Oral studies (see Table 2) 

Ten rats were dosed orally with 7-octen-2-ol, 2-methyl-6- 

methylene-, dihydro derivative at 2.56, 3.2, 4.0 or 5.0 g/kg/bodyweight. 

Animals were observed for 14 days. One animal died at 

dose of 2.56 g/kg; 5/10 died at 3.2 g/kg; 4/10 died at 4 g/kg and 

all animals died at 5.0 g/kg. Deaths occurred between 1–2 days. 

Lethargy was observed in all animals. The acute oral LD 50 dose 

was calculated to be 3.6 g/kg (95% C.I. 3.0–4.2 g/kg) (RIFM, 1973b). 

The acute oral LD 50 in rats was estimated to be 4.15 g/kg 

(5.0 ml/kg; 95% C.I. 3.5–7.3 ml/kg). Male and female adult Wistar 

rats (5/sex) were dosed by gavage with 7-octen-2-ol, 2-methyl-6- 

methylene-, dihydro derivative at the doses of 1.04, 2.08, 4.15, or 

8.31 g/kg (1.25, 2.5, 5.0 or 10 ml/kg). Animals were observed for 

14 days. Sluggishness and decreased activity was exhibited at all 

dose groups. Humpback behavior, diarrhea and decreased consciousness 

were observed at doses greater than 4.15 g/kg. Death 

occurred between 1 and 4 days after dosing. One animal died at 

2.08 g/kg, 2/10 and 6/10 died respectively at 4.15 and 8.31 g/kg 

(RIFM, 1977). 


Ten albino rabbits received a single dermal application of neat 

7-octen-2-ol, 2-methyl-6-methylene-, dihydro derivative at 5.0 g/ 

kg. Animals were observed for 14 days. No clinical symptoms were 

observed. The acute dermal LD 50 was calculated to be greater than 

5 g/kg based on 0/10 deaths at that dose (RIFM, 1973b). 


4.2.1. Human studies (see Table 3) 

Irritation was evaluated during the induction phase of human 

repeated insult patch tests (HRIPT). A 0.3 ml aliquot of 7-octen-2- 

ol, 2-methyl-6-methylene-, dihydro derivative in given vehicle 

was applied under semi-occlusion (25 mm Hilltop Ò Chamber system) 

for 24 h to each volunteer. Induction patches were applied 

three times a week (Monday, Wednesday and Friday) for a total 

of nine applications over a 3-week period. The following results 

were obtained. 

Two (2/99) irritation reactions of barely perceptible to moderate 

and marked erythema were observed when 20% 7-octen-2-ol, 

2-methyl-6-methylene-, dihydro derivative in 1:3 EtOH:DEP was 

applied to 99 male and female volunteers. Saline also produced 

irritant reactions causing barely perceptible to mild irritation with 

equivalent or less irritation (RIFM, 2006). 

No irritation (0/109) reactions were observed with 20% 7-octen- 

2-ol, 2-methyl-6-methylene-, dihydro derivative in DEP applied to 

109 volunteers (RIFM, 1995). 

No irritation was also observed with 0.5 ml of 5% 7-octen-2-ol, 

2-methyl-6-methylene-, dihydro derivative (vehicle not provided) 

applied to 42 male and female volunteers using 1 3 in. strip of 

adhesive elastic bandage (RIFM, 1964). 

In a maximization pre-test, no irritation reactions were observed 

when 4% 7-octen-2-ol, 2-methyl-6-methylene-, dihydro 

derivative in petrolatum was applied for 48 h under occlusion to 

normal sites on the backs of 5 healthy male volunteers (RIFM, 

1973a). 

4.2.2. Animal studies (see Table 4) 

A preliminary irritation test was conducted prior to a Buehler 

study using 2 female SPF Dunkin Hartley albino guinea pigs. A 

0.4 ml aliquot of 7-octen-2-ol, 2-methyl-6-methylene-, dihydro 

derivative at dose levels of 5%, 12.5%, 25%, 50% or 100% (vehicle 

not reported) was applied to clipped skin using a 3 5 cm Whitman 

No. 3 mm patch for 6 h under occlusion. The patches were 

placed on the clipped skin of all animals and fixed with 5 7cm 

Blenderm tape and trunk of the animal was wrapped with a Micropore 

tape. The procedure was repeated on days 7 and 14. After 24 h 

the test sites were assessed for irritancy. No irritation reactions 

were observed (RIFM, 1994a). 

As a part of an associated LD 50 study 10 rabbits received a single 

dermal application of neat 7-octen-2-ol, 2-methyl-6-methylene-, 

dihydro derivative at 5.0 g/kg. Slight (6/10) to moderate (1/10) erythema 

and slight (5/10) to moderate (1/10) edema was observed 

(RIFM, 1973b). 

Two, 4-h semi-occlusive primary irritation tests were conducted 

on 3 or 4 healthy female New Zealand White rabbits with 

neat 7-octen-2-ol, 2-methyl-6-methylene-, dihydro derivative. An 

0.5 ml aliquot of the test material was applied to the left flank of 

each animal using 2.5 cm square of lint B.P held in place with ‘‘Elastoplast” 

elastic adhesive bandage 10 cm wide. Reactions were 

evaluated 1 h after removal of patch and subsequent readings were 

performed at 24, 48 and 72 h. No irritation reactions were observed


when 4 rabbits were used, but irritation reactions were observed 

with 3 rabbits (RIFM, 1984; RIFM, 1985). 

4.3. Mucous membrane (eye) irritation (see Table 5) 

A rabbit eye irritation test was conducted in a group of 6 

healthy, albino rabbits weighing 2.0–3.5 kg. On the day of dosing 

the lower lid was reverted from the eyeball of the right eye to form 

a cup into which 0.1 ml aliquot of 7% in propylene glycol and 100% 

7-octen-2-ol, 2-methyl-6-methylene-, dihydro derivative was instilled. 

The eyes remained unwashed after instillation. The left 

eye remained untreated and served as a control. Reactions were assessed 

at 24, 48 and 72 h and at 4 and 7 days after dosing according 

to Draize Method. Mild irritation reactions were observed at both 

concentrations (RIFM, 1980c; RIFM, 1980d). 

An acute eye irritation study was conducted with 3 healthy albino 

rabbits. Each animal had 0.1 ml of 5% test material instilled 

into the right eye with no further treatment. The untreated left 

eye of each animal served as its own control. Both the treated 

and control eyes were examined every 24 h for 4 days and then 

again on day 7. Irritation reactions were observed in all animals 

(RIFM, 1980e). 



4.4.1.1. Induction studies (see Table 6) 

4.4.1.1.1. Human repeated insult patch test. Repeated insult patch 

tests were conducted to determine if 7-octen-2-ol, 2-methyl-6- 

methylene-, dihydro derivative would induce dermal sensitization 

in human volunteers. During the induction phase, 0.3 ml of 7-octen-2-ol, 

2-methyl-6-methylene-, dihydro derivative was applied 

onto a semi-occlusive absorbent patch (25 mm Hilltop Ò Chamber 

system) and applied to the upper arm or back of each volunteer 

for 24 h. Induction applications were made to the same site on 

Monday, Wednesday and Friday for a total of 9 applications during 

a 3-week period. Following a 14-day rest period, a challenge patch 

was applied to a site previously unexposed. Patches were applied 

as in the induction phase and kept in place for 24 h before removal. 

Reactions to the challenge were scored at 24, 48, and 72 h after 

application. The following results were obtained: 

Table 5 

Summary of eye irritation studies. 

Dose (%) Vehicle Reactions References 

100 N/A Irritation observed RIFM (1980c) 

7 Propylene glycol Irritation observed RIFM (1980d) 

5 Vehicle not provided Irritation observed RIFM (1980e) 

No reactions were observed with 20% (23620 lg/cm 2 ) 7-octen- 

2-ol, 2-methyl-6-methylene-, dihydro derivative in DEP when 

tested in 109 volunteers (84 female and 25 male) (RIFM, 1995). 

No sensitization reactions were observed with 20% (23620 lg/ 

cm 2 ) 7-octen-2-ol, 2-methyl-6-methylene-, dihydro derivative in 

1:3 EtOH:DEP when applied to the backs of 99 volunteers (RIFM, 

2006). 

No reactions were observed when 0.5 ml of 5% (5905 lg/cm 2 )7- 

octen-2-ol, 2-methyl-6-methylene-, dihydro derivative in ethanol 

was applied to 42 male and female volunteers using 1 3 in. strip 

of adhesive elastic bandage (RIFM, 1964). 

4.4.1.2. Maximization studies. A human maximization tests (Kligman, 

1966; Kligman and Epstein, 1975) was conducted with 4% 

(2760 lg/cm 2 ) 7-octen-2-ol, 2-methyl-6-methylene-, dihydro 

derivative in petrolatum on 25 healthy, male volunteers. The test 

material was applied under occlusion to the same sites on volar aspects 

forearms of all the subjects for five alternate days, 48 h periods. 

Patch sites were pre-treated with 5% aqueous SLS for 24 h 

under occlusion. Following a 10 day rest period a challenge patch 

was applied under occlusion for 48 h to a fresh site. The challenge 

applications were preceded by pretreatment with 10% SLS for 1 h. 

Reactions were read immediately after the removal of the patch 

and 48 and 72 h thereafter. No (0/25) sensitization reactions were 

observed (RIFM, 1973a). 


4.4.2.1. Maximization test. guinea pig maximization test was conducted 

with 30 female SPF albino guinea pigs. Twenty animals 

were assigned to the test group and 10 to the control. The induction 

procedure consisted of three pairs of intradermal injections: 

0.1 ml of Frauds Complete Adjuvant (FCA) diluted 1:1 with sterile 

distilled water; 5% 7-octen-2-ol, 2-methyl-6-methylene-, dihydro 

derivative in oleum arachidis and 10% in FCA. Seven days after 

intradermal injections, neat 7-octen-2-ol, 2-methyl-6-methylene- 

, dihydro derivative was applied to occluded patch (3 5cm 

Whatman No. 3 mm patch secured with 5 7 Blenderm bandage) 

which was placed on injection site (pre-treated with SLS, 24 h before 

application) for 48 h. Three weeks after intradermal induction, 

animals were challenge with 0.1 ml aliquot of 100% test material 

for 24 h under occlusion using Whatman No. 3 mm patch. Challenge 

reactions were assessed 24 and 48 h after removal of the 

patch. One week after original challenge, animals were rechallenged 

using the same concentration and method. No sensitization 

reactions were observed (RIFM, 1994b). 

4.4.3. Other studies 

A Buehler test was conducted with neat 7-octen-2-ol, 2-methyl- 

6-methylene-, dihydro derivative in 30 SPF female albino guinea 

pigs (20 test animals and 10 controls) with initial weight of 351– 

496 g. During the induction, an occluded patch (3 5cm 

Table 6 

Summary of human skin sensitization studies. 

Method Concentration Results References 

Reactions Incidence 

(%) 

HRIPT 20% in 1:3 EtOH:DEP 

(23620 lg/cm 2 ) 

0/99 0 RIFM 

(2006) 

HRIPT 20% in DEP (23620 lg/ 

cm 2 ) 

0/109 0 RIFM 

(1995) 

HRIPT 5% in EtOH (5905 lg/ 

cm 2 ) 

0/42 0 RIFM 

(1964) 

Maximization 4% in Petrolatum 

(2760 lg/cm 2 ) 

0/25 0 RIFM 

(1973a) 

Table 7 

Summary of guinea pig sensitization studies. 

Method 

Induction 

concentration 

Maximization 5% in Oleum 

arachidis, 10% 

w/w in FCAT 

for intradermal; 

100% for 

occluded 

Buehler Test 100% in EtOH/ 

DEP 1:1 or 

distilled water 

Challenge 

concentration (%) 

Reactions 

References 

100 No RIFM 

sensitization (1994b) 

observed (0/ 

20) 

100 No RIFM 

sensitization (1994a) 

observed (0/ 

20)

S50 


Whatman No. 3 mm secured with 5 7 cm Blenderm bandage) 

with 100% 7-octen-2-ol, 2-methyl-6-methylene-, dihydro derivative 

was applied to the clipped flank region of each animal for 

6 h. The procedure was repeated on days 7 and 14. Four weeks 

after the first induction, an occluded challenge application of 

0.2 ml of 100% test material was applied for 6 h. The challenge sites 

were examined 24 and 48 h after removal of patch. No sensitization 

reactions were observed (RIFM, 1994a). 

4.4.4. Local lymph node assay (LLNA) 

Sensitization was evaluated in a Local lymph node assay 

(LLNA). Groups of four male CBA strain mice were tested with 

7-octen-2-ol, 2-methyl-6-methylene-, dihydro derivative at dose 

levels of 1%, 10% or 30% in acetone. Each animal received a 

25 ll application of one concentration of 7-octen-2-ol, 2-methyl- 

6-methylene-, dihydro derivative on the dorsum surface of each 

ear for 3 consecutive days. The control group was treated solely 

with acetone. Three days following the third application all mice 

were injected in the tail vein with 250 ll of phosphate buffered 

saline containing 20 lCi of a 2.0 Ci/mmol specific activity 3Hmethyl 

thymidine 3H(Tdr) 3 H-TdR. All mice were sacrificed 5 h 

after the intravenous injection. The draining auricular lymph 

nodes were excised and placed in a PBS container. Single cell suspensions 

were prepared, washed with PBS, suspended in trichloroacetic 

acid (TCA) and left at 4 °C for overnight. The level of 

the T lymphocyte proliferation in the lymph node by measuring 

the amount of radiolabelled thymidine incorporated into the 

dividing cells was evaluated. The samples were then centrifuged 

and resuspended in TCA and then transferred to a scintillation 

cocktail. 

3 H-TdR incorporation was measured by b-scintillation 

counting. The increase in isotope incorporation was not greater 

than or equal to 3-fold at 1%, 10% and 30% (w/v) concentrations. 

7-octen-2-ol, 2-methyl-6-methylene-, dihydro derivative was considered 

unlikely to be potential sensitizer based on this study 

(RIFM, 1996). 

4.5. Phototoxicity and photoallergy 

4.5.1. Phototoxicity 

4.5.1.1. Human studies. Phototoxicity potential of 7-octen-2-ol, 2- 

methyl-6-methylene-, dihydro derivative at concentrations of 1%, 

2%, 4% or 8% in ethanol was evaluated in 10 female. The test material 

was applied under a semi-occlusive patch for 24 h, to two sites 

on the back of each volunteer (non-irradiated side served as control). 

Following 24 h exposure the test site was subject to irradiation 

for 12-min with Xenon Arc Solar simulator (150 W, emission 

spectrum 290–400 nm) covered by Schott WG 345 filter (to block 

transmission UVB:290–330 nm). Reactions were assessed 24 and 

48 h after irradiation. Equivocal findings in two patients during 

the study lead to a re-challenge with 2, 4, and 8 times the original 

concentrations but no phototoxic reactions were observed (RIFM, 

1981). 

4.5.1.2. Animal studies. No data available. 

4.5.2. Photoallergy 

No data available. 

4.6. Absorption, distribution, metabolism 

4.6.1. Absorption 

No available Information. 

4.6.2. Distribution 

4.6.2.1. In vivo studies in animals. Results from a study by Behan 

et al. (1996) show that after an application of 75 ll of a model 

cologne perfume with a 10-ingredient mixture (each at 1%), the 

residual quantities on the skin were 293 ng after 60 min of free 

evaporation. 

4.6.3. Metabolism 

No available information. 





4.9. Genotoxicity 





stand-alone document. Please refer to the Toxicologic and Dermatologic 

Assessment of Alcohols with Unsaturated Branched Chain 

when used as Fragrance Ingredients (Belsito et al., 2010) for an 

overall assessment of this material. 


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 

Arctander, S., 1969. Perfume and Flavor Chemicals (Aroma Chemicals). Vol. I, No. 

964. S. Arctander, Montclair, New Jersey. 

Behan, J.M., MacMaster, A.P., Perring, K.D., Tuck, K.M., 1996. Insight into how skin 

changes perfume. International Journal of Cosmetic Science 18 (5), 237– 

246. 


Sipes, I.G., Smith, R.L., Tagami, H., 2010. A toxicologic and dermatologic 

assessment of cyclic and non cyclic terpene alcohols when used as fragrance 

ingredients. Food and Chemical Toxicology 48 (S3), S151–S192. 

IFRA (International Fragrance Association), 2004. Use Level Survey, August 2004.. 

IFRA (International Fragrance Association), 2003. Volume of Use Survey, October 

2003.. 

Kligman, A.M., 1966. The identification of contact allergens by human assay. III. The 

maximization test. A procedure for screening and rating contact sensitizers. 

Journal of Investigative Dermatology 47, 393–409. 

Kligman, A.M., Epstein, W., 1975. Updating the maximization test for identifying 

contact allergens. Contact Dermatitis 1, 231–239. 

Opdyke, D., 1974. Fragrance raw materials monographs. Dihydromyrcenol. Food 

and Chemical Toxicology 12, 525. 

IFRA (International Fragrance Association), 2004. Use Level Survey, August 

2004. 

IFRA (International Fragrance Association), 2003. Volume of Use Survey, October 

2003. 

Kligman, A.M., 1966. The identification of contact allergens by human assay. III. The 

maximization test. A procedure for screening and rating contact sensitizers. 

Journal of Investigative Dermatology 47, 393–409. 

Kligman, A.M., Epstein, W., 1975. Updating the maximization test for identifying 

contact allergens. Contact Dermatitis 1, 231–239. 

Opdyke, D., 1974. Fragrance raw materials monographs. Dihydromyrcenol. Food 

and Chemical Toxicology 12, 525.


RIFM (Research Institute for Fragrance Materials, Inc.), 1964. Repeated insult patch 

test with dihydromyrcenol. Unpublished report from IFF. RIFM Report No. 


RIFM (Research Institute for Fragrance Materials, Inc.), 1973a. Report on human 

maximization studies. RIFM Report No. 1802, August 13. RIFM, Woodcliff Lake, 

NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1973b. Acute toxicity studies 

on rats and rabbits. RIFM Report No. 2021, June 4. RIFM, Woodcliff Lake, NJ, 

USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1977. Determination of the 

acute oral toxicity of dihydromyrcenol in rats. Unpublished report from Quest Inc. 

RIFM Report No. 45928. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1980c. Primary ocular 

irritation study of fragrance materials in rabbits. Unpublished report from IFF. 

RIFM Report No. 47078, June 12. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1980d. Primary ocular 

irritation study of dihydromyrcenol in rabbits. Unpublished report from IFF. 

RIFM Report No. 47079, November 11. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1980e. Eye irritation study of 

dihydromyrcenol in rabbits. Unpublished report from IFF. RIFM Report No. 

47080, November 11. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1981. Phototoxicity testing 

of fragrance materials. Unpublished report from IFF. RIFM Report No. 47075, 

March 9. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1984. Acute dermal irritation 

study in rabbits. RIFM Report No. 1795, June 1. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1985. Acute dermal irritation 

study in rabbits. RIFM Report No. 3099, June 1. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1994a. The Buehler test on 

dihydromyrcenol. RIFM Report No. 24242, September 30. RIFM, Woodcliff Lake, 

NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1994b. Test for delayed 

contact hypersensitivity of dihydromyrcenol using the guinea pig maximization 

test. RIFM Report No. 24241, July 29. RIFM, Woodcliff Lake, NJ, USA. 


test on dihydromyrcenol on human subjects. RIFM Report No. 25722, June 21. 


RIFM (Research Institute for Fragrance Materials, Inc.), 1996. Local lymph node assay of 

dihydromyrcenol. RIFM Report No. 35547. RIFM, Woodcliff Lake, NJ, USA. 


test (Modified Draize Procedure) with dihydromyrcenol and D-limonene. RIFM 

Report No. 45702, February 01. RIFM, Woodcliff Lake, NJ, USA.





Review 

Fragrance material review on 3,7-dimethyl-1,6-nonadien-3-ol 



article 

Keywords: 

Review 


info 

abstract 

A toxicologic and dermatologic review of 3,7-dimethyl-1,6-nonadien-3-ol when used as a fragrance 

ingredient is presented. 


Contents 




3. Usage. . . . . . ......................................................................................................... S53 


4.1. Acute toxicity (see Table 2) . . . . . . . . . . . ............................................................................ S53 

4.1.1. Oral studies. . . . . . . . . . . . ................................................................................. S53 





4.3. Mucous membrane (eye) irritation . . . . . ............................................................................ S54 





4.6. Absorption, distribution and metabolism ............................................................................ S54 



4.9. Mutagenicity and genotoxicity . . . . . . . . . ............................................................................ S54 

4.9.1. Bacterial studies. . . . . . . . ................................................................................. S54 

4.9.2. Mammalian studies . . . . . ................................................................................. S54 



References. . ......................................................................................................... S54 

Introduction 




review of 3,7-dimethyl-1,6-nonadien-3-ol when used as a 

fragrance ingredient including all human health endpoints. 3,7-Dimethyl-1,6-nonadien-3-ol 

(see Fig. 1; CAS Number 10339-55-6) 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. Its worldwide 

use is greater than 100–1000 metric tons per year (IFRA, 2004). It is 

a colorless slightly oily liquid with a floral only slightly woody 

green, soft odor of moderate tenacity (Arctander, 1969). This material 

has not been reported to occur in nature. 


doi:10.1016/j.fct.2009.11.010


4. Formula: C 11 H 20 O; 

5. Molecular weight: 168.28. 


1. Physical form: colorless, slightly oily liquid; 

2. Flash point: 177°F; CC; 

3. Henry’s law (calculated): 0.000561 atm m 3 /mol 25 °C; 

4. Log K ow (cis isomer): 3.2 @ 35 °C; 

5. Log K ow (trans isomer): 3.3 @ 35 °C; 

6. Specific gravity: 0.866; 

7. Vapor pressure (calculated): 0.0177 mm Hg @ 25 °C; 

8. Water solubility (calculated): 99.98 mg/l @ 25 °C; 

9. UV spectra available at RIFM, peaks at 200–210 and returns to 

base line at 220. 

In 2007, a complete literature search was conducted on 3,7-dimethyl-1,6-nonadien-3-ol. 

On-line databases that were surveyed 

included Chemical Abstract Services and the National Library of 

Medicine. In addition, fragrance companies were asked to submit 

all test data. 









3,7-Dimethyl-1,6-nonadien-3-ol is a member of the fragrance 

structural group alcohols branched chain unsaturated. Their common 

characteristic structural elements are one hydroxyl group 

per molecule, a C 4 to C 16 carbon chain with one or several methyl 

or ethyl side chains and up to 4 non-conjugated double bonds. This 

individual Fragrance Material Review is not intended as a standalone 

document. Please refer to A Safety Assessment of Alcohols 

with Unsaturated Branched Chain When Used as Fragrance Ingredients 

(Belsito et al., 2010) for an overall assessment of this 

material. 


Fig. 1. 3,7-Dimethyl-1,6-nonadien-3-ol. 

1. Synonyms: ethyl linalool; 1,6-nonadien-3-ol, 3,7-dimethyl; 

2. CAS Registry Number: 10339-55-6; 

3. EINECS Number: 233-732-6; 

3. Usage 

3,7-Dimethyl-1,6-nonadien-3-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 






use of the fragrance oil at levels up to 20% the final product. The 

97.5 percentile use level in formulae for use in cosmetics in general 

has been reported to be 7.12 (IFRA, 2007), which would result in a 

maximum daily exposure on the skin of 0.1814 mg/kg for high end 

users (see Table 1). 


4.1. Acute toxicity (see Table 2) 


The acute oral LD 50 of 3,7-dimethyl-1,6-nonadien-3-ol in male 

CFW-mice (17–22 g) was reported to be 5.283 ± 0.383 g/kg. The 

study was carried out on five male mice per dose. Observation period 

was 72 h. The LD 50 was calculated by the method of Miller and 

Tainter (1944). No additional details were reported (RIFM, 1967). 

The acute oral LD 50 of 3,7-dimethyl-1,6-nonadien-3-ol in was 

reported to be approximately 5.0 g/kg. Mortality was 5 of 10 rats 

at 5.0 g/kg. Three animals died on day 1, one on day 2, and one 

on day 3. There were no further deaths during the 14 day observation 

period. Lethargy was the only reported symptom. No additional 

details were reported (RIFM, 1975a). 

Table 1 

Calculation of the total human skin exposure from the use of multiple cosmetic products containing 3,7-dimethyl-1,6-nonadien-3-ol. 



Bath products 17 0.29 0.001 0.02 7.12 0.0001 

Body lotion 8 0.71 1 0.004 7.12 0.0270 


Face cream 0.8 2 1 0.003 7.12 0.0057 


Hair spray 5 2 0.01 0.005 7.12 0.0006 

Shampoo 8 1 0.01 0.005 7.12 0.0005 

Shower gel 5 1.07 0.01 0.012 7.12 0.0008 

Toilet soap 0.8 6 0.01 0.015 7.12 0.0009 

Total 0.1814 

a 

b 


Based on a 60-kg adult.

S54 


Table 2 


Route Species Number of 

animals/dose group 


The acute dermal LD 50 of 3,7-dimethyl-1,6-nonadien-3-ol in 

rabbits was reported to be greater than 5.0 g/kg. There was no mortality 

in 10 rabbits at 5.0 g/kg. Symptomology included three rabbits 

with slight erythema to six with moderate erythema and one 

slight to eight moderate edema cases. No additional details were 

reported (RIFM, 1975a). 



In a human maximization test pre-screen, 30% 3,7-dimethyl- 

1,6-nonadien-3-ol in petrolatum was applied to the backs of 25 

healthy subjects for 48 h under occlusion. No subject had any irritation 

(RIFM, 1975b). 


In an acute dermal toxicity test of 5.0 g/kg of 3,7-dimethyl-1,6- 

nonadien-3-ol in 10 rabbits, there was slight to moderate erythema 

and slight to moderate edema. No additional details were 

reported (RIFM, 1975a). 

In a rabbit dermal irritation study of undiluted and 5% 3,7-dimethyl-1,6-nonadien-3-ol 

in diethyl phthalate was applied to the 

abraded and intact skin of 3 white New Zealand rabbits. There 

was no edema and slight to moderate erythema which cleared by 

72 h. 3,7-Dimethyl-1,6-nonadien-3-ol at 5% in diethyl phthalate 

was considered not irritating to rabbit skin. Undiluted ethyl linalool 

elicited no edema. Slight to moderate erythema was observed, 

and did not clear by 72 h (RIFM, 1967). 

4.3. Mucous membrane (eye) irritation 

In a three rabbit eye irritation study conducted according to the 

method of Draize, 0.1 ml 5.0% 3,7-dimethyl-1,6-nonadien-3-ol in 

diethyl phthalate produced slight conjunctival redness at instillation 

which cleared by the 1 h observation time. Undiluted 3,7-dimethyl- 

1,6-nonadien-3-ol produced conjunctival redness, chemosis, and 

discharge, as well as slight corneal opacity which was still evident, 

but over a lesser area, at the end of the 72 h observation time (RIFM, 

1967). 


LD 50 

References 

Oral Mice 5 5.283 g/kg RIFM (1967) 

Oral Rats 10 5.0 g/kg RIFM (1975a) 

Dermal Rabbits 10 >5.0 g/kg RIFM (1975b) 


In a human maximization study involving 25 subjects, there 

was no evidence of contact sensitization to 30% 3,7-dimethyl-1,6- 

Table 3 


Method 

Dermal 

application 

Dermal 

application 

Concentration 

(%) 

Species Results References 

100 Rabbit Slight to moderate 

erythema and 

edema 

5 and 100 Rabbit Slight to moderate 

erythema 

RIFM 

(1975a,b) 

RIFM 

(1967) 

nonadien-3-ol applied 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 5% aqueous 

sodium lauryl sulfate. Following a 10-day rest period, challenge 

patches were applied under occlusion to fresh sites for 48 h. Challenge 

applications were preceded by 30 min applications of 2% sodium 

lauryl sulfate under occlusion on the left side and petrolatum 

on the right side (RIFM, 1975b). 











4.9. Mutagenicity and genotoxicity 

4.9.1. Bacterial studies 

In a GLP study conducted according to OECD, US FDA, US EPA- 

TSCA, and US EPA-FIFRA guidelines, 3,7-dimethyl-1,6-nonadien- 

3-ol was not mutagenic. Salmonella typhimurium strains TA98, 

TA100, TA102, TA1535 and TA1537 in the absence and presence 

of S9 mix (Aroclor-1254 induced rat liver) were tested up to concentrations 

of 1000 lg/plate in the pre-incubation method and 

3000 lg/plate in the plate incorporation test (RIFM, 2002). 

4.9.2. Mammalian studies 





stand-alone document. Please refer A Safety Assessment of Alcohols 



material. 






Institute of Fragrance Materials. 

References 

Arctander, S., 1969. Perfume and Flavor Chemicals (Aroma Chemicals), vol. I, no. 



Sipes, I.G., Calow, P., Tagami, H., 2010. A toxicologic and dermatologic


assessment of alcohols branched chain unsaturated when used as fragrance 

ingredients. Food Chem. Toxicol. 48 (S3), S151–S192. 

IFRA (International Fragrance Association), 2004. Use Level Survey, August. 

IFRA (International Fragrance Association), 2007. Volume of Use Survey, February. 

Miller and Tainter, 1944. Proc. Soc. Exptl. Biol. Med. 57, 261. 

Opdyke, D., 1976. Fragrance raw materials monographs. Ethyl Linalool. Food Chem. 

Toxicol. 14 (3), 767. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1967. Acute toxicity, eye and 

skin irritation test of fragrance materials. Unpublished report from Hoffmann- 

LaRoche, 20 September. Report number 30642, RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1975a. Acute toxicity studies 

on rats, rabbits and guinea pigs. RIFM report number 2020, April 09, RIFM, 


RIFM (Research Institute for Fragrance Materials, Inc.), 1975b. Report on human 

maximization studies. RIFM report number 1798, June 03, RIFM, Woodcliff Lake, 

NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 2002. Evaluation of the 

mutagenic activity of 3,7-dimethyl-1,6-nonadien-3-ol in the Salmonella 

typhimurium reverse mutation assay. Unpublished report from Givaudan, 31 

October. Report number 43045, RIFM, Woodcliff Lake, NJ, USA.





Review 

Fragrance material review on methylheptenol 



article 

Keywords: 

Review 


info 

abstract 

A toxicologic and dermatologic review of methylheptenol when used as a fragrance ingredient is 

presented. 


Contents 




3. Usage. . . . . . ......................................................................................................... S57 



4.1.1. Oral studies. . . . . . . . . . . . ................................................................................. S57 
















References. . ......................................................................................................... S58 

Introduction 


review of methylheptenol when used as a fragrance ingredient 

including all human health endpoints. Methylheptenol (see 

Fig. 1; CAS Number 1335-09-7) is a fragrance ingredient used in 





and detergents. Its worldwide use is greater than 0.01–0.1 

metric tons per year (IFRA, 2004). This material has been reported 

to occur in nature. 

In 2007, a complete literature search was conducted on methylheptenol. 

On-line databases that were surveyed included 

Chemical Abstract Services and the National Library of Medicine. 

In addition, fragrance companies were asked to submit all test 

data. 


doi:10.1016/j.fct.2009.11.011



7. Vapor pressure (calculated): 0.0608 mm @ Hg 25 °C; 

8. Water solubility (calculated): 1644 mg/l @ 25 °C; 

9. UV spectra available at RIFM, peaks at 200–210 and returns to 

base line at 230. 

3. Usage 

The safety data on this material was last reviewed by Opdyke, 

1978. All relevant references are included in this document. More 







Methylheptenol is a member of the fragrance structural group 

alcohols branched chain unsaturated. Their common characteristic 

structural elements are one hydroxyl group per molecule, a C 4 to 








1. Synonyms: heptenol, methyl-; methylheptenol; 

2. CAS Registry Number: 1335-09-7; 

3. EINECS Number: 215-619-3; 


5. Molecular weight: 128.22; 

6. FDA: methylheptenol was approved by the FDA as GRAS (21 

CFR 172.515). 


Fig. 1. Methylheptenol. 

1. Physical form: a colorless oily liquid; 

2. Flash point: 143°F; CC; 

3. Henry’s Law (calculated): 0.0000273 atm m 3 /mol 25 °C; 

4. Log K ow (calculated): 2.65; 

5. Refractive index: 1.4484; 

Methylheptenol 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 


0.01–0.1 metric tons per annum (IFRA, 2004). 

The maximum skin level that results from the use of methylheptenol 

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. 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). 




The acute oral LD 50 of methylheptenol in rats was reported to be 

greater than 5.0 g/kg. Mortality was two of 10 rats, one on the first 

day and another one on the second day, at 5.0 g/kg. No toxic signs 

were observed. No additional details were reported (RIFM, 1976a). 

The acute oral LD 50 of methylheptenol in male CFW mice (5/ 

dose) weighing 17–22 g was reported to be 3.9 ± 0.3 g/kg. Animals 

were observed for 72 h after dosing. No additional details were reported 

(RIFM, 1967a). 


The acute dermal LD 50 of methylheptenol in rabbits was reported 

to be greater than 5.0 g/kg. There was no mortality in 10 

rabbits at 5.0 g/kg. Symptomology was moderate to marked 

Table 2 


Route Species No. animals/dose group LD 50 References 

Oral Rats 10 >5.0 g/kg RIFM (1976a) 

Oral Mice 5 3.9 g/kg RIFM (1967a) 

Dermal Rabbits 10 >5.0 g/kg RIFM (1976a) 

Table 1 

Calculation of the total human skin exposure from the use of multiple cosmetic products containing methylheptenol. 

Type of cosmetic product Grams applied Applications per day Retention factor Mixture/product Ingredient/mixture a Ingredient (mg/kg/day) b 

Body lotion 8.00 0.71 1.000 0.004 0.02 0.0001 

Face cream 0.80 2.00 1.000 0.003 0.02 0.0000 

Eau de toilette 0.75 1.00 1.000 0.080 0.02 0.0002 

Fragrance cream 5.00 0.29 1.000 0.040 0.02 0.0002 

Anti-perspirant 0.50 1.00 1.000 0.010 0.02 0.0000 

Shampoo 8.00 1.00 0.010 0.005 0.02 0.0000 

Bath products 17.00 0.29 0.001 0.020 0.02 0.0000 

Shower gel 5.00 1.07 0.010 0.012 0.02 0.0000 

Toilet soap 0.80 6.00 0.010 0.015 0.02 0.0000 

Hair spray 5.00 2.00 0.010 0.005 0.02 0.0000 

Total 0.0005 

a 

b 



S58 


Table 3 


Method Concentration (%) Species Results References 

Dermal application 100 Rabbit Erythema and edema observed RIFM (1976a) 

Dermal application 100 Rabbits Well defined erythema RIFM (1967a) 

Dermal application 5 Rabbits No reaction at 48 h RIFM (1967a) 

erythema and slight to moderate edema. No additional details 

were reported (RIFM, 1976a). 



In a human maximization test pre-screen, 2% methylheptenol in 

petrolatum was applied to the backs of 25 healthy subjects for 48 h 

under occlusion. No subject had any irritation (RIFM, 1976b). 


In an acute dermal toxicity study of methylheptenol in rabbits, 

there was no mortality in 10 rabbits at 5.0 g/kg. Symptomology 

was moderate to marked erythema and slight to moderate edema. 

No additional details were reported (RIFM, 1976a). 

In a rabbit dermal irritation study, undiluted methylheptenol 

was applied to intact and abraded skin of 3 white New Zealand rabbits. 

Slight erythema without edema was observed at 24 h and well 

defined erythema without edema at 48 h. When diluted to 5% with 

diethylphthalate, there was only slight erythema at 24 h and no 

reaction at 48 h (RIFM, 1967b). 


In a rabbit eye irritation study conducted according to the 

method of Draize, undiluted methylheptenol produced erythema, 

chemosis, discharge and corneal opacity were reported. When diluted 

to 5%, conjunctival irritation was observed at instillation 

but cleared by 1 h. One animal had discharge in the first hour only. 

There were no other effects using the 5% dilution. (RIFM, 1967b). 




was no evidence of contact sensitization to 2% methylheptenol 

(1380 lg/cm 2 ). The application was in petrolatum and under 

occlusion to the forearms or the back for five alternate day, 48 h 

periods. Each application was preceded by a 24 h occlusive treatment 

of the patch sites with 2.5% aqueous sodium lauryl sulfate. 

Following a 10-day rest period, challenge patches were applied under 

occlusion to fresh sites for 48 h. Challenge applications were 

preceded by 1 h applications of 5–10% sodium lauryl sulfate under 

occlusion. Challenge sites were evaluated at removal of the patches 

and 24 h later (RIFM, 1976b). 


















material. 







References 





FDA (Food and Drug Administration), Code of Federal Regulations, 21 CFR 172.515. 

Title 21 – Food and Drugs, Volume 3, Chapter I – Food and Drug Administration, 

Department of Health and Human Services. Part 172 – Food Additives Permitted 

for Direct Addition to Food for Human Consumption. Subpart F – Flavoring 

Agents and Related Substances, 515 – Synthetic Flavoring Substances and 

Adjuvants. 

IFRA (International Fragrance Association), 2004. Use Level Survey, August. 

Opdyke, D., 1978. Fragrance raw materials monographs. Methylheptenol. Food and 

Chemical Toxicology 16 (4), 817. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1967a. Acute toxicity, eye 


Hoffmann-LaRoche, 20 September. Report number 30642, RIFM, Woodcliff 


RIFM (Research Institute for Fragrance Materials, Inc.), 1967b. Acute toxicity, eye 


Hoffmann-LaRoche, 20 September. Report number 30645, RIFM, Woodcliff 


RIFM (Research Institute for Fragrance Materials, Inc.), 1976a. Acute toxicity studies 

in rats, mice, rabbits and guinea pigs. RIFM report number 2019, September 07, 


RIFM (Research Institute for Fragrance Materials, Inc.), 1976b. Report on human 

maximization studies. RIFM report number 1797, June 25, RIFM, Woodcliff Lake, 

NJ, USA. 

No available information.





Review 

Fragrance material review on phytol 



article 

Keywords: 

Review 


info 

abstract 

A toxicological and dermatologic review of phytol when used as a fragrance ingredient is presented. 


Contents 




3. Usage. . . . . . . . . ...................................................................................................... S60 


4.1. Acute toxicity (see Table 2) . . . . . . . . . . . . . . ......................................................................... S60 

4.1.1. Oral studies . . . . . . . . . . . . . . .............................................................................. S60 




4.2.2. Animal studies (see Table 3) . .............................................................................. S61 

4.3. Mucous membrane (eye) irritation . . . . . . . . ......................................................................... S61 

4.4. Skin sensitization . . . . . . ......................................................................................... S61 



4.5. Phototoxicity and photoallergy . . . . . . . . . . . ......................................................................... S61 


4.6.1. Absorption . . . . . . . . . . . . . . . .............................................................................. S61 

4.6.2. Distribution . . . . . . . . . . . . . . .............................................................................. S61 


4.8. Mutagenicity and genotoxicity . . . . . . . . . . . . ......................................................................... S62 

4.8.1. Bacterial studies. . . . . . . . . . . .............................................................................. S62 

4.8.2. Mammalian studies . . . . . . . . .............................................................................. S62 


4.10. Carcinogenicity . . . . . . . . ......................................................................................... S62 


References . . . . ...................................................................................................... S63 

Introduction 


review of phytol when used as a fragrance ingredient including 

all human health endpoints. Phytol (see Fig. 1; CAS Number 150-86- 



7) is a fragrance ingredient used in cosmetics, fine fragrances, shampoos, 



use is 0.1 to 1.0 metric tons per year (IFRA, 2004). It is a viscous liquid, 

practically colorless with a delicate floral balsamic odor (Arctander, 

1969). This material has been reported to occur in nature. 

In 2007, a complete literature search was conducted on phytol. 



doi:10.1016/j.fct.2009.11.012

S60 


2. CAS registry number: 150-86-7; 

3. EINECS number: 205-776-6; 



6. FEMA: Flavor and Extract Manufacturers 0 Association states: 

generally recognized as safe as a flavor ingredient – GRAS 22. 


1. Boiling point: 132 °C (Private communication to FEMA); 

2. Boiling point: 202 °C (FMA); 

3. Flash point: >200 °F; CC; 

4. Henry’s Law (calculated): 0.000965 atm m 3 /mol 25 °C; 

5. Log Kow (calculated): 8.32; 

6. Refractive index: 1.460–1.466; 


8. Vapor pressure:


Table 2 


Route Species Number of animals/ 

dose group 


The acute dermal LD 50 of phytol in rabbits was reported to be 

greater than 5.0 g/kg. Mortality was 1 of 10 rabbits at 5.0 g/kg. 

The death occurred on day 11. Symptomology was mild to moderate 

erythema and moderate edema. The animal that died had an 

enlarged blotchy liver and dried fecal matter anogenitally. Necropsy 

of survivors revealed three with dark livers, one with a blotchy 

liver, and one red intestine (RIFM, 1977a). 



In a human maximization test pre-screen, 10% phytol in petrolatum 

was applied to the backs of 25 healthy subjects for 48 h under 

occlusion. No subject had any irritation (RIFM, 1977b). 


In an acute dermal toxicity study of phytol in rabbits, mortality 

was 1 in 10 rabbits at 5 g/kg. The death occurred on day 11. Symptomology 

was mild to moderate erythema and moderate edema 

(RIFM, 1977a). 

In a dermal irritation study of phytol groups of six rabbits with 

abraded and intact skin were exposed for 2 h with an eight day 

observational period. By the eighth day severe edema, erythema 

and scaling that extended beyond the exposure area was observed. 

The Primary Irritation Index was 5.0, considered moderately irritating 

(RIFM, 1978). 

In order to assess the possible irritating or corrosive potential of 

phytol to the dorsal skin, dermal applications were given for exposure 

periods of 1, 5, or 120 min to the intact skin of two rabbits. 

After 1 min, mild erythema was noted for 1 of 2 animals within 

24 h. At 5 and 120 min exposures, mild erythema and edema persisted 

to 48 h but returned to normal after 8 days (RIFM, 1978). 


In a rabbit eye irritation study (6/dose), phytol produced mild to 

moderate conjunctival erythema and mild secretion. No corneal 

opacity or iris congestion occurred. The Primary Irritation Index 

was 3.2 (RIFM, 1978). 


LD 50 

(g/kg) 

References 

Oral Rats 10 >5.0 RIFM (1977a), RIFM (1977a) 

Oral Rats NA >10 RIFM (1978) 

Dermal Rabbits 10 >5.0 RIFM (1977a), RIFM (1977a) 


In a human Maximization study involving 25 subjects, there 

was one case of contact sensitization to 10% phytol (6900 lg/ 

cm 2 ). The application of phytol was in petrolatum under occlusion 

to the forearms or back for five alternate day, 48 h periods. Each 

application was preceded by a 24 h occlusive treatment of the 

patch sites with 2.5% aqueous sodium lauryl sulfate. Following a 

10 day rest period, challenge patches were applied under occlusion 

to fresh sites for 48 h. Challenge applications were preceded by 1 h 

applications of 5–10% sodium lauryl sulfate (SLS) under occlusion. 

Challenge sites were evaluated at removal of the patches and 24 h 

later (RIFM, 1977b). 






4.6.1. Absorption 


4.6.2. Distribution 

4.6.2.1. In vivo studies in animals. When tritium labeled phytol was 

given to rats, the highest specific activity was found in the liver. 

The total activity remaining in the body was of the same order of 

magnitude as the levels of phytanic and phytenic acid in the liver, 

as determined by gas chromatography. After giving phytol in the 

diet, lipotropic effect was marked and both phytenic and phytanic 

acid were found in the liver. The fatty acid pattern of neutral lipids 

was markedly changed; the level of oleic acid was significantly 

lower than controls. Choline inhibited the deposition of both phytol 

metabolites in the liver (Bernhard et al., 1967). 

Twelve Shropshire sheep were orally dosed with 4 ml of 14 C- 

phytol in 50% ethanol solution. Four sheep were killed at days 1, 

5, and 12 after administration then necropsied. Plasma samples 

were also taken from sheep up to 96 h after administration of 

the radioisotope. The highest concentrations were found in the liver 

of all sheep. Especially at the 24 h sampling time, but at 5 days 

lung, fat, adrenal, spleen, heart, and muscle also showed radioactivity 

(Hidiroglou and Jenkins, 1972). 

Male sprague–dawley rats were given 0.2 mg of 14 C phytol 

dissolved in 0.5 ml of corn oil and administered via gavage or 

0.1 ml via a duodenal catheter. Tissue lipids and expired CO2 were 

collected. Usually after 24 h feces, urine, and various tissues were 

collected. Total recovery of radioactivity averaged 91% in 5 gavage 

phytol-fed rats. The administered radioactivity was recovered 

in lymph (33.1%), expired CO 2 (3%), liver (0.6%), urine (1%) and 

feces/intestinal contents (43.9%). Of the 14 C phytol administered 

through catheter into the duodenum, lymph was collected during 

successive periods and analyzed for radioactivity. Absorption was 

more rapid and regular with two thirds of total lymph radioactivity 

being collected in the first 2 h (Baxter et al., 1967). 

A pair of rats and mice were fed 2% phytol in the diet for 2 days, 

and then injected with uniformly labeled 14 C-phytol. The rats were 

sacrificed at 3 and 20 min, and the mice at 2 and 10 min after injection. 

More then 40% of the dose was found in total liver lipids at 2 

Table 3 


Method Dose (%) Species Results References 

Single dermal application 100% Rabbits Mild to moderate erythema and edema RIFM (1977a,b) 

Single dermal application NA Rabbits Erythema, scaling, and edema were observed RIFM (1978) 

Single dermal application NA Rabbits Mild erythema and mild edema, reversible at 8 days RIFM (1978) 

NA: not available.

S62 


or 3 min, respectively. Of this, over 80% was present as presumably 

unchanged phytol. Phytanic acid was accumulated to the extent of 

11% in the liver and 36% in the plasma. In contrast to the mouse, 

phytol-fed rats did not accumulate significant amounts of any of 

the metabolites of phytanic acid (Mize et al., 1969). 

Adult male and female inbred C57BL/6J mice were split into 

three groups (six/group) and given supplemented diets for 19 days. 

One group was supplemented with 0.5% phytol and ingested 

approximately 250 mg/kg (10 mg/kg body weight/day). A significant 

decrease in liver triglyceride and neutral lipid values as well 

as serum triglyceride and phospholipids values when phytol-fed 

males were compared to control-fed males. A significant decrease 

was seen in liver triglycerides, and neutral lipid values as well as 

serum cholesteryl ester, triglyceride, phopholipid, neutral lipid, 

and total lipid values when compared to control-fed females. There 

was also a significant increase in liver phospholipids in phytol-fed 

males as well as liver cholesteryl esters, cholesterol, and phospholipids 

values in phytol-fed females (Atshaves et al., 2004). 

4.6.2.2. Metabolism (see Table 4). In a study to evaluate the potential 

of a series of isoprenoid compounds to control hypercholesterolemia, 

phytol was reported to inhibit conversion of squalene to 

sterols, but not to inhibit incorporation of H 3 -mevalonic acid into 

sterols when introduced into sonicated liposomes (Morin and 

Srikantaiah, 1982). 

In another study of potential anti-hypercholesterolemic effects 

of a large number of compounds, it was reported that 2 mM phytol 

inhibited incorporation of acetate-2-C 14 into cholesterol and increased 

incorporation into fatty acids in rat liver homogenates 

(Piccinini, 1962). 

Male wild-type and PPARa / mice on a Sv/129 background 

(12/group) were used for this study. Mice (3/group) were fed with 

0 (control), or 0.5% phytol for 1, 2, 4, or 8 weeks. Phytol levels were 

determined in freshly prepared liver homogenates in PBS. 

Branched chain fatty acids were measured in liver and plasma to 

establish the extent of accumulating phytenic, phytanic, and pristanic 

acid after the enriched diet. The levels increased with increasing 

diet period, but were much stronger in wild-type mice 

(Gloerich et al., 2005). 


Adult male and female inbred C57BL/6J mice were split into 

three groups (six/group) and given supplemented diets for 19 days. 

One group was supplemented with 0.5% phytol to study liver toxicity 

and animal mortality. The phytol-fed mice ingested approximately 

250 mg/kg (10 mg/kg body weight/day). Control-fed 

female and male mice consumed food and gained weight at a similar 

rate, only females on the phytol diet lost weight (after 10 days). 

The weight loss was preferentially in fat tissue versus lean muscle. 

Phytol-fed male mice showed gross enlargement of the liver as 

indicated by a 27% increase in liver weight over male mice fed control 

food. Livers appeared normal based on gross examination. Phytol-fed 

females showed gross morphological changes in the liver 

when compared to control-fed females. Livers were consistently 

pale and friable, with a generalized mottled appearance. Histopathology 

revealed lesions, random hepatic cord disruption, and 

small multifocal areas of hepatocytes necrosis with early inflammatory 

cell infiltration of neutrophils and lymphocytes present 

in phytol-fed females (Atshaves et al., 2004). 



Salmonella typhimurium, strain TA100, a histidine requiring mutant, 

was used as a part of an Ames (plate incorporation and preincubation) 

test to study the mutagenicity of phytol. The inhibition 

ratios were 5, 40, 49, and 99% with concentrations of 0.5, 1.0, 2.5, 

and 5.0%, respectively. Phytol was not considered mutagenic (Choi 

et al., 1993). 


Phytol was reported to have slightly less promoting activity 

than TPA in a mouse initiation/promotion assay for skin cancer initiated 

by DMBA. Phytol was administered dermally at 120 mg 

2 days a week for about 4 months and 2.5 lg TPA was administered 

similarly. Squamous cell carcinoma incidence was 95% in 

the phytol-treated animals compared to 100% in the TPA-treated 

animals. The average number of tumors per mouse was significantly 

different between the TPA and the phytol-treated groups. 

No additional information was provided (Kagoura et al., 1993). 


Arnhold et al. (2002) reported that 500 mg/kg phytol greatly reduced 

teratogenesis induced by 500 mg/kg retinol or 200 mg/kg 

all-trans retinoic acid when co-administered by oral gavage to 

mice on gestational day 8.5. Phytol alone led to no malformations, 

3% resorptions, and fetal weights of 1.26 ± 0.13 g compared to historical 

control values of 4% resorptions and fetal weight of 

1.2 ± 0.13 g. There was no control group in this study. 


Phytol was reported to have slightly less promoting activity 

than TPA in a mouse initiation/promotion assay for skin cancer initiated 

by DMBA. The phytol was administered dermally at 120 mg 

2 days a week for about 4 months and 2.5 lg TPA was administered 

similarly. Squamous cell carcinoma incidence was 95% in 

the phytol-treated animals compared to 100% in the TPA-treated 

animals. The average number of tumors per mouse was significantly 

different between the TPA and the phytol-treated groups. No 

additional information was provided (Kagoura et al., 1993). 





material. 

Table 4 

Summary of in vitro animal studies. 

Test system (in vitro) Species Dose (%) Results References 

Liver microsomes and cytosol Rat 0.11 and 0.02 mM Inhibits conversion of squalene to sterols Morin and Srikantaiah (1982) 

Liver homogenates Rat 2.0 mM Inhibited incorporation into cholesterol and Piccinini (1962) 

increased incorporation into fatty acids 

Liver homogenates Mouse 0.5% in diet Hepatic levels of phytol and its metabolites 

increased with longer periods of the diet 

Gloerich et al. (2005)








References 

Arctander, S., 1969. In: Arctander, S. (Ed.), Perfume and Flavor Chemicals (Aroma 

Chemicals), vol. II. Montclair, New Jersey, p. 2613 

Arnhold, T., Elmazar, M.M.A., Nau, H., 2002. Prevention of vitamin A teratogenesis 

by phytol or phytanic acid results from reduced metabolism of retinol to the 

teratogenic metabolite, all-trans-retinoic acid. Toxicological Sciences 66 (2), 

274–282. 

Atshaves, B.P., Payne, H.R., McIntosh, A.L., Tichy, S.E., Russell, D., Kier, A.B., 

Schroeder, F., 2004. Sexually dimorphic metabolism of branched-chain lipids 

in C57BL/6J mice. Journal of Lipid Research 45 (5), 812–830. 

Baxter, J.H., Steinberg, D., Mize, C.E., Avigan, J., 1967. Absorption and metabolism of 

uniformly (14)C-labeled phytol and phytanic acid by the intestine of the rat 

studied with thoracic duct cannulation. Biochemica et Biophysica Acta 137, 

277–290. 





Bernhard, V.K., Maier, R., Ritzel, G., 1967. Effect of phytol on liver lipids. Hoppe- 

Seyler’s Z. Physiology and Chemistry 348 (7), 759–764. 

Choi, Y.-H., Ahn, S.-J., Park, K.-Y., Yoo, M.-A., Lee, W.-H., 1993. Effects of phytol on the 

mutagenicity of UV and EMS in salmonella and drosophila mutation assaying 

systems. Environmental Mutagens and Carcinogens 13 (2), 92–100. 

Gloerich, J., van Vlies, N., Jansen, G.A., Denis, S., Ruiter, J.P.N., van Werkhoven, M.A., 

Duran, M., Vaz, F.M., Wanders, R.J.A., Ferdinandusse, S., 2005. A phytol-enriched 

diet induces changes in fatty acid metabolism in mice both via PPAR alphadependent 

and -independent pathways. Journal of Lipid Research 46 (4), 716– 

726. 

Hidiroglou, M., Jenkins, K.J., 1972. Fate of (14)C-phytol administered orally to sheep. 

Canadian Journal of Physiology and Pharmacology 50 (5), 458–462. 


2004. 


2007. 

Kagoura, M., Matsui, C., Morohashi, M., 1993. Carcinogenicity study of phytol 

(3,7,11,15-tetramethyl-2-hexadecen-1-ol) in ICR mice. Journal of Investigative 

Dermatology 101 (3), 460. 

Mize, C.E., Steinberg, J.A.D., Pittman, R.C., Fales, H.M., Milne, G.W.A., 1969. A major 

pathway for the mammalian oxidative degradation of phytanic acid. Biochimica 

et Biophysica Acta, 720–739. 

Morin, R.J., Srikantaiah, M.V., 1982. Inhibition of rat liver sterol formation by 

isoprenoid and conjugated ene compounds. Pharmacological Research 

Communications 14 (10), 941–947. 

Opdyke, D., 1982. Fragrance raw materials monographs. Phytol. Food and Chemical 

Toxicology 20 (6), 811–815. 

Piccinini, F., 1962. Effect of some natural and synthetic isoprenoids on the 

metabolism of lipids: studies in vitro and in vivo. Arch. Ital. Sci. Aromet. 76 

(4), 111–117. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1977a. Acute Toxicity Study 

in Rats, Rabbits and Guinea Pigs. RIFM Report Number 1695, July 05, RIFM, 


RIFM (Research Institute for Fragrance Materials, Inc.), 1977b. Report on Human 

Maximization Studies. RIFM Report Number 1702, May 03, RIFM, Woodcliff 


RIFM (Research Institute for Fragrance Materials, Inc.), 1978. Acute Toxicity Studies 

on Phytol. Unpublished Report from BASF, 20 July. Report Number 4455, RIFM, 






Review 


D. McGinty * , L. Jones, C.S. Letizia, A.M. Api 


article 

Keywords: 

Review 


info 

abstract 

A toxicologic and dermatologic review of 3-methyl-2-buten-1-ol when used as a fragrance ingredient is 

presented. 


Contents 




3. Usage. . . . . . ......................................................................................................... S65 



4.1.1. Oral studies. . . . . . . . . . . . ................................................................................. S65 


4.1.3. Miscellaneous studies. . . . ................................................................................. S65 










4.7. Repeated dose toxicity (see Table 5) . . . . ............................................................................ S67 

4.7.1. Two to 30-day studies . . . ................................................................................. S67 

4.7.2. Subchronic studies . . . . . . ................................................................................. S67 

4.7.3. Chronic (90+ days) studies. ................................................................................ S67 



4.9.1. Bacterial studies . . . . . . . . ................................................................................. S68 


4.10. Carcinogenicity . ............................................................................................... S68 


References. . ......................................................................................................... S68 

Introduction 




review of 3-methyl-2-buten-1-ol when used as a fragrance 

ingredient including all human health endpoints. 3-Methyl-2-bu- 


doi:10.1016/j.fct.2009.11.013


3. Usage 

ten-1-ol (see Fig. 1; CAS Number 556-82-1) is a fragrance ingredient 



cleaners and detergents. Its worldwide use is 1–10 metric 

tons per year (IFRA, 2004). It is a colorless mobile liquid with a 

somewhat ‘‘gassy” odor (Arctander, 1969). 

In 2007, a complete literature search was conducted on 3- 

methyl-2-buten-1-ol. On-line databases that were surveyed included 

Chemical Abstract Services and the National Library of 











3-Methyl-2-buten-1-ol is a member of the fragrance structural 

group Alcohols Branched Chain Unsaturated. Their common characteristic 

structural elements are one hydroxyl group per molecule, 

aC 4 to C 16 carbon chain with one or several methyl or ethyl side 

chains and up to 4 non-conjugated double bonds. This individual 

Fragrance material review is not intended as a stand-alone document. 


Branched Chain When Used as Fragrance Ingredients 

(Belsito et al., 2010) for an overall assessment of this material. 


1.1. Synonyms: 2-buten-1-ol, 3-methyl-; 3-methylbut-2-en-1-ol 

prenol; 

1.2. CAS Registry Number: 556-82-1; 

1.3. EINECS Number: 209-141-4; 

1.4. Formula: C 5 H 10 O; 

1.5. Molecular weight: 86.13; 

1.6. FEMA: Flavor and Extract Manufacturers’ Association states: 

Generally Recognized as Safe as a flavor ingredient – GRAS 

12; 

1.7. JECFA: the Joint FAO/WHP Expert Committee on Food Additives 

(JECFA No. 1200) concluded that the substance does 

not present a safety concern at current levels of intake when 

used as a flavoring agent. 


Fig. 1. 3-Methyl-2-buten-1-ol. 

2.1. Physical form: a colorless liquid; 

2.2. Boiling point: 140 °C; 

2.3. Flash point: 110 °F; CC; 



2.6. Specific gravity: 0.845; 


2.8. Water solubility (calculated): 40940 mg/l @ 25 °C; 

2.9. UV spectra available at RIFM; peaks at 200–205 nm. 

3-Methyl-2-buten-1-ol is a fragrance ingredient used in many 

fragrance compounds. It may be found in fragrances used in decorative 



cleaners and detergents. Its use worldwide is in the region of 1– 

10 metric tons per annum (IFRA, 2004). 











The acute oral LD 50 of 3-methyl-2-buten-1-ol in rats was reported 

to be 0.81 (0.55–1.18) g/kg. Mortalities within the groups 

of 10 were 0, 3, 9, 10, and 10 rats at 0.34, 0.67, 1.31, 2.56, and 

5.0 g/kg, respectively. Toxic signs included lethargy, flaccidity, 

ataxia, ptosis, and piloerection. At the two highest doses, deaths 

occurred within 4 h. Gross pathology revealed red or yellow exudates 

around nose/mouth, bloody anogenital exudates, dark lungs, 

mottled liver, dark or mottled kidneys, red or yellow areas and 

bloating of the gastrointestinal tract, and dark spleens. No additional 


In an acute oral (gavage) toxicity study of 3-methyl-2-buten-1-ol 

as an aqueous emulsion in tragacanth at concentrations of 30%, 20%, 

and 2% in 20 (10/sex) Gassner rats, the LD 50 was calculated to be 

1.591 g/kg (1.85 ml/kg). Animals were inspected for signs of pharmacologic 

or toxicologic effects during a 7-day post observation 

period. No control animals were included. Mortality within the 

groups were 0, 0 (within 7 days), 17, 19, 20, and 20 (within 24 h) rats 

at 0.2, 1.6, 2.0, 2.5, 3.2, and 6.4 ml/kg (0.17, 1.38, 1.72, 2.15, 2.75 and 

5.5 g/kg), respectively. Toxic and clinical signs included staggering, 

abdominal/lateral position, partly dorsal position, apathy, labored/ 

irregular breathing, secretion from eyes/mouth, reddened eyes/ 

ears, and restlessness. In 2 rats from the 2.5 ml/kg group, necropsy 

found stomachs dilated and filled with liquid. All other animals 

were without adverse inner organ findings (RIFM, 1970, 2003a). 


In rats (3/sex), an acute dermal LD 50 (reduced method from 

OECD 402) of greater than 4.0 g/kg was reported when neat 3- 

methyl-2-buten-1-ol was applied at doses 2.0 and 4.0 g/kg body 

weight/day. Clinical symptoms of slight apathy, irregular breathing, 

and slight local skin irritation were noted but reversible in 

the post observational period. Necropsy did not find abnormalities 

in examined animals (RIFM, 1979a). 

The acute dermal LD 50 of 3-methyl-2-buten-1-ol in rabbits was 

reported to be 3.9 (2.5–6.0) g/kg. There was no mortality in the 

dosage groups of four rabbits at 1.25 or 2.5 g/kg, but three of the 

four died at 5.0 g/kg. Symptomatology was dose-dependent. Moderate 

to severe erythema and mild, moderate, or severe edema and 

ataxia were observed at the two highest doses. No additional details 

were reported (RIFM, 1977a). 

4.1.3. Miscellaneous studies 

In an inhalation risk test (reduced method from OECD 403), six rats 

(3/sex) were exposed to saturated vapor with 3-methyl-2-buten-1-ol

S66 


Table 1 

Calculation of the total human skin exposure from the use of multiple cosmetic products containing 3-methyl-2-buten-1-ol. 



Bath products 17 0.29 0.001 0.02 0.02 0.0000 

Body lotion 8 0.71 1 0.004 0.02 0.0001 


Face cream 0.8 2 1 0.003 0.02 0.0000 


Hair spray 5 2 0.01 0.005 0.02 0.0000 

Shampoo 8 1 0.01 0.005 0.02 0.0000 

Shower gel 5 1.07 0.01 0.012 0.02 0.0000 

Toilet soap 0.8 6 0.01 0.015 0.02 0.0000 

Total 0.0005 

a 

b 


Based on a 60-kg adult. 

Table 2 


Route Species No. animals/dose 

group 

at 20 °C for 8 h and observed for 7 days. An LC 50 was extrapolated 

to >16.8 mg/L (4 h). Mortality was observed in 1/6 rats during 

the first 24 h. Clinical signs included attempts to escape, strong 

secretion from eye/nose, and tremor after exposure. Necropsy 

found the dead animal to have multifocal congestion of the lung; 

all others were without abnormalities (RIFM, 1970, 2003e). 

Groups of 10 Kisslegg mice were given i.p. injections of 3- 

methyl-2-buten-1-ol at concentrations of 2%, 4%, 8%, or 20% in 

aqueous emulsion with tragacanth at doses of 0.172, 0.344, 0.43, 

0.55, 0.688, or 1.376 g/kg (0.2, 0.4, 0.5, 0.64, 0.8, or 1.6 ml/kg). An 

LD 50 was estimated to be 0.413 g/kg based on 0, 0, 7, 8, 10, and 

10 deaths, respectively. Clinical signs observed included abdominal/lateral/dorsal 

position, dyspnoea, and staggering. At the necropsy, 

adhesions in the abdomen were noted while other organs 

appeared normal (RIFM, 2003b). 


LD 50 g/kg 

References 

Oral Rat 10 0.81 RIFM (1977a) 

Oral Rat 20 1.59 RIFM (1970, 2003a) 

Dermal Rat 6 >4.0 RIFM (1979a) 

Dermal Rabbit 4 3.9 RIFM (1977a) 


In a human maximization test pre-screen, 10% 3-methyl-2-buten-1-ol 

was applied to the backs of 26 healthy subjects for 48 h 

under occlusion. No subject had any irritation (RIFM, 1977b). 


Dose-dependent symptomatology in an acute dermal toxicity 

study of 3-methyl-2-buten-1-ol in rabbits revealed moderate to severe 

erythema as well as mild, moderate, or severe edema. There 

was no mortality in four rabbits at 1.25 or 2.5 g/kg, but 3 of 4 died 

at 5 g/kg. No additional details were reported (RIFM, 1977a). 

In rats (3/sex), an acute dermal LD 50 (reduced method from 

OECD 402) reported that when neat 3-methyl-2-buten-1-ol was 

applied, clinical symptoms of slight apathy, irregular breathing, 

and slight local skin irritation were noted but reversible in the post 

observational period. Necropsy did not find abnormalities in examined 

animals (RIFM, 1979b). 

A 1 h corrosivity test was performed on 4 albino rabbits with 

0.5 ml of neat 3-methyl-2-buten-1-ol on an occlusive patch. Animals 

were observed for 8 days. Erythema, edema, and necrosis 

were observed. 3-Methyl-2-buten-1-ol was corrosive to rabbit skin 

in 2 out of 4 animals after 1 h of occlusive exposure (RIFM, 1979b). 

A 4 h occlusive patch with 0.5 ml of neat 3-methyl-2-buten-1-ol 

was applied to the backs of 4 (2/sex) white Vienna rabbits. Animals 

were observed for 24, 48 h, and 8 days after the exposure, then 

scored according to Draize. Erythema, edema, and necrosis was observed, 

and a primary irritation index was calculated to be 6.13 

(TSCAT, 1992 as cited in OECD/SIDS, 2005). 

In a similar method to Draize, 8 white Vienna rabbits were exposed 

to neat 3-methyl-2-buten-1-ol for 20 h. Occlusive patches 

with 0.5 ml test material were applied to intact skin at two different 

sites for exposure periods of 1, 5, 15 min or 20 h. At 20 h moderate 

erythema, slight edema, and necrosis (up to 8 days) were 

observed (RIFM, 1970, 2003g). 

Neat 3-methyl-2-buten-1-ol was applied occlusively to the intact 

and abraded skin of 6 albino New Zealand rabbits for 24 h. 

Table 3 


Method Dose (%) Species Reactions References 

Acute dermal toxicity 100 Rabbit Moderate to severe erythema 

RIFM (1977a) 

Mild to severe edema 

Acute dermal toxicity 100 Rabbit Slight local skin irritation RIFM (1979b) 

1 h Occluded patch test 100 Rabbit Corrosive in 2/4 animals 

RIFM (1979b) 

Erythema and edema observed 

4 h Occluded patch test 100 Rabbit Erythema, edema, and necrosis observed TSCAT (1992) as cited in OECD/SIDS 

(2005) a 

1, 5, 15 min, and 20 h 

100 Rabbit Corrosive: 1 and 5 min: slight erythema (at 24 h), slight scaling RIFM (1970, 2003g) 

Occluded patch test 

(8 days) 

15 min: moderate erythema, slight edema (at 24 h), moderate 

scaling (8 days) 

20 h: moderate erythema, slight edema, necrosis (at 24 h), 

necrosis (8 days) 

24 h Occluded patch test 100 Rabbit Extremely irritating RIFM (1979b) 

a 

Not all of the original reports were made available to RIFM.


Scores were made according to Draize and observed for 25 days. 

Severe irritation was observed (RIFM, 1979b). 


3-Methyl-2-buten-1-ol was evaluated for eye irritation in 3 

white Vienna rabbits (2 males, 1 female). A 0.1 ml aliquot was instilled 

into one eye and the untreated eye of each animal served as 

a control. Observations were made for 8 days. Slight to moderate 

corneal opacity and moderate conjunctival redness/chemosis were 

observed. Irritation was not completely reversible after 8 days 

(RIFM, 1979c). 

3-Methyl-2-buten-1-ol was evaluated for eye irritation in 2 

white Vienna rabbits. A 0.5 ml aliquot was instilled into one eye 

and the control eye of each animal was treated with sodium chloride. 

Observations were made for 8 days. Slight corneal opacity and 

moderate conjunctival redness/edema were observed. After 8 days 

only slight conjunctival redness remained (RIFM, 1970, 2003f). 




was no evidence of contact sensitization to 10% 3-methyl-2-buten-1-ol 

(6900 lg/cm 2 ). 3-Methyl-2-buten-1-ol was applied in petrolatum 

under occlusion to the forearms for a total of five 

alternate-day 48 h periods. The initial application was preceded 

by a 24 h occlusive treatment of the patch sites with 5% aqueous 

sodium lauryl sulfate. Following a 10-day rest period, challenge 

patches were applied under occlusion to fresh sites for 48 h. Challenge 

applications were preceded by 30 min applications of 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, 1977b). 







4.7. Repeated dose toxicity (see Table 5) 

4.7.1. Two to 30-day studies 

3-Methyl-2-buten-1-ol was administered to Wistar rats (3/sex/ 

dose) in the drinking water for two weeks at concentrations of 0, 

2.5, 5.0, or 7.5 ppm (approximately equal to 0.25, 0.5, or 0.75 mg/ 

kg body weight) and 250, 500, or 750 mg/kg body weight. Slight 

salivation was observed at 500 mg/kg and slight to moderate salivation 

was observed at 750 mg/kg for males and females. Males 

and females at 250 mg/kg showed a significant decrease in food 

and water consumption, by day 14 their body weight change were 

decreased from controls (RIFM, 2003c). 

3-Methyl-2-buten-1-ol was administered to Wistar rats (3/sex/ 

dose) in the drinking water at concentrations of 0, 5000, or 

15,000 ppm (approximately equal to 500 and 1500 mg/kg body 

weight). All general observations of the rats appeared normal. Food 

and water consumption was decreased in all dose groups, but drastically 

reduced in the 15,000 ppm dose group so that by day 5 

treatment was stopped (RIFM, 2003d). 

4.7.2. Subchronic studies 


4.7.3. Chronic (90+ days) studies 

In a 90-day study according to OECD test guideline 408, 3- 

methyl-2-buten-1-ol was administered to Wistar rats (10/sex/ 

dose) in the drinking water in concentrations of 0, 200, 1000 or 

5000 ppm (14.4 and 21.0 mg/kg body weight/day, 65.4 and 

82.1 mg/kg body weight/day or 243.8 and 307.2 mg/kg body 

weight/day for males and females). In the mid dose groups, decreased 

food and water consumption in males and reduced water 

consumption in females was noted. In males, the mean absolute liver 

weights (but not the relative liver weights) were significantly 

decreased (high dose: 14.9%, mid dose: 7.9%) when compared 

to controls. In males and females at the high dose, the urine volume 

was decreased with increased specific gravity (related to reduced 

water consumption). In males and females of the 

5000 ppm group (243.8 and 307.2 mg/kg body weight/day), body 

Table 4 


Dose (%) Reactions References 

100% Slight to moderate corneal opacity and moderate conjunctival redness/chemosis were observed RIFM (1979c) 

100% Slight corneal opacity and moderate conjunctival redness/edema were observed RIFM (1970, 2003f) 

Table 5 

Summary of repeated dose studies. 

Method 

Oral, 2 weeks 

(drinking water) 

Oral, 2 weeks 


Oral, 2 weeks 


Oral, 90 days 


Dose a (mg/kg 

body weight) 

0.25, 0.5, 0.75 Rat 3/sex/ 

dose 

250, 500, 750 Rat 3/sex/ 

dose 

500, 1500 Rat 3/sex/ 

dose 

14.4, 65.4, 243.8 Rat 

(m) 

3/sex/dose 

21, 82.1, 307.2 (f) 


No effects 

Slight to moderate salivation at 500 and 750 mg/kg 

Decreased food and water consumption at 250 mg/kg 

Significant decreases in food and water consumption 

NOAEL was assessed to be 65.4 and 82.1 mg/kg body weight/day 

Significant decrease of body weight as a consequence of reduced food and water 

consumption at 243.8 and 307.2 mg/kg body weight/day 

RIFM 

(2003c) 

RIFM 

(2003c) 

RIFM 

(2003d) 

RIFM 

(2002a) 

a 

Values have been converted for comparison, original units can be found in text.

S68 


weight and body weight gain were significantly reduced. The reduced 

absolute liver weight in high dose males can be explained 

by the reduced body weight, as the relative liver weight was not 

reduced. The NOAEL was assessed to be 1000 ppm (65.4 and 

82.1 mg/kg body weight/day) based on significant decrease of body 

weight as a consequence of reduced food and water consumption 

at 5000 ppm (243.8 and 307.2 mg/kg body weight/day) and the 

NOEL was 200 ppm (14.4 and 21.0 mg/kg body weight/day) (RIFM, 

2002a). 


An oral (gavage) developmental toxicity test was performed 

according to OECD guideline 414 in 25 pregnant female Wistar 

rats. On gestations days (GD) 6–19 the dams received doses of 0, 

50, 200, or 600 as aqueous suspension. One high dose dam was 

found dead on GD 19. Clinical symptoms in the high dose dams 

showed transient salivation, however, salivation was only observed 

for 1–2 h after gavage treatments. Furthermore, 20/25 were 

in an abdominal position, 24/25 had lacrimation, and 17/25 rats 

had piloerection shortly after treatment. The mean food consumption 

of the high dose dams was statistically reduced about 9% below 

control value on GDs 6–8. Similar or exceeding the control 

food consumption values followed until termination. Food consumption 

values of the mid and low dose rats were not affected. 

There were no substance related findings in any of the dams at necropsy. 

There were no substance related or biologically relevant differences 

between the test groups in conception rate, mean number 

of corpora lutea, implantation sites, number of resportion/viable 

fetuses, or the values calculated for the pre and post implantation 

losses. Authors felt that all differences observed reflected the normal 

range of fluctuation for Wistar rats at an age of 70–84 days. A 

NOAEL for maternal toxicity was set at 200 mg/kg body weight/day 

and a developmental NOAEL of 600 mg/kg body weight/day due to 

no signs of prenatal developmental toxicity or indications of teratogenicity 

(RIFM, 2002b). 

3-Methyl-2-buten-1-ol was tested for maternal toxicity by oral 

(gavage) administration as an aqueous suspension to female (10/ 

group) Wistar rats. The dams received doses of 100, 300, or 

1000 mg/kg body weight from days 6–19. On day 20, all animals 

were sacrificed, and the fetuses were removed without further 

examination. At the high dose, three dams died prematurely and 7 

were sacrificed early due to severe clinical findings. Clinical observations 

included: unsteady gait, abdominal position, salivation, ataxia, 

tremor, urine smeared fur, piloerection, fluid filled stomach, and 

ulceration. Also statistically significant reductions in food consumption 

(35% below control) and body weight loss were observed. At 

the mid dose only transient salivation was observed. No further 

substance-induced effects were observed (RIFM, 2003h). 



The Ames assay (OECD guideline 471, standard plate test, preincubation 

test, and liquid suspension assay) with and without 

S9 activation was not mutagenic with 3-methyl-2-buten-1-ol on 

Salmonella typhimurium strains TA98, TA100, TA1535, and 

TA1537 at doses of 20–5000 lg/plate (RIFM, 1989, 1991). 


In a mouse micronucleus assay (OECD guideline 474), 3- 

methyl-2-buten-1-ol was not genotoxic when NMRI males (5/ 

group) were dosed at 0, 125, 250, or 500 mg/kg body weight in olive 

oil via two i.p. injections at 24 h intervals. A slight inhibition of 

erythropoiesis, determined from the polychromatic to normochromatic 

erythrocytes (PCE/NCE) ratio, was detected at 250 and 

500 mg/kg body weight groups. Under the experimental conditions, 

3-methyl-2-buten-1-ol did not lead to any statistically significant 

increase in the number of PCEs containing either small 

or large micronuclei. The rate of micronuclei was nearly the range 

of the concurrent negative control in all dose groups and within the 

range of historical control data (RIFM, 2001). 



This individual Fragrance material review is not intended as a 




material. 







References 

Arctander, S., 1969. Perfume and Flavor Chemicals (Aroma Chemicals), vol. I. 

Montclair, New Jersey, p. 985. 





FEMA (Flavor and Extract Manufacturers’ Association), 1979. Recent progress in the 

consideration of flavoring ingredients under the Food Additives Amendment 12. 

GRAS substances. Food Technology 33 (7), 65–73. 



2007. 

JECFA (Joint Expert Committee on Food Additives), 2003. Safety Evaluation of 

Certain Food Additives. Who Food Additives Series: 52. Prepared by the Sixtyfirst 

Meeting of the Joint FAO/WHO Expert Committee on Food Additives 

(JECFA). World Health Organization, Geneva. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1970. Analytical Toxicology 

of 3-Methyl-2-buten-1-ol. Unpublished Report From BASF. Report Number 

55393, 20 June. RIFM, Woodcliff Lake, NJ, USA. 


in Rats, Rabbits and Guinea pigs. RIFM Report Number 1695, July 22. RIFM, 


RIFM (Research Institute for Fragrance Materials, Inc.), 1977b. Report on Human 

Maximization Studies. RIFM Report Number 1691, May 16. RIFM, Woodcliff 


RIFM (Research Institute for Fragrance Materials, Inc.), 1979a. Report on the Test of 

the Acute Dermal Toxicity of 3-Methyl-2-buten-1-ol in the Rat. Unpublished 

Report From BASF. Report Number 55385, 23 April. RIFM, Woodcliff Lake, NJ, 

USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1979b. Report on The 

Corrosive Effect of 3-Methyl-2-buten-1-ol in Rabbits. Unpublished Report From 

BASF. Report Number 55395, 23 April. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1979c. Report on the Primary 

Eye Irritant Effect of 3-Methyl-2-buten-1-ol in Rabbits. Unpublished Report 

From BASF. Report Number 55399, 23 April. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1989. Report on the Study of 

3-Methylbuten-2-o1-1 in the Ames Test with Salmonella typhimurium. 

Unpublished Report From BASF. Report Number 55387, 24 February. RIFM, 



3-Methylbuten-2-ol-1 in the Liquid Suspension Assay Modified Salmonella/ 

mammalian-microsome mutagenicity test. Unpublished Report From BASF. 

Report Number 55388, 19 September. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 2001. Cytogenetic Study In 

Vivo With 3-Methyl-2-buten-1-ol in the Mouse Micronucleus Test After Two 

Intraperitoneal Administrations. Unpublished Report From BASF. Report 

Number 55397, 14 May. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 2002a. 3-Methyl-2-buten-1- 

ol (Prenol): Subchronic Toxicity Study in Wistar Rats Administered in Drinking 

Water for 3 Months. Unpublished Report From BASF. Report Number 55401, 11 

April. RIFM, Woodcliff Lake, NJ, USA.


RIFM (Research Institute for Fragrance Materials, Inc.), 2002b. 3-Methyl-2-Buten-1- 

ol (Prenol) – Prenatal Developmental Toxicity Study in Wistar Rats by Oral 

Administration (gavage). Unpublished Report From BASF. Report Number 

55398, 27 March. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 2003a. Translation: Details 

on An Acute Oral Toxicity Study in the Rat with 3-Methyl-2-buten-1-ol. 

Unpublished Report From BASF. Report Number 55408, 8 January. RIFM, 


RIFM (Research Institute for Fragrance Materials, Inc.), 2003b. Translation: Details 

on An Acute Intraperitoneal Toxicity Study in the Mouse with 3-Methyl-2- 

buten-1-ol. Unpublished Report From BASF. Report Number 55406, 8 January. 


RIFM (Research Institute for Fragrance Materials, Inc.), 2003c. 3-Methyl-2-buten-1- 

ol (Prenol): Test Study in Wistar Rats Administered in the Drinking Water and 

by Gavage for 2 Weeks. Unpublished Report From BASF. Report Number 55403, 

24 January. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 2003d. 3-Methyl-2-buten-1- 

ol (Prenol): Palatability Study in Wistar Rats Administered in Drinking Water 

for 2 Weeks. Unpublished Report From BASF. Report number 55404, 24 January. 


RIFM (Research Institute for Fragrance Materials, Inc.), 2003e. Translation: Details on 

An Inhalation Risk Test in the Rat with 3-Methyl-2-buten-1-ol. UnpublishedReport 

From BASF. Report Number 55407, 8 January. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 2003f. Translation: Details 

on an Eye Irritation/Corrosion Study in Rabbits with 3-methyl-2-buten-1-ol. 

Unpublished Report From BASF. Report Number 55409, 8 January. RIFM, 


RIFM (Research Institute for Fragrance Materials, Inc.), 2003g. Details on a Skin 

Irritation/Corrosion Study in Rabbits with 3-Methyl-2-buten-1-ol. Unpublished 

Report From BASF. Report Number 55405, 8 January. RIFM, Woodcliff Lake, NJ, 

USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 2003h. 3-Methyl-2-buten-1- 

ol (Prenol): Maternal Toxicity Study in Wistar Rats By Oral Administration 

(gavage). Unpublished Report From BASF. Report Number 55402, 23 January. 


OECD and Screening Information Datasets (SIDS), 2005. High Production Volume 

Chemicals 3-Methylbut-2-en-1-ol (Cas No: 556-82-1). Processed by United 

Nations Environmental Program, (UNEP) Chemicals: Available From: (not all of the 

original reports were made available to RIFM).





Review 

Fragrance material review on dihydromyrcenol 



article 

Keywords: 

Review 


info 

abstract 

A toxicologic and dermatologic review of dihydromyrcenol when used as a fragrance ingredient is 

presented. 


Contents 




3. Usage. . . . . . ......................................................................................................... S71 



41.1. Oral studies . . . . . . . . . . . . ................................................................................. S71 



4.2.1. Human studies (see Table 3).. . . . . . . . . . . . . . ................................................................. S72 




4.4.1. Human studies (see Table 6) . . . . . . . . . . . . . . ................................................................. S73 




4.5.2. Photoallergy . . . . . . . . . . . ................................................................................. S73 






Conflict of interest statement. . . . . . . . . . . . . . . . . .......................................................................... S74 

References . ......................................................................................................... S74 

Introduction 


review of dihydromyrcenol when used as a fragrance ingredient 

including all human health endpoints. Dihydromyrcenol (see 

Fig. 1; CAS number 18479-58-8) is a fragrance ingredient used in 





and detergents. Its worldwide use is greater than >1000 metric tons 

per year (IFRA, 2004). A colorless, somewhat viscous liquid that is a 

mixture of approximately 50% 2,6-dimethyl-7-octen-2-ol and 50% 

2,6-dimethyl-7-octen-2-yl formate. It has a lime like citrusy-floral 

while sweet odor of considerable tenacity (Arctander, 1969). 

Dihydromyrcenol has apparently not been reported to occur in 

nature. 


doi:10.1016/j.fct.2009.11.014


2,6-Dimethyl-7-octen-2-ol 

2,6-Dimethyl-7-octen-2-yl formate 

OH 

O 

O 

Fig. 1. Dihydromyrcenol. 

In 2007, a complete literature search was conducted on 

dihydromyrcenol. On-line databases that were surveyed included 



data. 









Dihydromyrcenol is a member of the fragrance structural 



a C 4 to C 16 carbon chain with one or several methyl or 

ethyl side chains and up to 4 non-conjugated double bonds. This 


document. Please refer to A Safety Assessment of Alcohols 

with Unsaturated Branched Chain When Used as Fragrance Ingredients 

(Belsito et al., 2010) for an overall assessment of this 

material. 


1.1 Synonyms: dimyrcetol, dihydro myrcenol, 3,7-dimethyl-1- 

octen-7-ol, 7-octen-2-ol, 2,6-dimethyl; 

1.2 CAS Registry number: 18479-58-8; 

1.3 EINECS number: 242-362-4; 

1.4 Formula: C 10 H 20 O; 



2.1 Physical form: is a colorless liquid with a strong fresh-lime 

cologne odor that is a mixture of 44.2% 2,6-dimethyl-7- 

octen-2-ol and 54.8% 2,6-dimethyl-7-octen-2-yl formate. 

2.2 Boiling point: 80 °C @ 3 mm Hg; 

2.3 Flash point: 148 °F; CC; 

2.4 Henry’s law: 0.0000407 atm m 3 /mol 25 °C; 

2.5 Log K ow : 3.0 at 30 °C; 

2.6 Specific gravity: 0.83; 

2.7 Vapor pressure (calculated): 0.09 mm Hg 20 °C; 

2.8 Water solubility (calculated): 252.2 mg/l @ 25 °C; 

2.9 UV spectra available at RIFM, peaks at 200–210 nm and 

returns to base line at 350 nm. 

3. Usage 

Dihydromyrcenol is a fragrance ingredient used in many fragrance 




cleaners and detergents. Its use worldwide is >1000 metric tons 

per annum (IFRA, 2004). 










41.1. Oral studies 

The acute oral LD 50 of dihydromyrcenol in rats was reported to 

be 4.1 (3.5–4.8) g/kg. Mortality was 1, 3, 4, and 8 out of groups of 

10 at 2.56, 3.2, 4.0, and 5.0 g/kg, respectively. Toxic signs included 

lethargy, piloerection, blood on nose, flaccidity, ataxia, and diarrhea 

(RIFM, 1977a). 

Table 1 

Calculation of the total human skin exposure from the use of multiple cosmetic products containing dihydromyrcenol. 

Product type Grams applied Applications per day Retention factor Mixture/product Ingredient/mixture a Ingredient mg/kg/day b 


Bath products 17 0.29 0.001 0.02 12.91 0.0002 

Body lotion 8 0.71 1 0.004 12.91 0.0489 

Eau de Toilette 0.75 1 1 0.08 12.91 0.1291 

Face cream 0.8 2 1 0.003 12.91 0.0103 


Hair spray 5 2 0.01 0.005 12.91 0.0011 

Shampoo 8 1 0.01 0.005 12.91 0.0009 

Shower gel 5 1.07 0.01 0.012 12.91 0.0014 

Toilet soap 0.8 6 0.01 0.015 12.91 0.0015 

Total 0.3289 

a 

b 

Upper 97.5‰ levels of the fragrance ingredient in the fragrance mixture used in these products. 


S72 


Table 2 


Table 4 


Route Species No. animals/dose group LD 50 (g/kg) References 

Oral Rats 10 4.1 RIFM (1977a) 

Dermal Rabbits 10 >5.0 RIFM (1977a) 


The acute dermal LD 50 of dihydromyrcenol in rabbits was reported 

to be greater than 5.0 g/kg. Mortality was two out of 10 rabbits 

on days 2 and 6 from a single dose of 5.0 g/kg. Symptoms were 

moderate to severe erythema and mild to severe edema (RIFM, 

1977a). 

Method 

Dermal 

application 

Dermal 

application 

Dermal 

application 

Dermal 

application 

Concentration 

(%) 

Species Reactions References 

100 Rabbit Moderate to severe 

erythema, and 

moderate edema 

100 Rabbit Slight erythema 

and edema at 160 h 

50 Rabbit Slight reactions 

remained by day 7 

100 Rabbit Edematous 

reactions 

decreased by 48 h, 

slight reaction 

remained by day 7 

RIFM (1977) 

RIFM (1984b) 

RIFM (1986) 

RIFM (1985) 


4.2.1. Human studies (see Table 3). 

In a human maximization test pre-screen, 4% dihydromyrcenol 

(2760 lg/cm 2 ) in petrolatum was applied under occlusion to the 

backs of 25 healthy subjects for 48 h. No subject had any irritation 

(RIFM, 1977c). 

During a Human Repeated Insult Patch Test (HRIPT) moderate 

irritation was observed in 1 of 41 subjects treated with 0.5 ml of 

7.5% (14,764 lg/cm 2 ) dihydromyrcenol in alcohol SDA 39C. Applications 

were under occlusion with a 1 00 1 00 Webril patch for 24 h 

3 days per week for nine applications (RIFM, 1972). 

During an HRIPT no irritation was observed when 

dihydromyrcenol at 5% or 10% (2500 or 5000 lg/cm 2 ) was tested 

in two test panels of 104 and 107 volunteers, respectively. Approximately 

0.2 ml was applied onto occlusive Parke-Davis Readi-bandage, 

and then placed on the back of each subject every Monday, 

Wednesday, and Friday up to nine applications (RIFM, 2001, 2002). 


In an acute dermal toxicity study in 10 rabbits with 

dihydromyrcenol, erythema was moderate in seven animals and 

severe in three. Edema was mild in one, moderate in eight, and severe 

in one animal (RIFM, 1977). 

In a rabbit dermal irritation study conducted according to US 

FDA, Japanese Ministry of Health, and UK New Substance Regulation 

guidelines, erythema, edema, and desquamation were elicited 

by an undiluted single 4 h semi-occlusive application of 0.5 ml of 

dihydromyrcenol to the skin of three white New Zealand rabbits. 

At 1 h, two animals exhibited very slight erythema, and one exhibited 

very slight edema. The irritation response in these animals had 

between the 24 and 48 h observations. By 72 h, well defined erythema 

remained in both animals, one also exhibiting very slight 

edema, and the third animal exhibited very slight erythema and 

slight desquamation. At the final 160 h examination, two animals 

exhibited very slight erythema and marked desquamation, and 

Table 3 

Summary of human irritation studies. 



(%) 

Maximization 

(pre-test) 

4% (2760 ug/cm 2 ) 0/25 0 RIFM 

(1977c) 

HRIPT 

(induction) 

7.5% (14,764 ug/cm 2 ) 1/41 2.5 RIFM 

(1972) 

HRIPT 

(induction) 

5% (2500 ug/cm 2 ) 0/104 0 RIFM 

(2001) 

HRIPT 

(induction) 

10% (5000 ug/cm 2 ) 0/107 0 RIFM 

(2002) 

one very slight edema, while the third animal exhibited some desquamation 

(RIFM, 1984b). 

In a rabbit dermal irritation study conducted according to EEC 

Directive 79/831, erythema, edema, and desquamation were elicited 

by a single 4 h semi-occlusive application of 0.5 ml of 50% 

dihydromyrcenol in DEP to the skin of four white New Zealand rabbits. 

At 1 h, well defined erythema and very slight edema were 

apparent in three animals as well as very slight erythema in the 

fourth. There was an increase in severity of the response at the 

24 and 48 h examinations and slight desquamation was apparent 

in one animal. There was a decline in severity in one animal at 

72 h and no reaction remained in any animal at the final seventh 

day examination (RIFM, 1986). 

In a rabbit dermal irritation study conducted according to US 

FDA, Japanese Ministry of Health, UK New Substance Regulation, 

OECD, and Swiss IKS guidelines, erythema, edema, and desquamation 

were elicited by a single 4 h semi-occlusive application of 

0.5 ml of dihydromyrcenol to the skin of four white New Zealand 

rabbits. After dosing, at 1 h well defined erythema and moderate 

edema were noted in one animal, well defined erythema and slight 

edema in two, and very slight reactions in the remaining animal. 

Severity increased at 24 h. Edematous reactions decreased by 

48 h and had largely declined after 7 days, a very slight response 

remaining in one animal. Well defined erythema remained in three 

animals; desquamation was also noted in one animal. Average irritation 

scores at 24, 48, and 72 h were 2.0 for erythema and 1.6 for 

edema (RIFM, 1985). 


In a rabbit (n = 3) eye irritation study conducted according to 

the method of Draize, 0.1 ml of 7.5% dihydromyrcenol in alcohol 

SDA 39C produced conjunctival irritation with corneal involvement 

which did not clear on the seventh day of observation (RIFM, 

1977b). 

In a rabbit (n = 6) eye irritation study conducted according US 

FDA guidelines, 0.1 ml of dihydromyrcenol produced positive ocular 

responses at 1, 24, 48, and 72 h which cleared by the seventh 

day of observation. Corneal involvement was observed at 24, 48, 

and 72 h (RIFM, 1984a). 

Table 5 


Concentration (%) Reactions References 

7.5 Corneal, and conjunctival irritation RIFM (1977b) 

100 Irritation cleared after 7 days RIFM (1984a)



4.4.1. Human studies (see Table 6) 

4.4.1.1. Induction studies. In an HRIPT there was no evidence of 

sensitization in 41 (33 females, 8 males) subjects treated with 

0.5 ml of 7.5% dihydromyrcenol (14,764 lg/cm 2 ) in alcohol SDA 

39C applied under occlusion with 1 00 1 00 Webril patch for 24 h 

3 days per week for nine applications followed by challenge application 

10–21 days later (RIFM, 1972). 

During an HRIPT, no sensitization was observed when 

dihydromyrcenol at 5% or 10% (2500 or 5000 lg/cm 2 ) was tested 

in two test panels of 104 and 107 volunteers, respectively. Approximately 

0.2 ml was applied onto occlusive Parke-Davis Readi-bandage, 

and then placed on the back of each subject every Monday, 

Wednesday, and Friday up to 9 applications. A challenge application 

was applied to a virgin site approximately 2 weeks after 

induction. The site was scored 24 and 72 h after the challenge 

application (RIFM 2001, 2002). 

In a human Maximization study involving 25 subjects, there 

was no evidence of contact sensitization to 4% dihydromyrcenol 

(2760 lg/cm 2 ) in petrolatum. Dihydromyrcenol was applied under 

occlusion to the forearms or backs 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 2.5% aqueous 

sodium lauryl sulfate. Following a 10 day rest period, challenge 

patches were applied under occlusion to fresh sites for 48 h. 

Challenge applications were preceded by 1 h applications of 5– 

10% sodium lauryl sulfate under occlusion. Challenge sites were 

evaluated at removal of the patches and 24 h later (RIFM, 

1977c). 


4.4.2.1. Local Lymph Node Assay (LLNA). A Local Lymph Node Assay 

(LLNA) in mice was conducted according to UK GLP guidelines and 

OECD principles of good labor practice, using 0.5%, 1.0%, 2.5%, 10%, 

or 25% dihydromyrcenol in (1:3) EtOH:DEP. Four female CBA/Ca 

mice were used per treatment group. Dihydromyrcenol (25 ll) 

was applied to the dorsum of each ear lobe on three consecutive 

days. Three days after the third application, the mice were injected 

intravenously into the tail vein with tritiated thymidine. Approximately 

5 h after injection, the mice were sacrificed and the draining 

auricular lymph nodes were excised and pooled per group. 

Single cell suspensions were prepared. The proliferative capacity 

of pooled lymph node cells was determined by measurement of 

incorporation of tritiated thymidine in a beta-scinillation counter. 

The SI values were 0.9, 0.8, 0.8, 0.9, and 1.4 at 0.5, 1.0, 2.5%, 10%, 

and 25%, respectively. Dihydromyrcenol was determined unlikely 

to be a skin sensitizer under the conditions of this test, an EC3 value 

could not be determined but is estimated to be greater than 

(6250 ug/cm 2 ) 25% (RIFM, 2007a). 

Table 6 

Summary of human skin sensitization studies. 



(%) 

HRIPT 7.5% (14,764 ug/ 

cm 2 ) 

0/41 0 RIFM 

(1972) 

HRIPT 5% (2500 ug/cm 2 ) 0/104 0 RIFM 

(2001) 

HRIPT 10% (5000 ug/cm 2 ) 0/107 0 RIFM 

(2002) 

Maximization 4% (2760 ug/cm 2 ) 0/25 0 RIFM 

(1977c) 



4.5.1.1. Human studies. There was no evidence of a phototoxic reaction 

when 12% dihydromyrcenol was applied semi-occlusively to 

the backs of 10 human subjects for 24 h, followed by irradiation 

for 12 min with 31.5 mW/cm 2 of light at 320–400 nm (RIFM, 

1981). 

In an in vitro screening procedure for phototoxicity, following 

UV irradiation of agar plates innocualted with commercially available 

Bakers’ Yeast, a zone of growth inhibition was observed 

around filter paper disks impregnated with dihydromyrcenol at 

10%, but not at 1.0% or 0.1% (RIFM, 1980). 

4.5.1.2. Animal studies. No available information. 




An in vitro human skin absorption study was conducted on the 

fragrance material dihydromyrcenol under both in-use (unoccluded) 

and occluded conditions. The absorption of each 

dihydromyrcenol component (A and B) was measured via GC–MS 

and used to calculate the total dihydromyrcenol absorption. Skin 

permeation and distribution was determined using epidermal 

membranes from cosmetic surgery donors. Skin membranes were 

mounted into Franz-type diffusion cells with the stratum corneum 

facing the donor chamber. The average area available for diffusion 

was 1.2 cm 2 . Dihydromyrcenol was applied, at the maximum inuse 

concentration of 6%, in 70/30 (v/v) ethanol/water to the skin 

surface at a dose of 5 ll/cm 2 . The donor chamber of the occluded 

cells was covered with a greased, glass coverslip immediately after 

dosing. Permeation was measured over 24 h at 12 time points, 

using EPBS as receptor. At 24 h, 3.85 + 0.29 lg/cm 2 (unoccluded) 

and 15.0 + 1.6 lg/cm 2 (occluded) (mean ± standard error, SE) of 

dihydromyrcenol had permeated, corresponding to 1.30 + 0.10% 

(unoccluded) and 5.06 + 0.53% (occluded) of the applied dose of 

296.2 lg/cm 2 . Levels of dihydromyrcenol in the epidermis (plus 

any remaining stratum corneum after tape stripping), filter paper 

membrane support and receptor fluid were combined (as per 

SCCFP guidelines) to result in a total absorbed dose value of 

1.45 + 0.10% (unoccluded) and 5.67 + 0.58% (occluded). Differential 

absorption of the two components was observed, with greater levels 

of dihydromyrcenol A being absorbed under both unoccluded 

and occluded conditions. Overall recovery of dihydromyrcenol at 

24 h was 2.36 + 0.24% (unoccluded) and 22.5 + 2.1% (occluded). 

Low recoveries were attributed due to rapid evaporative loss of 

dihydromyrcenol. Under occluded conditions dihydromyrcenol 

may have undergone evaporation from the skin surface and 

subsequent loss through donor chamber sealing grease (RIFM, 

2007d,e). 


In compliance with UK GLP, OECD 408 principals on good laboratory 

practice, and the requirements of directives 2004/9/EC 

and 2004/10/EC a 90 day oral gavage study was conducted. 

Dihydromyrcenol was administered to four groups of ten male 

and ten female Sprague–Dawley Crl:CD (SD) IGS BR strain rats 

at dose levels of 0 (corn oil), 10, 50, 500, and 1000 mg/kg/day. 

Clinical signs, functional observations, bodyweight development, 

and food/water consumption were monitored. Haematology, 

blood chemistry, and urinalysis were also evaluated. Oestrous cy-

S74 


cle assessments and sperm analyses were performed. Statistically 

significant reduction in body weight gains were evident in either 

sex treated with 500, and 1000 mg/kg/day. A reduction in food 

efficiency and an increase in water consumption were also observed 

for 500, and 1000 mg/kg/day. Week 13 haematology revealed 

reductions in haemoglobin, haematocrit, and erythrocyte 

counts for females treated with 1000 mg/kg/day. Increases in cholesterol 

were evident during week 13 in either sex treated with 

500, and 1000 mg/kg/day. Females treated with 1000 mg/kg/day 

continued to show reductions in albumin/globulin ratios. Animals 

of either sex treated with 500, and 1000 mg/kg/day showed a significant 

increase in liver and kidney weight both absolute and relative 

to terminal bodyweight. The effect on liver weight extended 

to males treated with 50 mg/kg/day. The oral administration of 

dihydromyrcenol to rats for 90 consecutive days resulted in treatment 

related effects in males and females at 500, and 1000 mg/ 

kg/day. A No Observed Effect Level of 50 mg/kg/day has been 

established for females, and a NOAEL of 10 mg/kg/day for males 

(RIFM, 2007c). 


One hundred pregnant Crl:CD(SD) rats (25/group) were orally 

administered via gavage 10 ml/kg of dihydromyrcenol at 0 (corn 

oil), 250, 500, and 1000 mg/kg/day. All rats were examined for clinical 

observations, abortions, premature deliveries, deaths, and 

bodyweights. Rats were sacrificed on gestation day (GD) 21, cesarean-sectioned 

and necropsied. Fetuses were removed from the 

uterus, weighed, and examined macroscopically for sex and gross 

external alterations. Live fetuses were euthanized by intraperitoneal 

injection of sodium pentobarbital. Approximately one half of 

each litter was examined for soft tissue alterations, using a variation 

of the Wilson’s staining technique. The remaining fetuses were 

eviscerated, cleared, stained and examined for skeletal alterations. 

All rats survived until scheduled sacrifice, and there were no clinical 

observations, or gross lesions attributed to dihydromyrcenol. 

Overall maternal bodyweight gain was 5% less than the vehicle/ 

control group at 1000 mg/kg/day, although none of the maternal 

bodyweight gains were statistically significant. Both maternal 

absolute (g/day) and relative (g/kg/day) feed consumption values 

were significantly reduced in the 1000 mg/kg/day group for the entire 

dosage period, compared to vehicle control. Reduced feed consumption 

was most prominent on gestational days 7–10, which 

correlated with the weight losses and reduced weight gains that 

occurred during the initial days of the dosage period. Dosages of 

dihydromyrcenol as high as 500 mg/kg/day had no adverse effects 

on maternal feed consumption or body weight gains. Pregnancy 

occurred in 22–25 rats per dosage group, and 295–358 live fetuses 

per dosage group. Body weights for combined male and female fetuses 

were reduced approximately 3% in the 1000 mg/kg/day dosage 

group, compared to concurrent vehicle controls. The reduction 

was statistically significant (p 6 0.05) for females. Although the 

values were within historical control values for the testing facility, 

the reduction correlated with the reduced maternal body weight 

gains and feed consumption that occurred at 1000 mg/kg/day early 

in the dosage period and for the entire dosage and entire gestation 

periods. Minimal reductions in fetal weights and small increases in 

reversible variations in skeletal ossification were observed at 

1000 mg/kg/day. Skeletal variations were limited reversible minor 

changes, such as: a threshold but statistically significant increase 

in supernumerary ribs, along with associated significant increases 

and decreases in the respective numbers of thoracic and lumbar; 

also a small but statistically significant retardation in ossification 

of the metatarsal bones in the hindpaws, evident as a reduction 

in the mean number of ossified metatarsal bones. No other 

caesarean-sectioning or litter parameters were affected by dosages 

of dihydromyrcenol as high as 1000 mg/kg/day. Based on this 

data the maternal and developmental No Observable Adverse 

Effect Level (NOAEL) of dihydromyrcenol is 500 mg/kg/day (RIFM, 

2007b). 









material. 







References 

Arctander, S., 1969. Perfume and Flavor Chemicals (Aroma Chemicals), vol. I (964). 

S. Arctander, Montclair, New Jersey. 







2007. 

Opdyke, D., 1980. Fragrance raw materials monographs. Dimyrcetol. Food and 

Chemical Toxicology 18 (6), 679. 


test with dimyrcetol. Unpublished Report from International Flavors and 

Fragrances, 72 July. Report Number 50437. RIFM, Woodcliff Lake, NJ, USA. 


in Rats, Rabbits and Guinea Pigs. RIFM Report Number 1695, July 22. RIFM, 


RIFM (Research Institute for Fragrance Materials, Inc.), 1977b. Rabbit eye 

irritation study with dimyrcetol. Unpublished Report from International 

Flavors and Fragrances, 77 February. Report Number 50434. RIFM, Woodcliff 


RIFM (Research Institute for Fragrance Materials, Inc.), 1977c. Report on Human 

Maximization Studies. RIFM Report Number 1702, May 04. RIFM, Woodcliff 


RIFM (Research Institute for Fragrance Materials, Inc.), 1980. Phototoxicity study of 

dimyrcetol. Unpublished Report from International Flavors and Fragrance. 

Report Number 50436. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1981. Phototoxicity testing 

of fragrance materials. Unpublished Report from IFF Incorporated, 09 March. 

Report Number 47075. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1984a. Acute eye irritation 

test of dimyrcetol in rabbits. Unpublished Report from International Flavors 

and Fragrances, 84 December. Report Number 50435. RIFM, Woodcliff Lake, 

NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1984b. Primary Irritation 

Test in Rabbits. RIFM Report Number 1795, June 01. RIFM, Woodcliff Lake, NJ, 

USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1985. Acute Dermal 

Irritation Study in Rabbits. RIFM Report Number 3099, June 01. RIFM, 


RIFM (Research Institute for Fragrance Materials, Inc.), 1986. Acute Dermal 

Irritation Study in Rabbits. RIFM Report Number 5664, June 01. RIFM, 



test with dihydromyrcenol. Unpublished report from International Flavors and 

Fragrances, 09 November. Report number 54405. RIFM, Woodcliff Lake, NJ, 

USA.


RIFM (Research Institute for Fragrance Materials, Inc.), 2002. Repeated insult 

patch test with dihydromyrcenol. Unpublished report from International 

Flavors and Fragrances, 24 January. Report number 54404. RIFM, Woodcliff 


RIFM (Research Institute for Fragrance Materials, Inc.), 2007a. Dimyrcetol: Local 

Lymph Node Assay. RIFM Report Number 52911, May 21. RIFM, Woodcliff Lake, 

NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 2007b. Oral (gavage) 

developmental toxicity study of dimyrcetol in rats. Oral (Gavage) Dose-range 

Developmental Toxicity Study of Dimyrcetol in Rats. RIFM Report Number 


RIFM (Research Institute for Fragrance Materials, Inc.), 2007c. Dimyrcetol: Ninety 

Day Repeated Dose Oral (Gavage) Toxicity Study in the Rat. RIFM Report 

Number 52794, April 27. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 2007d. In vitro human 

skin penetration of fragrance material dimyrcetol under occluded 

conditions from a 70% ethanol vehicle. IN DRAFT. RIFM, Woodcliff Lake, 

NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 2007e. In vitro human skin 

penetration of fragrance material dimyrcetol under in-use (unoccluded) 

conditions from a 70% ethanol vehicle. IN DRAFT. RIFM, Woodcliff Lake, NJ, 

USA.





Review 

Fragrance material review on isophytol 



article 

Keywords: 

Review 


info 

abstract 

A toxicologic and dermatologic review of isophytol when used as a fragrance ingredient is presented. 


Contents 




3. Usage. . . . . . ......................................................................................................... S77 



4.1.1. Oral studies. . . . . . . . . . . . ................................................................................. S78 


4.1.3. Inhalation studies . . . . . . . ................................................................................. S78 

4.1.4. Intraperitoneal studies . . . ................................................................................. S78 








4.5. Photoirritation and photoallergy . . . . . . . ............................................................................ S79 





4.9. Mutagenicity and genotoxicity (see Table 5). . . . . . . . . . . . . . ............................................................ S80 

4.9.1. Bacterial studies . . . . . . . . ................................................................................. S80 


4.9.3. Carcinogenicity . . . . . . . . . ................................................................................. S80 


References . ......................................................................................................... S80 

Introduction 

* Corresponding author. Tel./fax: +1 201 689 8089. 



review of isophytol when used as a fragrance ingredient 

including all human health endpoints. isophytol (see Fig. 1; CAS 


doi:10.1016/j.fct.2009.11.015





Branched Chain when used as Fragrance Ingredients (Belsito 



1. Synonyms: 1-Hexadecen-3-ol,3,7,11,15-tetramethyl-3,7,11,15- 

tetramethyl-1-hexadecen-3-ol; 

2. CAS Registry number: 505-32-8; 





Fig. 1. Isophytol. 

number 505-32-8) is a fragrance ingredient used in cosmetics, fine 

fragrances, shampoos, toilet soaps and other toiletries as well as in 


Its worldwide use is greater than 1–10 metric tons per year (IFRA, 

2004). It is a colorless viscous liquid with a delicate dry leaf, tealike, 

and slightly carmellic sweet odor (Arctander, 1969). This 

material has been reported to occur in nature. 

In 2007, a complete literature search was conducted on isophytol. 


Services and the National Library of Medicine. 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, 

diagnostic patch test data with fewer than 100 consecutive patients 

have been omitted. 

Isophytol is a member of the fragrance structural group Alcohols 

Branched Chain Unsaturated. Their common characteristic 

structural elements are one hydroxyl group per molecule, a C 4 to 


1. Physical form: oily liquid; 

2. Boiling point: 334.88 °C; 

3. Flash point: >200 F; CC; 

4. Henry’s law (calculated): 0.000692 atm m 3 /mol 25C; 



7. Vapor pressure:

S78 


Table 2 


Route Species NO. Animals/dose group LD 50 (g/kg) References 

Oral Mice 5 or 10 >8.0 Bächtold (1980) as cited in OECD/SIDS (2006) a 

Oral Rats 10 >5.0 RIFM (1982) 

Oral Rats 5 or 10 >8.0 Bächtold (1973) as cited in OECD/SIDS (2006) a 

Oral Rats Not reported >5.4 RIFM (1969) 

RIFM (1970a) 

Oral Rats 5 or 10 >12.0 Bächtold (1980) as cited in OECD/SIDS (2006) a 

Dermal Rabbits 10 5.0 RIFM (1982) 

Intraperitoneal Mice Not reported 0.2 RIFM (1969) 

RIFM (1970a) 

a 

Not all of the original reports were made available to RIFM. 

Table 3 


Method 

Concentration 

(%) 


Single Dermal Application 100 Rabbits Moderate to severe skin 

reactions 

RIFM (1982) 

Up to 20 h dermal exposures 100 Rabbits Erythema at 24 h RIFM (1969) 

Desquamation at 8 days RIFM 

(1970a) 

Dermal application 5, 10, 30, 50 Guinea 

pig 

Slight to moderate RIFM (1999) 

Irritation 




Groups of 5 or 10 mice were administered isophytol (or crude 

isophytol) by gavage as part of an acute oral LD 50. A value of greater 

than 8.0 g/kg was reported due to one death in the highest dose 

group within 24 h of administration. No mouse from the highest 

dose of crude isophytol died within 24 h or 10 days of administration 

(Bächtold, 1980 as cited in OECD/SIDS, 2006). 

The acute oral LD 50 of isophytol in male Wistar rats was reported 

to be greater than 5.0 g/kg. Mortality was 2 of 10 rats at 

5.0 g/kg. Principal toxic signs were diarrhea and oily fur. Gross necropsy 

revealed lung, kidney, thoracic cavity, and intestinal abnormalities. 

Gross necropsy of survivors revealed kidney 

abnormalities (RIFM, 1982). 

Groups of 5 or 10 rats were administered isophytol by gavage as 

part of an acute oral LD 50. A value of greater than 8.0 g/kg was reported 

due to no mortality within 24 h of administration at the 

highest dosage group (Bächtold, 1973 as cited in OECD/SIDS, 2006). 

The acute oral LD 50 of isophytol in rats, administered as a 1–30% 

emulsion in gum tragacanth, was reported to be greater than 

6.4 ml/kg (>5.4 g/kg). Symptoms included apathy and dyspnea. 

Gross necropsy observations were normal. No additional details 

were reported (RIFM, 1969, 1970a). 

Groups of 5 or 10 rats were administered crude isophytol by gavage 

as part of an acute oral LD 50. A value of greater than 12.0 g/kg 

was reported due to no mortality within 24 h of administration at 

the highest dosage group (Bächtold, 1980 as cited in OECD/SIDS, 

2006). 


The acute dermal LD 50 of isophytol in rabbits was reported to be 

greater than 5.0 g/kg. There was no mortality in 10 rabbits at 5.0 g/ 

kg. Symptomology included moderate to severe skin reactions and 

few feces. Gross necropsy revealed intestinal abnormalities in two 

animals (RIFM, 1982). 

4.1.3. Inhalation studies 

There was no mortality when 12 rats were exposed for up to 8 h 

to air saturated with steam that passed through a 5 cm thick layer 

of isophytol at either 20 or 100 °C. Symptoms included only attempts 

to escape, but otherwise normal. Gross necropsy revealed 

no abnormalities (RIFM, 1969, 1970a). 

4.1.4. Intraperitoneal studies 

The acute intraperitoneal LD 50 of isophytol in mice was reported 

to be approximately 0.2 ml/kg (0.169 g/kg). Symptoms included 

staggering, trembling, and dyspnea. Gross necropsy 

revealed intra-abdominal adhesions and substance incorporates. 

No additional details were reported (RIFM, 1969, 1970a). 



In a human maximization pre-screen, isophytol was applied at 

10% in petrolatum under occlusion to the backs of 27 healthy subjects 

for 48 h. No subject had any irritation (RIFM, 1981). 


In an acute dermal toxicity study, with 10 rabbits, of isophytol 

there were moderate to severe skin reactions at 5.0 g/kg (RIFM, 

1982). 

Rabbits were exposed to undiluted isophytol on their backs or 

ears for up to 20 h of dermal exposures. Erythema was observed 

24 h after all exposures and persisted to 8 days when isophytol 

was tested on the back for 20 h. Desquamation was observed at 

8 days after all exposure scenarios (RIFM, 1969, 1970a). 

Female Hartley strain albino guinea pigs (5/dose), weighing 

310–415 g, were used in a phototoxicity study of isophytol. Four 

hours after depilation, a total of eight applications consisting of 

5%, 10%, 30%, and 50% isophytol dissolved in acetone was applied 

to a circle of 1.5 cm in diameter to both sides of the animal. At 

all test doses (5%, 10%, 30%, and 50%), isophytol was a slight to 

moderate irritant without UV irradiation (RIFM, 1999).


Table 4 


Method Induction concentration Challenge concentration Reactions References 

Skin painting 10% Acetone (1) 0.5% in acetone Mild-erythema in 5/10 animals RIFM (1970a) 

1% Acetone (9) 

RIFM (1970b) 

Maximization 1% i.d. in light paraffin 25% Dermal in ethanol 15/20 skin reactions at 25% Csato and Chubb (1996) as cited in OECD/SIDS (2006) a 

50% Dermal in ethanol Re-challenged at 12.5% 7/20 Skin reactions at 12.5% 

a 



When applied to the eyes of rabbits, a 0.05 ml aliquot of undiluted 

isophytol produced redness at 1 and 24 h and dullness at 

24 h. By 8 days irritation had cleared (RIFM, 1969, 1970a). 




was no evidence of contact sensitization to 10% isophytol in petrolatum. 

Applications were under occlusion to the forearms for a total 

of five alternate days, 48 h periods. The initial application was 

preceded by a 24 h occlusive treatment of the patch sites with 

5% aqueous sodium lauryl sulfate (SLS). Following a 10-day rest 

period, challenge patches were applied under occlusion to fresh 

sites for 48 h. Challenge applications were preceded by 30 min 

applications of 10% sodium lauryl sulfate under occlusion on the 

left side and no SLS on the right side. Challenge sites were evaluated 

at removal of the patches and 24 h later (RIFM, 1981). 


An area on the front flanks of ten guinea pigs, measuring 

25 cm 2 , was tested for sensitization. Hair was removed from the 

site and after 4 h, isophytol and acetone was applied by means of 

a soaked swab, in cross form, three times consecutively (10% one 

time, 1% nine times). Flaking, but no erythema or edema was reported 

following application by cotton swab. After an interval of 

14 days, an application of 0.5% isophytol in acetone resulted in 

mild erythema in 5/10 animals and in 0/3 control animals. Meanwhile 

1% isophytol in acetone resulted in mild erythema in 2/3 

control animals. The authors concluded that this test did not result 

in any skin sensitization (RIFM, 1970a,b). 

A guinea pig maximization test, following OECD 406, was used 

to study the sensitization effects of isophytol. In total, 30 female albino 

Dunk Hartley guinea pigs (20 test and 10 control) were used. 

Induction consisted of three 0.1 ml intracutaneous injections at 1% 

in light paraffin, followed by a 50% occlusive patch in ethanol. The 

challenge was a 25% in ethanol occlusive patch given two weeks 

after the epidermal induction. Patches were removed 24 h later, 

to find 15/20 animals with positive skin reactions. A re-challenge 

was conducted 7 days later, at a less irritating concentration of 

12.5% in ethanol, and 7/20 animals exhibited a positive response. 

The authors feel that this test elicited primary irritation rather than 

sensitization reactions (Csato and Chubb, 1996 as cited in OECD/ 

SIDS, 2006). 

4.5. Photoirritation and photoallergy 


4.5.1.1. Human studies. No information available. 

4.5.1.2. Animal studies. A guinea pig (5/dose) phototoxicity study of 

isophytol was conducted, but no conclusion regarding phototoxicity 

potential was made because all the test doses (5%, 10%, 30% and 

50% in acetone) were irritant with or without UV irradiation at 

320–400 nm for 70 min (RIFM, 1999). 

4.5.1.3. Photoallergy. No information available. 


No information available. 


Once daily for 28 days, Cr1:CD (SD) BR (VAF plus) rats (12 or 24 

per group) were given isophytol via oral gavage at doses of 0 (corn 

oil), 250, 500, or 1000 mg/kg bodyweight/day. All animals were 

examined twice daily for mortality and morbidity. All visible signs 

(including behavioral) of reaction to treatment were recorded daily. 

Blood and urine samples were obtained, and all animals were 

necropsied. Sexes were analyzed separately. There were no mortalities 

during this study. Clinical observations at 1000 mg/kg bodyweight/day 

included fur stains, hypoactivity, hunched posture, 

weight loss, and pallor. At the 1000 mg/kg bodyweight/day there 

was an increase in white blood cells noted in females, whereas 

males showed reduced prothrombin time. Statistically significant 

increases in alanine aminotransferase were observed in both sexes 

(and in mid-dose males). Specific gravity decreased, as urine volume 

increased in both sexes (and in mid-dose males). Absolute 

and relative liver weights were increased in both sexes. Absolute 

spleen and kidney weight (relative to bodyweight) was increased 

in high dose females. At the end of the treatment period there were 

some reversible effects. No obvious treatment related abnormalities 

were observed at dissection, or histopathology. This study 

established a NOEL of 250 mg/kg bodyweight/day and a NOAEL 

of 500 mg/kg bodyweight/day. A LOEL could be 1000 mg/kg bodyweight/day 

based on the reversible changes, and no signs of overt 

toxicity (Strobel and Lamber, 1998 as cited in OECD/SIDS, 2006). 

During a one-generation reproductive toxicity study, following 

OECD 415, four groups of 24 males Wistar rats were exposed to 

daily gavage treatments of isophytol at 0 (corn oil), 250, 500, or 

1000 mg/kg bodyweight/day for 91–134 days. At 1000 mg/kg 

bodyweight/day there was a slight decrease in bodyweight (as well 

as terminal bodyweight), absolute/relative prostate weight, absolute 

seminal vesicles weight, increased relative kidneys weight. 

At the highest dose group and extending into the mid-dose group 

(1000, or 500 mg/kg bodyweight/day) increased incidence and 

severity of renal basophilic aggregates and tubules were noted. 

At 500 mg/kg bodyweight/day there was also an increase in absolute/relative 

kidney weights. At all dose levels; dilated renal tubules, 

renal mineralization, and decrease in renal hyaline 

droplets were observed. A NOEL/NOAEL could not be established 

because of the renal changes judged by the authors to be unambiguous 

adverse effects. A LOEL of 250 mg/kg bodyweight/day was 

established (Beekhuijzen, 2002 as cited in OECD/SIDS, 2006).

S80 


Table 5 

Summary of mutagenicity and genotoxicity studies. 

Test system Concentration Results References 

Ames assay with and without S9 activation Salmonella typhimurium Not reported Equivocal Zeiger and Margolin (2000) 

TA97, TA98, TA 100, and 

TA 1535 

Ames assay with and without S9 activation Salmonella typhimurium Up to 10,000 lg/plate Not 

US National Toxicology 

TA97, TA98, TA100, 

TA102, TA104, TA1535 

mutagenic Program (1993,2000) 

Ames assay with and without S9 activation (plate 

Salmonella typhimurium 20 to 5000 lg/plate Not 

RIFM (1989) 

incorporation/ pre-incubation test) 

TA98, TA100, TA1535, 

TA1537 

mutagenic 

Modified ames assay with and without S9 activation Salmonella typhimurium 20 to 5000 lg/plate Not 

RIFM (1991) 

(liquid suspension) 

TA98, TA100 

mutagenic 

Micronucleus assay NMR BR mice Oral gavage dose of 

2000 mg/kg in corn oil 

Not 

genotoxic 

Meerts (2002) as cited in 

OECD/SIDS (2006) a 

a 



A one-generation reproductive toxicity study, following OECD 

415, four groups of 24 female Wistar rats were exposed to daily gavage 

treatments of isophytol at 0 (corn oil), 250, 500, or 1000 mg/ 

kg bodyweight/day for 52–108 days. Prior to mating, males were 

exposed for 10 weeks and females were treated for 2 weeks. Females 

were paired on a one to one basis with males from the same 

treatment group. The pregnant females were allowed to litter normally, 

but culled on day 4, to 8 pups (4/sex/litter). Parental animals 

were observed twice daily for behavioral and clinical signs, as well 

as abortions or premature deaths. Bodyweights, food/water consumption, 

as well as mating data, confirmation of pregnancy, and 

deliveries were recorded. In the off spring, number of live/dead 

pups, individual weights, sex, ano-genital distance, or physical/ 

behavioral abnormalities were noted. There were eight unscheduled 

deaths of the female rats, however, they were considered 

not be related to isophytol treatments. At 1000 mg/kg bodyweight/day 

females showed an increased incidence in lethargy, 

hunched posture, and piloerection. Bodyweights and food consumption 

(relative and absolute) were decreased during lactation 

at the highest dose level. Females also showed increased absolute 

and relative kidney and uterus weights. Reproduction parameters 

were affected at 1000 mg/kg bodyweight/day when females 

showed an increased mean pre-coital time, decreased fertility index, 

decreased conception rate, and decreased number of pups at 

birth. Seven females were not pregnant and one female discarded 

of her pups. Increased absolute/relative kidney weights, terminal 

bodyweight, and absolute/relative liver and spleen weight extended 

to mid-dose (500 mg/kg bodyweight/day) females as well. 

At 1000 mg/kg bodyweight/day pups showed poor health, decreased 

number of pups born, increased postnatal losses, and decreased 

bodyweights. One pup from the mid-dose group showed 

multiple malformation, but was not considered to be treatment related. 

A NOAEL for doses administered to parental animals was 

500 mg/kg bodyweight/day (Beekhuijzen, 2002 as cited in OECD/ 

SIDS, 2006). 

4.9. Mutagenicity and genotoxicity (see Table 5) 


In a summary of a mutagenicity testing of a large number of 

chemicals, it was reported that isophytol gave equivocal results 

in tests with Salmonella typhimurium strains TA97, TA98, TA100, 

and TA1535 with and without addition of S9 liver fractions from 

Aroclor induced rats and guinea pigs. Additional details were not 

provided (Zeiger and Margolin, 2000). 

Isophytol was found to be not mutagenic in three different assays. 

All assays tested in the presence and absence of S9 metabolic 

activation. The first assay was a reverse mutation assay with S. 

typhimurium strains TA97, TA98, TA100, TA102, TA104 and 

TA1535 at concentrations of 100, 333, 1000, 3333, and 

10,000 lg/plate. The second was an Ames assay, following OECD 

471, in S. typhimurium strains TA98, TA100, TA1535 and TA1537 

at concentrations of 20, 100, 500, 2500, and 5000 lg/plate. Then finally 

a liquid suspension assay (modified Ames) in S. typhimurium 

strains TA98, and TA100 at concentrations of 20, 100, 500, 2500 

and 5000 lg/plate (US National Toxicology Program, 1993, 2000; 

RIFM, 1989; and RIFM, 1991). 


A micronucleus assay was performed in NMR BR mice (SPF) (5/ 

sex/dose) according to OECD 474. Animals were given an oral gavage 

dose of 2000 mg/kg isophytol in corn oil then sampled at an 

exposure period of 24 and 48 h. Under the conditions of this study 

isophytol was regarded as not genotoxic since it was unable to induce 

any increase in the incidence of micronucleated polychromatic 

erythrocytes (Meerts, 2002 as cited in OECD/SIDS, 2006). 

4.9.3. Carcinogenicity 




with Unsaturated Branched Chain when used as Fragrance 


material. 







References 

Arctander, S., 1969. Perfume and Flavor Chemicals (Aroma Chemicals). Volume II, 

No. 2614. S. Arctander, Montclair, New Jersey. 







2007. 

Organization for Economic Co-Operation and Development (OECD) and Screening 

Information Datasets (SIDS), 2006. High Production Volume Chemicals


Isophytol (CAS No. 505-32-8). Processed by United Nations Environmental 

Program, (UNEP) Chemicals. Available online: (not all of the original reports were 

made available to RIFM). 

RIFM (Research Institute for Fragrance Materials, Inc.), 1969. Acute Toxicity Studies 

on Isophytol. Unpublished Report from BASF, 23 June. Report Number 55376, 


RIFM (Research Institute for Fragrance Materials, Inc.), 1970a. Acute Toxicity 

Studies on Isophytol. Unpublished Report from BASF, 23 June. Report Number 

4449, RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1970b. Report on the 

Examination of Isophytol for Any Skin Sensitizing Effect. Unpublished Report 

from BASF, 17 August. Report Number 55382, RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1981. Report on Human 

Maximization Studies. RIFM Report Number 1792, October 27, RIFM, Woodcliff 


RIFM (Research Institute for Fragrance Materials, Inc.), 1982. Acute Toxicity Studies. 

RIFM Report Number 1689, February 22, RIFM, Woodcliff Lake, NJ, USA. 


Isophytol in the AMES Test with Salmonella typhimurium. Unpublished report 

from BASF, 15 February. Report Number 55368, RIFM, Woodcliff Lake, NJ, USA. 


Isophytol in the Liquid Suspension Assay Modified Salmonella/Mammalian- 

Microsome Mutagenicity Test. Unpublished Report from BASF, 15 October. 

Report Number 55369, RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1999. Toxicology Studies 

of Isophytol in the Guinea Pig. Unpublished Report from Takasago 

International Corporation, Report Number 35058, RIFM, Woodcliff Lake, 

NJ, USA. 

US National Toxicology Program, 1993. NTP unpublished results. NTP Test 

Results Report. Results, status and publication information on all NTP 

chemicals produced from NTP Chemtrack system. Available online: 

http://ntp-apps. niehs.nih.gov/ntp_tox/index. cfm?fuseaction=salmonella. 

salmonellaData& 

study_no=A37965&cas_no=505%2D32%2D8&endpointlist=SA. 



produced from NTP Chemtrack system. Available online: http://ntp-apps. niehs. 

nih.gov/ntp_tox/index.cfm?fuseaction=salmonella.salmonellaData&study_no= 

A23522&cas_no=505%2D32%2D8&endpointlist=SA. 

Zeiger, E., Margolin, B.H., 2000. The proportions of mutagens among chemicals in 

commerce. Regulatory Toxicology and Pharmacology 32 (2), 219–225.





Review 

Fragrance material review on 2-methyl-2-hepten-6-ol 



article 

Keywords: 

Review 


info 

abstract 

A toxicologic and dermatologic review of 2-methyl-2-hepten-6-ol when used as a fragrance ingredient is 

presented. 


Contents 




3. Usage (see Table 1) . . . . . . . . . . ......................................................................................... S83 



References . ......................................................................................................... S83 

Introduction 


review of 2-methyl-2-hepten-6-ol when used as a 

fragrance ingredient including all human health endpoints. 

2-Methyl-2-hepten-6-ol (see Fig. 1; CAS No. 1569-60-4) 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. Its worldwide 

use is 0.01–0.1 metric tons per year (IFRA, 2004). 


methyl-2-hepten-6-ol. On-line databases that were surveyed included 













2-Methyl-2-hepten-6-ol is a member of the fragrance structural 

group Alcohols Branched Chain Unsaturated. Their common 

characteristic structural elements are one hydroxyl group per 

molecule, a C 4 to C 16 carbon chain with one or several methyl 

or ethyl side chains and up to four non-conjugated double bonds. 


stand-alone document. Please refer to A Safety Assessment of 

Alcohols with Unsaturated Branched Chain When Used as Fragrance 

Ingredients (Belsito et al., 2010) for an overall assessment 




Fig. 1. 2-Methyl-2-hepten-6-ol. 


doi:10.1016/j.fct.2009.11.016


Table 1 

Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2-methyl-2-hepten-6-ol. 



Bath products 17 0.29 0.001 0.02 0.04 0.0000 

Body lotion 8 0.71 1 0.004 0.04 0.0002 


Face cream 0.8 2 1 0.003 0.04 0.0000 


Hair spray 5 2 0.01 0.005 0.04 0.0000 

Shampoo 8 1 0.01 0.005 0.04 0.0000 

Shower gel 5 1.07 0.01 0.012 0.04 0.0000 

Toilet soap 0.8 6 0.01 0.015 0.04 0.0000 

Total 0.0010 

a 

b 




1. Synonyms: 5-Hepten-2-ol, 6-methyl-; 6-hydroxy-2-methyl-2- 

heptene; methyl heptenol; 6-methylhept-5-en-2-ol; 

2. CAS Registry No.: 1569-60-4; 

3. EINECS No.: 204-068-4; 




1. Henry’s Law (calculated): 0.0000322 atm m 3 /mol at 25 °C; 


3. Vapor pressure (calculated): 0.352 mm Hg at 25 °C; 

4. Water solubility (calculated): 1919 mg/l at 25 °C. 

3. Usage 

2-Methyl-2-hepten-6-ol is a fragrance ingredient used in many 



















material. 




by the manufacturers of fragrances and cosumer products containing 

fragrances. The authors are all employees of the Research Institute 

for Fragrance Materials. 

References 




Chemical Technology 48 (S3), S151–S192. 



2007.





Review 

Fragrance material review on (Z)-2-penten-1-ol 



article 

Keywords: 

Review 


info 

abstract 

A toxicologic and dermatologic review of (Z)-2-penten-1-ol when used as a fragrance ingredient is 

presented. 


Contents 




3. Usage. . . . . . ......................................................................................................... S85 


4.1. Acute toxicity . . . ............................................................................................... S85 













4.10. Carcinogenicity . ............................................................................................... S86 


References. . ......................................................................................................... S86 

Introduction 


review of (Z)-2-penten-1-ol when used as a fragrance 

ingredient including all human health endpoints. (Z)-2-Penten-1- 

ol (see Fig. 1; CAS No. 1576-95-0) 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. Its worldwide use is less than 0.01 metric 

tons per year (IFRA, 2004). 

In 2007, a complete literature search was conducted on (Z)-2- 

penten-1-ol. On-line databases that were surveyed included 



data. 







doi:10.1016/j.fct.2009.11.017






(Z)-2-Penten-1-ol is a member of the fragrance structural group 

Alcohols Branched Chain Unsaturated. Their common characteristic 

structural elements are one hydroxyl group per molecule, a C 4 

to C 16 carbon chain with one or several methyl or ethyl side chains 







1.1. Synonyms: 2-penten-1-ol, (Z)-; pent-2-en-1-ol; cis-pent-2- 

en-1-ol; cis-2-pentenol; 

1.2. CAS Registry No.: 1576-95-0; 

1.3. EINECS No.: 216-415-7; 

1.4. Formula: C 5 H 10 O; 

1.5. Molecular weight: 86.34. 



2.2. Henry’s law (calculated): 0.0000117 atm m 3 /mol at 25 °C; 

2.3. Vapor pressure (calculated): 0.0023 mm Hg at 25 °C; 

2.4. Water solubility (calculated): 45720 mg/l at 25 °C; 


3. Usage 

HO 

(Z)-2-Penten-1-ol is a fragrance ingredient used in many fragrance 




cleaners and detergents. Its use worldwide is in the region of less 

than 0.01 metric tons per annum (IFRA, 2004). 




Z 

Fig. 1. (Z)-2-Penten-1-ol. 










In a human repeated insult patch test (induction), 0.25% (Z)-2- 

penten-1-ol in alcohol SDA 40 was applied to the upper arms of 

38 healthy subjects for 24 h under occlusion. No subject had any 

irritation (RIFM, 1971). 


(Z)-2-Penten-1-ol at 0.25% was applied (0.5 ml) over the intact 

and abraded skin of three healthy, normal, albino rabbits. The 

2 2 patch area was covered and occluded for a 24 h exposure. 

Erythema and eschar formation was observed on the abraded skin 

at 24 h. Under the conditions of this study (Z)-2-penten-1-ol produced 

a primary irritation index of 1 (RIFM, 1970a). 


Three normal, healthy, albino rabbits were used to determine if 

(Z)-2-penten-1-ol produced any irritation when instilled into the 

eye. Each animal had a 0.1 ml aliquot instilled into the right eye 

without further treatment, the left eye served as its own control. 

Both eyes were examined every 24 h for 4 days and then again 

on the 7th day. (Z)-2-Penten-1-ol produced a moderate irritation 

involving the conjunctivae of the treated eyes. By day 7 eyes returned 

to normal (RIFM, 1970b). 



4.4.1.1. Induction studies. A repeated insult patch tests was conducted 

to determine if (Z)-2-penten-1-ol (0.25%) would induce 

dermal sensitization in human volunteers. During the induction 

phase, 0.5 ml was applied onto a 1 1 inch semi-occlusive absorbent 

patch and applied to the upper arm of each volunteer for 24 h. 

Following a rest period, a challenge patch was applied to the original 

site as well as a site previously unexposed. Patches were applied 

as in the induction phase and kept in place for 24 h before 

Table 1 

Calculation of the total human skin exposure from the use of multiple cosmetic products containing (Z)-2-penten-1-ol. 



Bath products 17 0.29 0.001 0.02 0.02 0.0000 

Body lotion 8 0.71 1 0.004 0.02 0.0001 


Face cream 0.8 2 1 0.003 0.02 0.0000 


Hair spray 5 2 0.01 0.005 0.02 0.0000 

Shampoo 8 1 0.01 0.005 0.02 0.0000 

Shower gel 5 1.07 0.01 0.012 0.02 0.0000 

Toilet soap 0.8 6 0.01 0.015 0.02 0.0000 

Total 0.0005 

a 

b 



S86 


removal. Sensitization reactions were not observed in any of the 38 

volunteers (RIFM, 1971). 



















material. 







References 







2007. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1970a. Skin Irritation Study 

with (Z)-2-Penten-1-ol (cis-2-Pentenol) in Rabbits. Unpublished Report from 

International Flavors and Fragrances, 20 November. Report No. 54718. RIFM, 


RIFM (Research Institute for Fragrance Materials, Inc.), 1970b. Eye Irritation Study 

with (Z)-2-Penten-1-ol (cis-2-Pentenol) in Rabbits. Unpublished Report from 

International Flavors and Fragrances, 16 November. Report No. 54717. RIFM, 


RIFM (Research Institute for Fragrance Materials, Inc.), 1971. Repeated Insult Patch 

Test with (Z)-2-Penten-1-ol (cis-2-Pentenol) Humans. Unpublished Report from 

International Flavors and Fragrances, 23 October. Report No. 54716. RIFM, 






Review 

Fragrance material review on 2,6,10-trimethylundeca-5,9-dienol 



article 

Keywords: 

Review 


info 

abstract 

A toxicologic and dermatologic review of 2,6,10-trimethylundeca-5,9-dienol when used as a fragrance 



Contents 




3. Usage. . . . . . . . . ...................................................................................................... S88 



References. . . . . ...................................................................................................... S88 

Introduction 


review of 2,6,10-trimethylundeca-5,9-dienol when used as 

a fragrance ingredient including all human health endpoints. 

2,6,10-Trimethylundeca-5,9-dienol (see Fig. 1; CAS Number 

24048-14-4) is a fragrance ingredient used in cosmetics, fine fragrances, 

shampoos, toilet soaps and other toiletries as well as in 


Its worldwide use is in the region of 0.01–0.1 metric tons per year 

(IFRA, 2004). 

In 2007, a complete literature search was conducted on 2,6,10- 

trimethylundeca-5,9-dienol. On-line databases that were surveyed 

included Chemical Abstract Services and the National Library of 














2,6,10-Trimethylundeca-5,9-dienol is a member of the fragrance 

structural group Alcohols Branched Chain Unsaturated. 

Their common characteristic structural elements are one hydroxyl 

group per molecule, a C 4 to C 16 carbon chain with one or several 

methyl or ethyl side chains and up to four non-conjugated double 

bonds. This individual Fragrance Material Review is not intended 


of Alcohols with Unsaturated Branched Chain When Used as Fragrance 




1.1 Synonyms: dihydroapofarnesol; 5,9-undecadien-1-ol, 

2,6,10-trimethyl; 

1.2 CAS Registry Number: 24048-14-4; 

1.3 EINECS Number: 246-000-6; 

1.4 Formula: C 14 H 26 O; 



doi:10.1016/j.fct.2009.11.018

S88 


Table 1 

Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2,6,10-trimethylundeca-5,9-dienol. 

Product type Grams applied Applications/day Retention factor Mixture/product Ingredient/mixture a Ingredient mg/kg/day b 


Bath products 17 0.29 0.001 0.02 0.85 0.0000 

Body lotion 8 0.71 1 0.004 0.85 0.0032 


Face cream 0.8 2 1 0.003 0.85 0.0007 


Hair spray 5 2 0.01 0.005 0.85 0.0001 

Shampoo 8 1 0.01 0.005 0.85 0.0001 

Shower gel 5 1.07 0.01 0.012 0.85 0.0001 

Toilet soap 0.8 6 0.01 0.015 0.85 0.0001 

Total 0.0217 

a 

b 













2.1 Henry’s Law (calculated): 0.000183 atm m 3 /mol 25 °C; 

2.2 Log K ow (calculated): 5.36; 

2.3 Vapor pressure (calculated): 0.000176 mm Hg 25 °C; 

2.4 Water solubility (calculated): 3.306 mg/l @ 25 °C. 

3. Usage 

Fig. 1. 2,6,10-Trimethylundeca-5,9-dienol. 

2,6,10-Trimethylundeca-5,9-dienol 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). 





material. 







References 







2007.





Review 

Fragrance material review on 3,5,6,6-tetramethyl-4-methyleneheptan-2-ol 



article 

Keywords: 

Review 


info 

abstract 

A toxicologic and dermatologic review of 3,5,6,6-tetramethyl-4-methyleneheptan-2-ol when used as a 

fragrance ingredient is presented. 


Contents 




3. Usage. . . . . . . . . ...................................................................................................... S90 



References . . . . ...................................................................................................... S90 

Introduction 


review of 3,5,6,6-tetramethyl-4-methyleneheptan-2-ol 

when used as a fragrance ingredient including all human health 

endpoints. 3,5,6,6-Tetramethyl-4-methyleneheptan-2-ol (see 

Fig. 1; CAS Number 81787-06-6) is a fragrance ingredient used in 



and detergents. Its worldwide use is 0.01–1.0 metric tons per 

year (IFRA, 2004). 

In 2007, a complete literature search was conducted on 3,5,6,6- 

tetramethyl-4-methyleneheptan-2-ol. On-line databases that were 

surveyed included Chemical Abstract Services and the National Library 

of Medicine. In addition, fragrance companies were asked to 

submit all test data. 












3,5,6,6-Tetramethyl-4-methyleneheptan-2-ol is a member of 

the fragrance structural group Alcohols Branched Chain Unsaturated. 


group per molecule, a C 4 to C 16 carbon chain with one or 

several methyl or ethyl side chains and up to four non-conjugated 

double bonds. This individual Fragrance Material Review is not intended 






1.1. Synonyms: 2-heptanol, 3,5,6,6-tetramethyl-4-methylene; 

1.2. CAS registry number: 81787-06-6; 

1.3. EINECS number: 401-030-0; 

1.4. Formula: C 12 H 24 O 4 ; 



doi:10.1016/j.fct.2009.11.019

S90 


Fig. 1. 3,5,6,6-Tetramethyl-4-methyleneheptan-2-ol. 

Table 1 

Calculation of the total human skin exposure from the use of multiple cosmetic products containing 3,5,6,6-tetramethyl-4-methyleneheptan-2-ol. 


Body lotion 8.00 0.71 1.000 0.004 0.02 0.0001 

Face cream 0.80 2.00 1.000 0.003 0.02 0.0000 




Shampoo 8.00 1.00 0.010 0.005 0.02 0.0000 

Bath products 17.00 0.29 0.001 0.020 0.02 0.0000 

Shower gel 5.00 1.07 0.010 0.012 0.02 0.0000 

Toilet soap 0.80 6.00 0.010 0.015 0.02 0.0000 

Hair spray 5.00 2.00 0.010 0.005 0.02 0.0000 

Total 0.0005 

a 

b 






2.3. Vapor pressure (calculated): 0.038 mm Hg @ 25 °C; 

2.4. Water solubility (calculated): 32.21 mg/l @ 25 °C. 

3. Usage 

3,5,6,6-Tetramethyl-4-methyleneheptan-2-ol is a fragrance 

ingredient used in many fragrance compounds. It may be found 

in fragrances used in decorative cosmetics, fine fragrances, shampoos, 


products such as household cleaners and detergents. Its use worldwide 

is in the region of 0.01–1.0 metric tons per annum (IFRA, 

2004). 

The maximum skin level that results from the use of 3,5,6,6-tetramethyl-4-methyleneheptan-2-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. 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). 







material. 







References 





IFRA (International Fragrance Association), 2004. Use Level Survey, August 2004.





Review 

Fragrance material review on (2E,6Z)-nona-2,6-dien-1-ol 



article 

Keywords: 

Review 


info 

abstract 

A toxicologic and dermatologic review of (2E,6Z)-nona-2,6-dien-1-ol when used as a fragrance ingredient 

is presented. 


Contents 




3. Usage. . . . . . . . . ...................................................................................................... S92 



References. . . . . ...................................................................................................... S92 

Introduction 

This document provides a comprehensive summary of the 

toxicologic review of (2E,6Z)-nona-2,6-dien-1-ol when used as a 

fragrance ingredient including all human health endpoints. 

(2E,6Z)-Nona-2,6-dien-1-ol (see Fig. 1; CAS Number 28069-72-9) 

is a fragrance ingredient used in cosmetics, fine fragrances, shampoos, 



use is greater than 0.1–1.0 metric tons per year (IFRA, 2004). 

In 2007, a complete literature search was conducted on (2E,6Z)- 

nona-2,6-dien-1-ol. On-line databases that were surveyed included 

Chemical Abstract Services and the National Library of Medicine. In 

addition, fragrance companies were asked to submit all test data. 










(2E,6Z)-Nona-2,6-dien-1-ol is a member of the fragrance structural 




characteristic structural elements are one hydroxyl group per molecule, 

a C 4 to C 16 carbon chain with one or several methyl or ethyl 

side chains and up to four non-conjugated double bonds. This individual 

Fragrance Material Review is not intended as a stand-alone 

document. Please refer to A Safety Assessment of Alcohols with 

Unsaturated Branched Chain When Used as Fragrance Ingredients 



1.1. Synonyms: 2,6-nonadien-1-ol, (E,Z)-; 2-trans-6-cis-nonadien-1-ol; 

1.2. CAS Registry Number: 28069-72-9; 

1.3. EINECS Number: 248-816-8; 

1.4. Formula: C 9 H 16 O; 






2.4. Water solubility (calculated): 963.8 mg/l at 25 °C; 



doi:10.1016/j.fct.2009.11.020

S92 


Table 1 

Calculation of the total human skin exposure from the use of multiple cosmetic products containing (2E,6Z)-nona-2,6-dien-1-ol. 



Bath products 17 0.29 0.001 0.02 0.01 0.0000 

Body lotion 8 0.71 1 0.004 0.01 0.0000 


Face cream 0.8 2 1 0.003 0.01 0.0000 


Hair spray 5 2 0.01 0.005 0.01 0.0000 

Shampoo 8 1 0.01 0.005 0.01 0.0000 

Shower gel 5 1.07 0.01 0.012 0.01 0.0000 

Toilet soap 0.8 6 0.01 0.015 0.01 0.0000 

Total 0.0003 

a 

b 





Z 

E 

Fig. 1. (2E,6Z)-Nona-2,6-dien-1-ol. 

OH 





material. 

3. Usage 

(2E,6Z)-Nona-2,6-dien-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 0.1–1.0 metric tons per annum (IFRA, 2004). 







users of these products (see Table 1). 







References 







2007.





Review 

Fragrance material review on 4-methyl-3-decen-5-ol 



article 

Keywords: 

Review 


info 

abstract 

A toxicologic and dermatologic review of 4-methyl-3-decen-5-ol when used as a fragrance ingredient is 

presented. 


Contents 

Introduction. . . . . . . . . . . . . . . . . . ....................................................................................... S94 



3. Usage. . . . . . . . . ...................................................................................................... S94 



4.1.1. Oral studies. . . . . . . . . . . . . . . .............................................................................. S94 


4.1.3. Intraperitoneal studies . . . . . . .............................................................................. S95 



4.2.2. Animal studies (see Table 3) . .............................................................................. S95 






4.5.1. Phototoxicity. . . . . . . . . . . . . . .............................................................................. S95 

4.5.2. Photoallergy . . . . . . . . . . . . . . .............................................................................. S95 




4.9. Mutagenicity and genotoxicity . . . . . . . . . . . . ......................................................................... S96 

4.9.1. Bacterial studies . . . . . . . . . . . .............................................................................. S96 


4.10. Carcinogenicity . . . . . . . ......................................................................................... S96 

Conflict of interest statement. . . . ....................................................................................... S96 

References .......................................................................................................... S96 




doi:10.1016/j.fct.2009.11.021

S94 


Table 2 


Route Species No. animals/ 

dose group 

LD 50 

(g/kg) 

References 

Oral Mice 10 8.0 RIFM (1980a,b,c) 

Intraperitoneal Mice 10 1.0–2.0 RIFM (1980a,b,c) 

Fig. 1. 4-Methyl-3-decen-5-ol. 




Introduction 


review of 4-methyl-3-decen-5-ol when used as a fragrance 

ingredient including all human health endpoints. 4-Methyl-3-decen-5-ol 

(see Fig. 1; CAS number 81782-77-6) is a fragrance ingredient 



cleaners and detergents. Its worldwide use is in the range of 

100 to 1000 metric tons per year (IFRA, 2004). 

In 2007, a complete literature search was conducted on 4-methyl- 

3-decen-5-ol. On-line databases that were surveyed included 



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, diagnostic patch test data 

with fewer than 100 consecutive patients have been omitted. 

4-Methyl-3-decen-5-ol is a member of the fragrance structural 



aC 4 –C 16 carbon chain with one or several methyl or ethyl side 

chains and up to four non-conjugated double bonds. This individual 


document. Please refer, A Safety Assessment of Alcohols with 


(Belsito et al., 2010), for an overall assessment of this material. 


1. Synonyms: 3-decen-5-ol, 4-methyl-; undecavertol; 



1. Henry’s law (calculated): 0.0000753 atm m 3 /mol @ 25 °C; 

2. Log K ow (calculated): 3.9 @ 30 °C; 


4. Water solubility (calculated): 69.47 mg/l @ 25 °C; 

5. UV spectra available at RIFM, peaks at 200–210 nm and returns 

to base line at 220 nm. 

3. Usage 

4-Methyl-3-decen-5-ol is a fragrance ingredient used in many 
















The acute oral LD 50 of 4-methyl-3-decen-5-ol in mice was reported 

to be approximately 8.0 g/kg. Mortality was 3 of 10 mice 

at 8.0 g/kg. There was no mortality at 1.0, 2.0, or 4.0 g/kg. No additional 


Table 1 

Calculation of the total human skin exposure from the use of multiple cosmetic products containing 4-methyl-3-decen-5-ol. 



Bath products 17 0.29 0.001 0.02 1.55 0.0000 

Body lotion 8 0.71 1 0.004 1.55 0.0059 


Face cream 0.8 2 1 0.003 1.55 0.0012 


Hair spray 5 2 0.01 0.005 1.55 0.0001 

Shampoo 8 1 0.01 0.005 1.55 0.0001 

Shower gel 5 1.07 0.01 0.012 1.55 0.0002 

Toilet soap 0.8 6 0.01 0.015 1.55 0.0002 

Total 0.0395 

a 

b 




Table 3 


Method Concentration (%) Species Results References 

Single dermal application 100 Rabbit Irritation observed up to 21 days RIFM (2000) 

Patch test 10 Guinea pig Irritation cleared by 48 h RIFM (1980a,b,c) 



4.1.3. Intraperitoneal studies 

The acute intraperitoneal LD 50 of 4-methyl-3-decen-5-ol in 

mice was reported to be between 1.0 and 2.0 g/kg. Mortality was 

10 of 10 mice at 2.0 g/kg. There was no mortality at 0.25, 0.5, or 

1.0 g/kg. No additional details were reported (RIFM, 1980a). 



In a Human Repeated Insult Patch Test (HRIPT), irritation was 

not induced in 50 subjects treated with 10% 4-methyl-3-decen-5- 

ol in dimethyl phthalate. The application was under occlusion for 

24 h, 3 days per week for 10 applications or after the final application 

10–24 days later (RIFM, 1981). 


In a GLP rabbit dermal irritation study conducted according to 

EEC and OECD guidelines, transient slight dermal irritation was 

elicited by a single 4 h semi-occlusive application of 0.5 ml of 

4-methyl-3-decen-5-ol to 6 cm 2 intact skin of three white New 

Zealand rabbits. Grade 1.33 erythema and grade 0.56 edema were 

reported. There was well defined erythema at 1 and 24 h, resolving 

by 72 h in one animal and by day 7 in the remaining two animals. 

Very slight to slight edema was observed in all animals at 1 and 

24 h, disappearing by 48 h in one and by 72 h in two animals. 

Slight scaling was observed in one animal at 48 and 72 h. Slight 

to moderate scaling was observed in all animals at day 7, disappearing 

by day 10 in one animal, day 14 in one animal, and day 

21 in the remaining animal. No staining of skin or corrosive effects 

was noted (RIFM, 2000). 

A group of eight albino guinea pigs were patch tested for a reaction 

time of 48 h on both flanks with 0.1 ml 4-methyl-3-decen-5-ol 

in dilution with acetone/ethanol (1:1) at 10%. Reactions were read 

at 4, 24, and 48 h. At 4 h slight irritation was observed in two of 

eight animals, by 48 h irritation was no longer present (RIFM, 

1980b). 


A rabbit eye irritation study was conducted according to the 

method of Draize in three animals/group. A 0.1 ml of 100%, 30%, 

and 10% 4-methyl-3-decen-5-ol (vehicle: diethyl phthalate) was 

instilled into the eye and observed for up to 14 days. Undiluted, 

the material produced moderate conjunctival irritation accompanied 

by corneal opacity lasting for 3 days. At 10% and 30% 4- 

methyl-3-decen-5-ol caused mild erythema which resolved in all 

animals by 72 h and 4 days, respectively. No alteration of the cornea 

was observed at this dose (RIFM, 1980c). 



In a Human Repeated Insult Patch Test (HRIPT), there was no 

evidence of sensitization in 50 subjects treated with 10% 

4-methyl-3-decen-5-ol (11810 lg/cm 2 ) in dimethyl phthalate 

applied under occlusion for 24 h, 3 days per week for 10 applications 

followed by challenge application 10–24 days later (RIFM, 

1981). 


In a photoallergenicity study, 0.1 ml 4-methyl-3-decen-5-ol, applied 

in dilution with acetone/ethanol (1:1) at 10% for induction 

and 1%, 3%, 10%, and 30% for challenge, was reported to show no 

allergenicity potential in guinea pigs (10 per treatment group). 

Induction doses were administered topically, initially following 

intradermal injection of Freunds complete adjuvant, and subsequently 

on days 3, 5, 8, and 10 without adjuvant. Challenge doses 

were administered 3 weeks after initiation of induction. No erythema 

was observed 24 h after challenge (RIFM, 1989). 



4.5.1.1. Human studies. No available information. 

4.5.1.2. Animal studies. At 10%, a 0.1 ml of 4-methyl-3-decen-5-ol in 

dilution with acetone/ethanol (1:1) was reported to show no 

phototoxicity potential in guinea pigs (eight/group) exposed for 

48 h with or without subsequent exposure to 320–400 nM light 

for 30 min (group A) or 280–370 nM light for 15 min (group B), 

each at 1 10(4) Ergs/cm/s. Skin reactions were evaluated at 4, 

24, and 48 h after irradiation. After 4 h, all but one rabbit showed 

slight irritation; by 48 h, all were normal (RIFM, 1980b). 


4.5.2.1. Human studies. No available information. 

4.5.2.2. Animal studies. 4-Methyl-3-decen-5-ol (10%) was applied 

(0.1 ml) in an acetonic/ethanolic (1:1) dilution, for induction and 

1%, 3%, 10%, and 30% for challenge, was reported to show no photoallergenicity 

potential in guinea pigs (10/dose) with or without 

subsequent exposure to 320–400 nM at 10 J/cm 2 and 280– 

370 nM light at 1.8 J/cm 2 . Induction doses were administered topically, 

initially following intradermal injection of Freunds complete 

adjuvant, and subsequently on days 3, 5, 8, and 10 without adjuvant. 

Challenge doses were administered three weeks after initiation 

of induction. No erythema was observed 24 h after challenge 

(RIFM, 1989). 






No available information.

S96 




4-Methyl-3-decen-5-ol tested up to concentrations of 333 or 

1000 lg/plate and dissolved in dimethyl sulfoxide, was not mutagenic 

in Salmonella typhimurium strains TA 98, TA 100, TA 102, TA 

1535, and TA 1537 with or without the addition of S9 liver fractions 

from Aroclor induced adult male Wistar rats. Both the direct 

plate and preincubation assays were conducted up to the toxic 

dose for each tester strain, as determined by range finding studies 

(RIFM, 2002). 









material. 







References 


Sipes, I.G., Calow, P., Tagami, H., 2010. A Safety Assessment of Alcohols with 

Unsaturated Branched Chain When Used as Fragrance Ingredients. Food Chem. 

Toxicol. 48 (S3), S151–S192. 



2007. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1980a. Acute Toxicity 

Studies with 4-Methyl-3-decen-5-ol. Unpublished Report from Givaudan, 19 

November. Report Number 49101, RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1980b. Determination of 

Phototoxicity in Guinea Pigs with 4-Methyl-3-decen-5-ol. Unpublished Report 

from Givaudan, 29 November. Report Number 49102, RIFM, Woodcliff Lake, NJ, 

USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1980c. Irritation Test with 4- 

Methyl-3-decen-5-ol on the Rabbit Eye. Unpublished Report from Givaudan, 24 

June. Report Number 49103, RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1981. Repeated Insult Patch 

Test with 4-Methyl-3-decen-5-ol. Unpublished Report from Givaudan, 28 April. 

Report Number 49104, RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1989. Determination of 

Photoallergenicity in Albino Guinea Pigs with 4-Methyl-3-decen-5-ol. 

Unpublished Report from Givaudan, 27 November. Report Number 49105, 


RIFM (Research Institute for Fragrance Materials, Inc.), 2000. 4-Methyl-3-decen-5- 

ol: Primary Skin Irritation Study in Rabbits (4 h Semi-occlusive Application). 

Unpublished Report from Givaudan, 02 November. Report Number 41335, 


RIFM (Research Institute for Fragrance Materials, Inc.), 2002. Evaluation of the 

Mutagenic Activity of 4-Methyl-3-decen-5-ol in the Salmonella typhimurium 

Reverse Mutation Assay. Unpublished Report from Givaudan, 11 November. 

Report Number 42179, RIFM, Woodcliff Lake, NJ, USA.





Review 




article 

Keywords: 

Review 


info 

abstract 

A toxicologic and dermatologic review of 2-methyl-3-buten-2-ol when used as a fragrance ingredient is 

presented. 


Contents 




3. Usage. . . . . . . . . ...................................................................................................... S98 



4.1.1. Oral studies. . . . . . . . . . . . . . . .............................................................................. S98 


4.1.3. Miscellaneous studies. . . . . . . .............................................................................. S98 








4.9. Mutagenicity and genotoxicity (see Table 3). ......................................................................... S99 

4.9.1. Bacterial studies . . . . . . . . . . . .............................................................................. S99 


4.10. Carcinogenicity. . . . . . . . . ........................................................................................ S100 

Conflict of interest statement . . . . . . . . .................................................................................. S100 

References . . . . ..................................................................................................... S100 

Introduction 


review of 2-methyl-3-buten-2-ol when used as a fragrance 

ingredient including all human health endpoints. 2-Methyl-3-buten-2-ol 

(see Fig. 1; CAS No. 115-18-4) is a fragrance ingredient 



cleaners and detergents. Its worldwide use is 0.01–0.1 metric 



tons per year (IFRA, 2004). It is a colorless mobile liquid with an 

earthy, fungus-like, odor of considerable radiance, but poor tenacity 

(Arctander, 1969). This material has been reported to occur in 

nature. 


methyl-3-buten-2-ol. On-line databases that were surveyed included 









doi:10.1016/j.fct.2009.11.022

S98 


Fig. 1. 2-Methyl-3-buten-2-ol. 

Table 1 

Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2-methyl-3-buten-2-ol. 

Type of cosmetic 

product 

Grams applied Applications per day Retention factor Mixture/product Ingredient/mixture a Ingredient mg/kg/day b 

Body lotion 8.00 0.71 1.000 0.004 0.02 0.0001 

Face cream 0.80 2.00 1.000 0.003 0.02 0.0000 




Shampoo 8.00 1.00 0.010 0.005 0.02 0.0000 

Bath products 17.00 0.29 0.001 0.020 0.02 0.0000 

Shower gel 5.00 1.07 0.010 0.012 0.02 0.0000 

Toilet soap 0.80 6.00 0.010 0.015 0.02 0.0000 

Hair spray 5.00 2.00 0.010 0.005 0.02 0.0000 

a 

b 

Total 0.0005 


Based on a 60 kg adult. 






2-Methyl-3-buten-2-ol is a member of the fragrance structural 



molecule, a C 4 to C 16 carbon chain with one or several methyl 

or ethyl side chains and up to four non-conjugated double 







1. Synonyms: 3-buten-2-ol, 2-methyl-; 1,1,-dimethyl-2-propenol; 


3. INECS No.: 204-068-4; 



6. FDA: 2-methyl-3-buten-2-ol was approved by the FDA as GRAS 

(21 CFR 172.515). 


1. Henry’s law (calculated): 0.00000988 atm m 3 /mol @ 25 °C; 



4. Water solubility (calculated): 48,740 mg/l @ 25 °C; 

5. UV spectra available at RIFM; peaks at 200–205 nm. 

3. Usage 

2-Methyl-3-buten-2-ol is a fragrance ingredient used in many 

fragrance compounds. It may be found in fragrances used in 





The maximum skin level that results from the use of 2-methyl- 

3-buten-2-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. 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 





Acute oral LD 50 values of 1.8 g/kg and 2.28 g/kg were reported 

in rats (BASF, 1991b and Roche, 1990 as cited in OECD/SIDS 

(2005)). 


An acute dermal LD 50 value greater then 2.0 g/kg was reported 

in rabbits (BASF, 1991b as cited in OECD/SIDS (2005)). 

4.1.3. Miscellaneous studies 

Wistar male rats were given an intraperitoneal injection of 2- 

methyl-3-buten-2-ol to calculate an LD 50 value of 1.315 g/kg 

(Wohlfahrt et al., 1993). 

Male NMRI mice were given an intraperitoneal injection of 2- 

methyl-3-buten-2-ol to calculate an LD 50 value of 1.117 g/kg 

(Wohlfahrt et al., 1993). 

In a test method based off of OECD guidelines 403, male and female 

SPF Wistar/Chbb:THOM rats (5/sex) were exposed for 4 h by 

whole body inhalation to 2-methyl-3-buten-2-ol. Two animals 

died on the first day of observations. Clinical signs such as ruffled 

fur, and ataxia were observed, but from days 6–14 appeared nor-


Table 2 



Oral Rat Not reported 1.8 BASF, 1991b as cited in OECD/SIDS (2005) a 

Oral Rat Not reported 2.28 Roche, 1990 as cited in OECD/SIDS (2005) a 

Dermal Rabbit Not reported >2.0 BASF, 1991b as cited in OECD/SIDS (2005) a 

Intraperitoneal Rat Not reported 1.3 Wohlfahrt et al. (1993) 

Intraperitoneal Mice Not reported 1.1 Wohlfahrt et al. (1993) 

a 


Table 3 

Summary of mutagenicity and genotoxicity studies. 

Test system Concentration Results References 


Salmonella typhimurium TA98, 

20–5000 lg/plate Not mutagenic RIFM (1989b) 


TA100, TA1535 and TA1537 

Micronucleus assay NMRI mice Oral gavage dose of 500, 

1000, or 1500 mg/kg in corn oil 

Not genotoxic RIFM (1992) 

mal. The estimated LC 50 value in rats is greater then 21.2 mg/l 

(RIFM, 1989a). 












A repeated dose oral toxicity study with 2-methyl-3-buten-2-ol 

was administered by gavage in olive oil (30, 150, and 750 mg/kg 

body weight) to Wistar rats for 4 weeks. The three different dosage 

groups (5/sex/dose) were observed for clinical symptoms, chemistry 

and hematology. At 750 mg/kg/day, all male and female rats 

showed ataxia. There was a decrease in chloride (both sexes) triglycerides 

(males) and potassium (females). There was an increase 

in cholesterol (both sexes) and magnesium (males). No substance 

related findings were observed at 30, or 150 mg/kg body weight. 

A NOAEL was set for 150 mg/kg bodyweight under the conditions 

of this study (RIFM, 1994). 

An oral 28-day study according to OECD test guideline 407 was 

conducted with 2-methyl-3-buten-2-ol (Roche, 1994 as cited in 

OECD/SIDS (2005)). Wistar rats (10–14/sex/dose) were exposed 

to 0, 50, 200 or 600 mg/kg body weight/day by gavage. No toxicologically 

relevant changes were noted in the low dose group. In 

mid dose female rats minimally increased (not stated whether relative 

or absolute) liver weights and hypertrophy of hepatocytes 

were observed. In males minimally increased (not stated whether 

relative or absolute) kidney weights and a slight to moderate accumulation 

of renal hyaline droplets were noted. The high dose induced 

sedation, ataxia and uncoordinated gait during the first 

days of application and salivation after repeated administration. 

The death of one animal of each sex as exposure-related could 

not be excluded. In males and females minimally increased liver 

weight and periacinar hypertrophy of hepatocytes were observed. 

Transaminases were minimally increased. It was concluded that 

the hyaline droplet accumulation is due to a2u-globulin accumulation, 

a male-rat-specific renal syndrome. The NOAEL of this study 

was 50 mg/kg body weight/day. The LOEL was 200 mg/kg body 

weight/day based on increased liver weight and hypertrophy of 

hepatocytes (probably enzyme induction). 


A one generation study of reproductive toxicity was studied in 

Fü-Albino (RORO) rats. Males and females (10/sex/dose) were given 

doses of 12.5, 50, or 200 mg/kg bodyweight/day for 2 weeks 

before mating. At 200 mg/kg bodyweight/day male rats tended to 

have reduced body weight gains. Female rats had a slight decrease 

in food consumption at the highest dose level during lactation. 

There was no parental necropsy observations considered compound 

related. Mating and fertility indices were comparable between 

all groups. The number of pups dying during lactation was 

increased and the number of pups surviving day 5 of lactation 

was decrease, which caused an over all reduction of viability to 

nearly 23% at the 200 mg/kg bodyweight/day group. No compound 

related adverse clinical findings were observed in any of the dose 

groups. There were no abnormal findings at the macroscopic or visceral 

examination of the pups. A NOAEL for parental and offspring 

was reported as 50 mg/kg bodyweight/day (Roche, 1995b as cited 

in OECD/SIDS (2005)). 

4.9. Mutagenicity and genotoxicity (see Table 3) 


An Ames assay in Salmonella typhimurium strains TA98, TA100, 

TA1535, and TA1537 reported 2-methyl-3-buten-2-ol not to be 

mutagenic with and without S9 activation (RIFM, 1989b). 


A micronucleus assay, according to OECD 474, in NMRI mice did 

not affect the ratio of polychromatic erythrocytes to normochromatic 

erythrocytes, determining it is not genotoxic. Mice were 

given 2-methyl-3-buten-2-ol in single doses of 500, 1000, or

S100 


1500 mg/kg bodyweight/day. Signs of toxicity were observed such 

as irregular respiration, piloerection and in a few cases apathy. 

Symptoms cleared the day after treatment (RIFM, 1992). 







material. 







References 

Arctander, S., 1969. Perfume and Flavor Chemicals (Aroma Chemicals), vol. II, No. 



Sipes, I.G., Calow, P., Tagami, H., 2010. A Safety Assessment of Alcohols with 

Unsaturated Branched Chain When Used as Fragrance Ingredients. Food Chem. 

Toxicol. 48 (S3), S151–S192. 


Organization for Economic Co-Operation and Development (OECD) and Screening 

Information Datasets (SIDS), 2005. High Production Volume Chemicals 2- 

Methy-3-buten-2-ol (Cas No: 115-18-4). Processed by United Nations 

Environmental Program, (UNEP) Chemicals. Available from: . 

RIFM (Research Institute for Fragrance Materials, Inc.), 1989a. Study on the Acute 

Inhalation Toxicity of 2-Methyl-3-Buten-2-ol as a Vapor in Rats. Unpublished 

Report from BASF. Report No. 55325. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1989b. Report on the Study 

of 2-Methyl-3-Buten-2-ol in the Ames Test. Unpublished Report from BASF. 

Report No. 55328. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1992. Cytogenetic Study 2- 

Methyl-3-Buten-2-ol in Mice. Unpublished Report from BASF. Report No. 


RIFM (Research Institute for Fragrance Materials, Inc.), 1994. Repeated Dose Oral 

Toxicity Study with 2-Methyl-3-Buten-2-ol in Wistar Rats. Unpublished Report 

from BASF. Report No. 55324. RIFM, Woodcliff Lake, NJ, USA. 

Wohlfahrt, R., Hansel, R., Schmidt, H., 1993. Pharmacology of 2-methyl-3-buten-2- 

ol. Planta Medica 48, 120–123.





Review 

Fragrance material review on 2-hexadecen-1-ol, 3,7,11,15-tetramethyl 



article 

Keywords: 

Review 


info 

abstract 

A toxicologic and dermatologic review of 2-hexadecen-1-ol, 3,7,11,15-tetramethyl when used as a fragrance 



Contents 

Introduction. . . . . . . . . . . . . . . . . . ...................................................................................... S101 

1. Identification . . ..................................................................................................... S101 

2. Physical properties . . . . . . . . . . . . . . . . . .................................................................................. S102 

3. Usage. . . . . . . . . ..................................................................................................... S102 

4. Toxicology data ..................................................................................................... S102 

Conflict of interest statement. . . . ...................................................................................... S102 

References . . . . ..................................................................................................... S102 

Introduction 


review of 2-hexadecen-1-ol, 3,7,11,15-tetramethyl when 

used as a fragrance ingredient including all human health endpoints. 

2-Hexadecen-1-ol, 3,7,11,15-tetramethyl (see Fig. 1; CAS 

number 7541-49-3) 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. 

Its worldwide use is less than 0.01 metric tons per year 

(IFRA, 2004). It is a viscous liquid, practically colorless with a delicate 

floral balsamic odor (Arctander, 1969). 

In 2007, a complete literature search was conducted on 2-hexadecen-1-ol, 

3,7,11,15-tetramethyl. On-line databases that were 

surveyed included Chemical Abstract Services and the National Library 

of Medicine. In addition, fragrance companies were asked to 

submit all test data. 












2-Hexadecen-1-ol, 3,7,11,15-tetramethyl is a member of the 

fragrance structural group Alcohols Branched Chain Unsaturated. 


group per molecule, a C 4 to C 16 carbon chain with one or several 

methyl or ethyl side chains and up to four non-conjugated double 



of Alcohols with Unsaturated Branched Chain When Used as Fragrance 




1. Synonyms: 3,7,11,15-tetramethyl-2-hexadecen-1-ol; 





doi:10.1016/j.fct.2009.11.023

S102 


Fig. 1. 2-Hexadecen-1-ol, 3,7,11,15-tetramethyl. 

Table 1 

Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2-hexadecen-1-ol, 3,7,11,15-tetramethyl. 



Bath products 17 0.29 0.001 0.02 0.98 0.0000 

Body lotion 8 0.71 1 0.004 0.98 0.0037 


Face cream 0.8 2 1 0.003 0.98 0.0008 


Hair spray 5 2 0.01 0.005 0.98 0.0001 

Shampoo 8 1 0.01 0.005 0.98 0.0001 

Shower gel 5 1.07 0.01 0.012 0.98 0.0001 

Toilet soap 0.8 6 0.01 0.015 0.98 0.0001 

Total 0.0250 

a 

b 


Based on a 60 kg adult. 


1. Log K OW (calculated): 8.32; 

2. Vapor pressure (calculated): 0.000000524 mm Hg 25 °C. 

3. Usage 

2-Hexadecen-1-ol, 3,7,11,15-tetramethyl is a fragrance ingredient 

used in many fragrance compounds. It may be found in fragrances 

used in decorative cosmetics, fine fragrances, shampoos, 


such as household cleaners and detergents. Its use worldwide 

is in the region of less than 0.01 metric tons per annum (IFRA, 

2004). 










stand-alone document. Please refer to a safety assessment of alcohols 

with unsaturated branched chain when used as fragrance 

ingredients (Belsito et al., 2010) for an overall assessment of this 

material. 







References 

Arctander, S., 1969. Perfume and Flavor Chemicals (Aroma Chemicals), vol. II, No. 


Belsito, D., Bickers, D., Bruze, M., Calow, P., Greim, H., Hanifin, J.H., Rogers, A.E., 

Saurat, J.H., Sipes, I.G., Tagami, H., 2010. A safety assessment of alcohols with 



IFRA (International Fragrance Association), 2004. Use Level Survey. 

IFRA (International Fragrance Association), 2007. Volume of Use Survey. 

No data available.





Review 

Fragrance material review on 7-nonen-2-ol, 4,8-dimethyl- 

D. McGinty * , L. Jones, C.S. Letizia, A.M. Api 


article 

Keywords: 

Review 


info 

abstract 

A toxicologic and dermatologic review of 7-nonen-2-ol, 4,8-dimethyl- when used as a fragrance ingredient 

is presented. 


Contents 

Introduction. . . . . . . . . . . . . . . . . . ...................................................................................... S103 

1. Identification . . ..................................................................................................... S104 

2. Physical properties . . . . . . . . . . . . . . . . . .................................................................................. S104 

3. Usage. . . . . . . . . ..................................................................................................... S104 

4. Toxicology data ..................................................................................................... S104 

4.1. Acute toxicity (see Table 2) . . . . . . . . . . . . . . ........................................................................ S104 

4.1.1. Oral studies. . . . . . . . . . . . . . . ............................................................................. S104 

4.1.2. Dermal studies . . . . . . . . . . . . ............................................................................. S104 

4.2. Skin irritation . . . . . . . . . ........................................................................................ S105 

4.2.1. Human studies . . . . . . . . . . . . ............................................................................. S105 

4.2.2. Animal studies (see Table 3) . ............................................................................. 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 . . . . . . . . . . . ........................................................................ S106 

4.5.1. Phototoxicity. . . . . . . . . . . . . . ............................................................................. S106 

4.5.2. Photoallergy . . . . . . . . . . . . . . ............................................................................. S106 

4.6. Absorption, distribution and metabolism . . . ........................................................................ S106 

4.7. Repeated dose toxicity . . ........................................................................................ S106 

4.8. Reproductive and developmental toxicity . . . ........................................................................ S106 

4.9. Mutagenicity and genotoxicity . . . . . . . . . . . . ........................................................................ S106 

4.9.1. Bacterial studies . . . . . . . . . . . ............................................................................. S106 

4.10. Carcinogenicity . . . . . . . . ........................................................................................ S106 

Conflict of interest statement . . . . . . . . .................................................................................. S106 

References . . . . ..................................................................................................... S106 

Introduction 



This document provides a comprehensive summary of the 

toxicologic review of 7-nonen-2-ol, 4,8-dimethyl- when used as a 

fragrance ingredient including all human health endpoints. 7- 

Nonen-2-ol, 4,8-dimethyl- (see Fig. 1; CAS No. 40596-76-7) is a fra- 


doi:10.1016/j.fct.2009.11.024

S104 


3. Usage 

grance ingredient used in cosmetics, fine fragrances, shampoos, 


such as household cleaners and detergents. Its worldwide 

use is greater than 0.01–0.1 metric tons per year (IFRA, 2004). It 

is a colorless oily liquid with a mild-rosy odor (Arctander, 1969). 

In 2007, a complete literature search was conducted on 7-nonen- 

2-ol, 4,8-dimethyl-. On-line databases that were surveyed included 












7-Nonen-2-ol, 4,8-dimethyl- is a member of the fragrance structural 


characteristic structural elements are one hydroxyl group per molecule, 

a C 4 to C 16 carbon chain with one or several methyl or ethyl 

side chains and up to four non-conjugated double bonds. This individual 


document. Please refer to A Safety Assessment of Alcohols with 




1. Synonyms: 4,8-dimethylnon-7-en-2-ol; homocitronellol; 


3. EINECS No.: 254-994-8; 




Fig. 1. 7-Nonen-2-ol, 4,8-dimethyl-. 

1. Boiling point: 74 °C/1.9 mm Hg. 

7-Nonen-2-ol, 4,8-dimethyl- is a fragrance ingredient used in 






The maximum skin level that results from the use of 7-nonen-2- 

ol, 4,8-dimethyl- in formulae that go into fine fragrances has not 

been reported. A default value of 0.2% is used, assuming use of 

the fragrance oil at levels up to 20% in the final product. The 97.5 

percentile use level in formulae for use in cosmetics in general 

has not been reported. As such, a default value of 0.02% is used 

to calculate maximum daily exposure on the skin of 0.0005 mg/ 

kg for high end users of these products (Table 1). 




Ten rats per dose were dosed via gavage with neat 7-nonen-2- 

ol, 4,8-dimethyl- at 5.0 g/kg body weight. Observations for mortality, 

toxicity and pharmacological effects were made. Animals were 

not examined for gross pathology at termination. At 5.0 g/kg, 0/10 

deaths were observed. Lethargy, ataxia, ptosis, piloerection, chromodacryorrhea, 

chromorhinorrhea and diarrhea were noted. The 

acute oral LD 50 in rats was reported to be greater than 5.0 g/kg 

(RIFM, 1979a). 

Ten Wistar rats (5/sex) were orally dosed once via gavage with 

7-nonen-2-ol, 4,8-dimethyl- at 2.0 g/kg body weight. Severity, onset 

and progress reversibility of toxic signs were observed for 

14 days and recorded with relation to dose and time. All animals 

were necropsied. At 2.0 g/kg, 0/10 deaths were observed. The acute 

oral LD50 in rats was reported to be greater than 2.0 g/kg (RIFM, 

2004a). 


The acute LD50 in New Zealand white rabbits exceeded 2.0 g/kg 

based on 0 deaths in 10 animals tested at that dose. Rabbits received 

a single undiluted dermal application at a dose level of 

2.0 g/kg body weight. Observations for mortality and/or systemic 

effects were made for 14 days. Isolated instances of diarrhea and 

lethargy were the only clinical signs observed during the study 

(RIFM, 1979b). 

Table 1 

Calculation of the total human skin exposure from the use of multiple cosmetic products containing 7-nonen-2-ol, 4,8-dimethyl-. 



Bath products 17 0.29 0.001 0.02 0.02 0.0000 

Body lotion 8 0.71 1 0.004 0.02 0.0001 


Face cream 0.8 2 1 0.003 0.02 0.0000 


Hair spray 5 2 0.01 0.005 0.02 0.0000 

Shampoo 8 1 0.01 0.005 0.02 0.0000 

Shower gel 5 1.07 0.01 0.012 0.02 0.0000 

Toilet soap 0.8 6 0.01 0.015 0.02 0.0000 

Total 0.0005 

a 

b 






Irritation was evaluated during the induction phase in a human 

repeated insult patch test (HRIPT) with 50 (8 male and 42 female) 

volunteers. A 0.2 g sample of 7-nonen-2-ol, 4,8-dimethyl- at 20% in 

white petrolatum was applied for 24 h with a semi-occlusive gauze 

patch. Patch removal was followed by a 24 h rest period then the 

next patch at the same site. A total of nine applications were made 

over a three-week period. Irritation was not observed in the 50 

male and female volunteers (RIFM, 1979c). 

Table 2 



Oral Rat 10 >5.0 RIFM (1979a) 

Oral Rats 10 >2.0 RIFM (2004a) 

Dermal Rabbit 10 >2.0 RIFM (1979b) 


Rabbits received a single 24 h application on intact and abraded 

skin at a dose level of 2.0 g/kg body weight. Observations for mortality 

and/or systemic effects were made. Isolated instances of 

diarrhea and lethargy were the only clinical signs observed during 

the study. Very slight to well-defined erythema and very slight to 

slight edema were noted at 24 h (RIFM, 1979b). 

Six New Zealand white rabbits were dosed once dermally on 

one abraded and one intact site per animal. The 0.5 ml (0.5 g/ 

kg) application of undiluted 7-nonen-2-ol, 4,8-dimethyl- to each 

site beneath a 2.5 cm2 gauze patch was kept in contact with the 

skin for 24 h. Reactions were scored at 24 and 72 h according to 

Draize. Very slight to well-defined erythema which increased 

slightly from 24 to 72 h was noted during the observation period. 

Very slight to slight edema was also observed (RIFM, 

1979d). 

A primary skin irritation test was performed using young female 

albino Hartley strain guinea pigs (3/group). Each animal received 

a single occlusive application of 0.3 ml (approximately 

0.3 g/kg or 5.3 cm2) at doses of 1%, 10% or 100% in a petrolatumbased 

ointment. At the end of the exposure period, the residual 

material was removed. The site was examined for evidence of irritation 

and scored 48 and 72 h after dosing. The vehicle alone, and 

at 1%, caused mild irritation. Moderate irritation was noted for the 

10% dosage group. Undiluted 7-nonen-2-ol, 4,8-dimethyl- was 

found to be severely irritating (RIFM, 2004a). 

A cumulative open application of 7-nonen-2-ol, 4,8-dimethylusing 

female albino Hartley strain guinea pigs (3/group) was performed 

on clipped, normal skin. A 0.3 ml (approximately 0.3 g/kg 

or 12 cm2) solution was applied at concentrations of 10% or 100% 

in ethanol once a day (five days/week) for two weeks. Each application 

site was examined for evidence of irritation (erythema, edema 

and desquamation) then scored. Scores were recorded before 

dosing, at 24 h, every subsequent day and 72 h after the final application. 

With 10% a weak irritation reaction was noted, but the 

study was discontinued at 100% due to severe irritation reactions 

(RIFM, 2004a). 

A guinea pig maximization test according to the Kligman (1969) 

method was conducted using 10 male albino Hartley/Dunkin guinea 

pigs. Induction consisted of a series of six intradermal injections 

of 0.05% v/v 7-nonen-2-ol, 4,8-dimethyl- in dipropylene 

glycol:propylene glycol (1:3) with and without Freund’s complete 

adjuvant (FCA) followed one week later with a 10% in dipropylene 

glycol occluded 48 h patch application. Animals were challenged 

two weeks later with a 0.4 ml (0.4 g/kg) application of 5% 7- 

nonen-2-ol, 4,8-dimethyl- in dipropylene glycol:propylene glycol 

(1:3) on an occluded 24 h dermal patch. Reactions were read 

48 h after patch removal. Intradermal injections of Freund’s complete 

adjuvant both alone and mixed with 7-nonen-2-ol, 4,8-dimethyl- 

elicited dermal irritation. No dermal irritation was 

observed following intradermal injections of 7-nonen-2-ol, 4,8-dimethyl- 

in solution alone. Reactions produced by the topically applied 

7-nonen-2-ol, 4,8-dimethyl- were obscured by the 

intradermal reactions still present (RIFM, 1976). 

4.3. Mucous membrane (Eye) irritation 

Undiluted 7-nonen-2-ol, 4,8-dimethyl- was evaluated for eye 

irritation in six New Zealand white rabbits. A 0.1 ml aliquot was instilled 

into one eye, and the untreated eye served as a control. 

Observations were made for three days. Irritation was observed. 

Corneal and conjunctival irritation persisted until day three (RIFM, 

1979e; RIFM, 1979f). 



4.4.1.1. Induction studies. An HRIPT was conducted to determine if 

7-nonen-2-ol, 4,8-dimethylwould induce dermal sensitization 

in human volunteers. During the induction phase, 0.2 g of 20% 7- 

nonen-2-ol, 4,8-dimethyl- in white petrolatum was applied onto 

a semi-occlusive patch. Each application remained in contact with 

the skin for 24 h. Induction applications were made to the same 

site for a total of nine applications during a three-week period. Following 

a two-week rest period, a challenge patch was applied to 

the same site as well as a site previously unexposed. 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. Sensitization was not 

observed in the 50 male and female volunteers (RIFM, 1979c). 


4.4.2.1. Maximization test (see Table 4). A maximization test according 

to the Kligman (1969) method was conducted on 10 male albino 

Hartley/Dunkin guinea pigs. Induction consisted of a series of 

six intradermal injections of 0.05% 7-nonen-2-ol, 4,8-dimethylwith 

and without FCA, followed by a 48 h occluded patch application 

one week later. Animals were challenged two weeks later with 

5% 7-nonen-2-ol, 4,8-dimethyl- by an occluded 24 h dermal patch. 

Table 3 


Method Dose (g/kg) Species Reactions References 

Dermal application 2.0 Rabbit Irritation observed RIFM (1979b) 

Dermal application 0.5 Rabbit Irritation observed RIFM (1979d) 

Primary irritation 0.3 Guinea pig Mild, moderate, and severe irritation observed RIFM (2004a) 

Open dermal application 0.3 Guinea pig Weak reaction at 10% 

RIFM (2004a) 

severe reaction at 100% 

Maximization 0.4 Guinea pig Irritation observed RIFM (1976)

S106 


Table 4 


Method Induction concentration Challenge concentration Reactions References 

Maximization 

Maximization 

10% i.d. injections 

100% dermal 

30% i.d. injection 

100% dermal 

100% dermal No reactions RIFM (1976) 

0.1%, 1%, 3%, 5% or 30% dermal No reactions RIFM (2004a) 

Reactions were read 24, 48 and 72 h after patch removal. No dermal 

reactions were seen in any of the guinea pigs following the 

challenge application (RIFM, 1976). 

A maximization test with female albino Hartley strain guinea 

pigs (5/group) was conducted using a series of six induction injections 

of 0.1 ml 7-nonen-2-ol, 4,8-dimethyl- at 30%, with and without 

FCA, followed one week later with a 48 h occluded patch 

application of 10% sodium lauryl sulfate in petrolatum. An open 

topical challenge application was given two weeks later at concentrations 

of 0.1%, 1%, 3%, 5%, 10% or 30% in ethanol. At 24, 48 and 

72 h after the challenge, the degree of erythema and edema was 

quantified based on each application site. At all concentration levels, 

7-nonen-2-ol, 4,8-dimethyl- did not elicit sensitizing reactions 

(RIFM, 2004a). 



4.5.1.1. Human studies. As part of an HRIPT, 20 male and female 

volunteers were tested to determine if 7-nonen-2-ol, 4,8-dimethylwould 

induce phototoxicity. During the induction phase, 0.2 g of 

20% 7-nonen-2-ol, 4,8-dimethyl- in white petrolatum was applied 

with a semi-occlusive patch for 24 h. The sites were irradiated 

using a Spectroline Model B-100, Black Light flood lamp (365 nm, 

1680 lW/cm2) for 15 min at a distance of 15 in. After the exposure 

period the experimental samples were covered with a semi-occlusive 

gauze patch for 24 h. The subjects were rested for another 24 h 

before a second application was administered. Nine applications 

were made over three weeks, and the challenge was after a twoweek 

rest period. The 1st, 4th, 7th, 9th and challenge applications 

were irradiated. Reactions to the challenge were scored at 24, 48 

and 72 h after application. Phototoxicity was not observed (RIFM, 

1979c). 

4.5.1.2. Animal studies. Young female albino Hartley strain guinea 

pigs (3/group) were tested for the phototoxicity of 7-nonen-2-ol, 

4,8-dimethyl- at concentrations of 3%, 10% or 30% in ethanol. An 

open application was made to two sites on the dorsal skin with 

0.02 ml in a 1.5 cm 1.5 cm area and subsequently irradiated with 

320–400 nm of UV wavelength with five FL20S BLB lamps (Toshiba 

Co., 20 W) from a distance of 10 cm for 60 min. Each application 

site was examined at 24, 48 and 72 h after the end of the irradiation 

period. The degree of erythema and edema was then evaluated. 

No phototoxicity was observed at 3% or 10%. Weak 

phototoxic reactions were observed at 30% (RIFM, 2004a). 


4.5.2.1. Human studies. As part of an HRIPT, 20 male and female 

volunteers were tested to determine if 0.2 g of 20% 7-nonen-2-ol, 

4,8-dimethyl- in white petrolatum would induce phototallergy. 

The sites were irradiated using a Spectroline Model B-100, Black 

Light flood lamp (365 nm, 1680 lW/cm2) for 15 min at a distance 

of 15 in. After the exposure period the experimental samples were 

covered with a semi-occlusive gauze patch for 24 h. The subjects 

were rested for another 24 h before a second application was 

administered. Nine applications were made over three weeks, 

and the challenge was after a two-week rest period. The 1st, 4th, 

7th, 9th and challenge applications were irradiated. Reactions to 

the challenge were scored at 24, 48 and 72 h after application. Photoallergy 

was not observed (RIFM, 1979c). 









In a reverse mutation Ames test, Salmonella typhimurium 

strains TA98, TA100, TA1535 and TA1537 and E. coli strain WP2uvrA 

were treated with the 7-nonen-2-ol, 4,8-dimethyl- in dimethyl 

sulfoxide (DMSO). No mutagenicity was observed using the preincubation 

method of Ames et al. (1975), with and without metabolic 

activation (S-9 mix), at dose levels up to 313 lg/ml (RIFM, 2004b). 





with Unsaturated Branched Chain when Used as Fragrance 


material. 







References 

Ames, B.N., McCann, J., Yamasaki, E., 1975. Methods for detecting carcinogens and 

mutagens with the Salmonella/mammalian-microsome mutagenicity test. 

Mutation Research 31, 347–363. 

Arctander, S., 1969. Perfume and Flavor Chemicals (Aroma Chemicals), vol. I, No. 


Belsito, D., Bickers, D., Bruze, P., Calow, M., Greim, H., Hanifin, J.H., Rogers, A.E., 

Saurat, J.H., Sipes, I.G., Tagami, H., 2010. A safety assessment of alcohols with 





2004.


Kligman, A.M., 1969. The identification of contact allergens by animal assay. The 

guinea pig maximization test. Journal of Investigative Dermatology 52, 268– 

276. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1976. Screening Test for 

Delayed Contact Hypersensitivity with 7-Nonen-2-ol, 4,8-Dimethyl- in the 

Albino Guinea Pig. Unpublished Report from Firmenich Incorporated, 28 July. 

Report No. 38741. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1979a. Acute Oral Toxicity of 

7-Nonen-2-ol, 4,8-Dimethyl- in Rats. Unpublished Report from Firmenich 

Incorporated, Report No. 38735. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1979b. Acute Dermal Toxicity 

of 7-Nonen-2-ol, 4,8-Dimethyl- in Rabbits. Unpublished Report from Firmenich 

Incorporated, 18 September. Report No. 38736. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1979c. Human Repeated 

Insult Patch Test of 7-Nonen-2-ol, 4,8-Dimethyl. Unpublished Report from 

Firmenich Incorporated, 19 September. Report No. 38740. RIFM, Woodcliff Lake, 

NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1979d. Primary Dermal 

Irritation of 7-Nonen-2-ol, 4,8-Dimethyl- in Rabbits. Unpublished Report from 

Firmenich Incorporated, 26 July. Report No. 38737. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1979e. Eye Irritation Study of 

7-Nonen-2-ol, 4,8-Dimethyl- in Rabbits. Unpublished Report from Firmenich 

Incorporated, 18 December. Report No. 38738. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 1979f. Eye Irritation Study of 

7-Nonen-2-ol, 4,8-Dimethyl- in Rabbits. Unpublished Report from Firmenich 

Incorporated, 13 August. Report No. 38739. RIFM, Woodcliff Lake, NJ, USA. 

RIFM (Research Institute for Fragrance Materials, Inc.), 2004a. Toxicity Studies with 

7-Nonen-2-ol, 4,8-Dimethyl- in Guinea Pigs and Rats. Unpublished Report from 

Takasago International Corporation, 29 July. Report No. 46339. RIFM, Woodcliff 


RIFM (Research Institute for Fragrance Materials, Inc.), 2004b. Reverse Mutation 

Test ‘‘Ames Test” with S. typhimurium and E. coli. Unpublished Report from 

Takasago International Corporation, 29 January. Report No. 46338. RIFM, 






Review 

Fragrance Material Review on 6-ethyl-3-methyloct-6-en-1-ol 



article 

Keywords: 

Review 


info 

abstract 

A toxicologic and dermatologic review of 6-ethyl-3-methyloct-6-en-1-ol when used as a fragrance ingredient 

is presented. 


Contents 

Introduction ........................................................................................................ S108 

1. Identification . . . . . . . . . . . . . . . ........................................................................................ S109 

2. Physical properties . . . . . . . . . . . ........................................................................................ S109 

3. Usage. . . . . . ........................................................................................................ S109 

4. Toxicology data . . . . . . . . . . . . . ........................................................................................ S109 

4.1. Acute toxicity . . . .............................................................................................. S109 

4.2. Skin irritation . . . .............................................................................................. S109 

4.3. Mucous membrane (eye) irritation . . . . . ........................................................................... S109 

4.4. Skin sensitization .............................................................................................. S109 

4.4.1. Animal studies . . . . . . . . . ................................................................................ S109 

4.5. Phototoxicity and photoallergy . . . . . . . . ........................................................................... S109 

4.6. Absorption, distribution and metabolism ........................................................................... S109 

4.7. Repeated dose toxicity . . . . . . . . . . . . . . . ........................................................................... S109 

4.8. Reproductive and developmental toxicity ........................................................................... S109 

4.9. Mutagenicity and genotoxicity . . . . . . . . . ........................................................................... S109 

4.10. Carcinogenicity . .............................................................................................. S110 

Conflict of interest statement . . ........................................................................................ S110 

References. . ........................................................................................................ S110 

Introduction 


review of 6-ethyl-3-methyloct-6-en-1-ol when used as a 

fragrance ingredient including all human health endpoints. 6- 

Ethyl-3-methyloct-6-en-1-ol (see Fig. 1; CAS number 26330-65- 

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. Its 

worldwide use is greater than 1–10 metric tons per year (IFRA, 

2004). 



In 2007, a complete literature search was conducted on 6-ethyl- 

3-methyloct-6-en-1-ol. On-line databases that were surveyed included 














doi:10.1016/j.fct.2009.11.025


of the fragrance oil at levels up to 20% in the final product. The 


has not been reported. As such, a default value of 0.02% is used to 

calculate maximum daily exposure on the skin of 0.0005 mg/kg for 




6-Ethyl-3-methyloct-6-en-1-ol is a member of the fragrance 

structural group Alcohols Branched Chain Unsaturated. Their common 


molecule, a C 4 to C 16 carbon chain with one or several methyl or 

ethyl side chains and up to four non-conjugated double bonds. This 


document. Please refer A Safety Assessment of Alcohols with 




1. Synonyms: 6-ethyl-3-methyloct-6-ene-1-ol; 6-ethyl-3-methyl- 

6-octen-1-ol; 3-methyl-6-ethyl-6-octen-1-ol; 6-octen-1-ol, 

6-ethyl-3-methyl-; 






1. UV spectra available at RIFM, peaks at 210–215. 

3. Usage 

Fig. 1. 6-Ethyl-3-methyloct-6-en-1-ol. 

6-Ethyl-3-methyloct-6-en-1-ol is a fragrance ingredient used in 

many fragrance compounds. It may be found in fragrances used in 





The maximum skin level that results from the use of 6-ethyl-3- 

methyloct-6-en-1-ol in formulae that go into fine fragrances has 

not been reported. A default value of 0.2% is used, assuming use 








A study comparing an in vitro skin sensitization method to the 

Local Lymph Node Assay (LLNA) listed an EC3 value of 19.3 and 

classified 6-ethyl-3-methyloct-6-en-1-ol as weak sensitizer under 

OECD guideline 429 (Natsch et al., 2007). 











Table 1 

Calculation of the total human skin exposure from the use of multiple cosmetic products containing 6-ethyl-3-methyloct-6-en-1-ol. 


Body lotion 8.00 0.71 1.000 0.004 0.02 0.0001 

Face cream 0.80 2.00 1.000 0.003 0.02 0.0000 



Antiperspirant 0.50 1.00 1.000 0.010 0.02 0.0000 

Shampoo 8.00 1.00 0.010 0.005 0.02 0.0000 

Bath products 17.00 0.29 0.001 0.020 0.02 0.0000 

Shower gel 5.00 1.07 0.010 0.012 0.02 0.0000 

Toilet soap 0.80 6.00 0.010 0.015 0.02 0.0000 

Hair spray 5.00 2.00 0.010 0.005 0.02 0.0000 

Total 0.0005 

a 

b 



S110 











material. 




References 

Belsito, D., Bickers, D., Bruze, M., Calow, P., Greim, H., Hanifin, J.H., Rogers, A.E., 

Saurat, J.H., Sipes, I.G., Tagami, H., 2010. A Safety Assessment of Alcohols with 

Unsaturated Branched Chain When Used as Fragrance Ingredients. Food and 



2004. 

Natsch, A., Feller, H.G., Ellis, G., Rothaupt, M., 2007. Utility and limitations of a 

peptide reactivity assay to predict fragrance allergens in vitro. Toxicology In 

Vitro 21 (7), 1220–1226.

FOOD AND CHEMICAL TOXICOLOGY 

VOLUME 48 (2010) SUPPLEMENT 3 

CONTENTS 

A Safety Assessment of Non-cyclic Alcohols with Unsaturated Branched Chain 

when used as Fragrance Ingredients 

The RIFM expert panel, 

D. Belsito, D. Bickers, M. Bruze, 

P. Calow, H. Greim, J. M. Hanifin, 

A. E. Rogers, J. H. Saurat, I. G. Sipes 

and H. Tagami 


A. M. Api 

D. McGinty, A. Lapczynski, 

S. P. Bhatia, C. S. Letizia and 

A. M. Api 


A. M. Api 


A. M. Api 


A. M. Api 

D. McGinty, L. Jones, C. S. Letizia and 

A. M. Api 


A. M. Api 


A. M. Api 


A. M. Api 


A. M. Api 


A. M. Api 


A. M. Api 


A. M. Api 

S1–S42 

S43–S45 

S46–S51 

S52–S55 

S56–S58 

S59–S63 

S64–S69 

S70–S75 

S76–S81 

S82–S83 

S84–S86 

S87–S88 

S89–S90 

S91–S92 

A safety assessment of non-cyclic alcohols with unsaturated branched chain 

when used as fragrance ingredients. 

Addendum to Fragrance material review on Nerolidol (isomer unspecified) 

Fragrance material review on 7-octen-2-ol, 2-methyl-6-methylene-, dihydro 

derivative 

Fragrance material review on 3,7-dimethyl-1,6-nonadien-3-ol 

Fragrance material review on methylheptenol 

Fragrance material review on phytol 


Fragrance material review on dihydromyrcenol 

Fragrance material review on isophytol 

Fragrance material review on 2-methyl-2-hepten-6-ol 

Fragrance material review on (Z)-2-penten-1-ol 

Fragrance material review on 2,6,10-trimethylundeca-5,9-dienol 

Fragrance material review on 3,5,6,6-tetramethyl-4-methyleneheptan-2-ol 

Fragrance material review on (2E,6Z)-nona-2,6-dien-1-ol 

(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(S3) S1–S110 (2010) 

Printed by Polestar Wheatons Ltd, Exeter, UK 237

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