Review

Fragrance materials review on isoamyl alcohol

D. McGinty
*
, A. Lapczynski, J. Scognamiglio, C.S. Letizia, A.M. Api
Research Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
a r t i c l e i n f o
Keywords:
Review
Frangrance
a b s t r a c t
A toxicologic and dermatologic review of isoamyl alcohol when used as a fragrance ingredient is pre-
sented. Isoamyl alcohol is a member of the fragrance structural group branched chain saturated alcohols.
The common characteristic structural elements of the alcohols with saturated branched chain are one
hydroxyl group per molecule, and a C
4
C
12
carbon chain with one or several methyl side chains. This
review contains a detailed summary of all available toxicology and dermatology papers that are related
to this individual fragrance ingredient and is not intended as a stand-alone document. A safety assess-
ment of the entire branched chain saturated alcohol group will be published simultaneously with this
document; please refer to Belsito et al. (2010) for an overall assessment of the safe use of this material
and all other branched chain saturated alcohols in fragrances.
2010 Published by Elsevier Ltd.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S103
1. Identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S103
2. Physical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S103
3. Usage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S103
4. Toxicology data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S104
4.1. Acute toxicity (see Table 2). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S104
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S104
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105
4.1.3. Intravenous studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105
4.1.4. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105
4.2. Skin irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105
4.2.1. Human studies (see Table 3). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105
4.2.2. Animal studies (see Table 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105
4.3. Mucous membrane (eye) irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105
4.4. Skin sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105
4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105
4.4.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105
4.5. Phototoxicity and photoallergy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105
4.6. Absorption, distribution, and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105
4.6.1. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105
4.6.2. Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S106
4.7. Repeated dose toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S106
4.7.1. Subchronic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S106
4.7.2. Chronic studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S106
4.8. Reproductive and developmental . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S107
4.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S107
4.9.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S107
4.9.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S107
0278-6915/$ - see front matter 2010 Published by Elsevier Ltd.
doi:10.1016/j.fct.2010.05.040
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.
E-mail address: dmcginty@RIFM.org (D. McGinty).
Food and Chemical Toxicology 48 (2010) S102S109
Contents lists available at ScienceDirect
Food and Chemical Toxicology
j our nal homepage: www. el sevi er . com/ l ocat e/ f oodchemt ox
4.10. Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S107
4.11. Neurotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S108
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S108
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S108
Introduction
This document provides a comprehensive summary of the tox-
icologic review of isoamyl alcohol when used as a fragrance ingre-
dient including all human health endpoints. Isoamyl alcohol (see
Fig. 1; CAS Number 123-51-3) is a fragrance ingredient used in cos-
metics, ne fragrances, shampoos, toilet soaps, and other toiletries
as well as in non-cosmetic products such as household cleaners
and detergents. It is a colorless liquid with a disagreeable alcohol
odor only becoming a pleasant fruity-winey odor at high dilutions
(Arctander, 1969). This material has been reported to occur in nat-
ure, with the highest quantities observed in the brassica species of
mustard (VCF, 2009).
In 2006, a complete literature search was conducted on isoamyl
alcohol. On-line toxicological databases were searched including
those from the Chemical Abstract Services [e.g. ToxCenter (which
in itself contains 18 databases including Chemical Abstracts)],
and the National Library of Medicine [e.g. Medline, Toxnet (which
contains 14 databases)] as well as 26 additional sources (e.g. BIO-
SIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance companies
were asked to submit all test data.
The safety data on this material was last reviewed by Opdyke
(1979). All relevant references are included in this document. More
details have been provided for unpublished data. The number of
animals, sex, and strain are always provided unless they are not gi-
ven in the original report or paper. Any papers in which the vehi-
cles and/or the doses are not given have not been included in this
review. In addition, diagnostic patch test data with fewer than 100
consecutive patients have been omitted.
1. Identication
1.1. Synonyms: 1-butanol, 3-methyl-; isobutyl carbinol; isopent-
anol; isopentyl alcohol; 3-methyl-1-butanol; 3-methylb-
utan-1-ol.
1.2. CAS Registry Number: 123-51-3.
1.3. EINECS Number: 204-633-5.
1.4. Formula: C
5
H
12
O.
1.5. Molecular weight: 88.15.
1.6. Council of Europe (2000): isoamyl alcohol was included by
the Council of Europe in the list of substances granted A
may be used in foodstuffs (COE Number 51).
1.7. FDA: isoamyl alcohol was approved by the FDA as avor (21
CFR 172.515).
1.8. FEMA (1965): Flavor and Extract Manufacturers Association
states: Generally Recognized as Safe as a avor ingredient
GRAS 3 (2057).
1.9. JECFA (1996): the Joint FAO/WHO Expert Committee on
Food Additives (JECFA) concluded that the substance does
not present a safety concern at current levels of intake when
used as a avoring agent (52).
1.10. OSHA: isoamyl alcohol was listed by the Occupational Safety
and Health Administration as PEL-TWA 100 ppm, 360 mg/
m
3
(for primary and secondary).
2. Physical properties
2.1. Physical form: colorless liquid with a disagreeable alcohol
odor and pungent, repulsive taste.
2.2. Flash point: 109 F; CC.
2.3. Boiling point: 132 C.
2.4. Henrys law (calculated; EPA, 2010): 0.0000133 atm m
3
/mol
(25 C).
2.5. Log K
ow
(measured; EPA, 2010): 1.16.
2.6. Specic gravity: 0.81.
2.7. Refractive index: 1.4.
2.8. Vapor pressure (calculated; EPA, 2010): 3.84 mm Hg at
(25 C); 512 Pa (25 C).
2.9. Water solubility (calculated; EPA, 2010): 41,580 mg/l at
25 C.
2.10. UV spectra available at RIFM. Does not absorb UV light. Fig. 1. Isoamyl alcohol.
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing isoamyl alcohol.
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixture
a
Ingredient (mg/kg/day)
b
Anti-perspirant 0.5 1 1 0.01 0.01 0.000001
Bath products 17 0.29 0.001 0.02 0.01 0.000001
Body lotion 8 0.71 1 0.004 0.01 0.000001
Eau de toilette 0.75 1 1 0.08 0.01 0.000100
Face cream 0.8 2 1 0.003 0.01 0.000001
Fragrance cream 5 0.29 1 0.04 0.01 0.000100
Hair spray 5 2 0.01 0.005 0.01 0.000001
Shampoo 8 1 0.01 0.005 0.01 0.000001
Shower gel 5 1.07 0.01 0.012 0.01 0.000001
Toilet soap 0.8 6 0.01 0.015 0.01 0.000001
Total 0.0002
a
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.
b
Based on a 60-kg adult.
D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S102S109 S103
3. Usage
Isoamyl alcohol is a fragrance ingredient used in decorative cos-
metics, ne fragrances, shampoos, toilet soaps, and other toiletries
as well as in non-cosmetic products such as household cleaners
and detergents. Its use worldwide is in the region 0.11.0 metric
tons/annum (IFRA, 2004). The reported volume of use is for iso-
amyl alcohol as used in fragrance compounds (mixtures) in all n-
ished consumer product categories. The volume of use is surveyed
by IFRA approximately every four years through a comprehensive
survey of IFRA and RIFM member companies. As such the volume
of use data from this survey provides volume of use of fragrance
ingredients for the majority of the fragrance industry.
The dermal systemic exposure in cosmetic products (see Table 1)
is calculated based on the concentrations of the same fragrance
ingredient in 10 types of the most frequently used personal care
and cosmetic products (anti-perspirant, bath products, body lotion,
eau de toilette, face cream, fragrance cream, hair spray, shampoo,
shower gel, and toilet soap). The concentration of the fragrance
ingredient inne fragrances is obtainedfromexaminationof several
thousand commercial formulations. The upper 97.5 percentile con-
centrationis calculated fromthe data obtained. This upper 97.5 per-
centile concentration is then used for all 10 consumer products.
These concentrations are multiplied by the amount of product ap-
plied, the number of applications per day for each product type,
and a retention factor (ranging from 0.001 to 1.0) to account for
the length of time a product may remain on the skin and/or likeli-
hood of the fragrance ingredient being removed by washing. The
resultant calculation represents the total consumer exposure (mg/
kg/day) (Cadby et al., 2002; Ford et al., 2000).
This is a conservative calculation of dermal systemic exposure
because it makes the unlikely assumption that a consumer will
use these 10 products containing; which are all perfumed with
the upper 97.5 percentile level of the fragrance ingredient from a
ne fragrance type of product (Cadby et al., 2002; Ford et al.,
2000). The 97.5 percentile use level in formulae for use in cosmet-
ics in general has been reported to be 0.01% (IFRA, 2007), which
would result in a conservative calculated maximum daily exposure
on the skin of 0.0002 mg/kg for high end users of these products
(see Table 1).
A maximum skin level is then determined for consideration of
potential sensitization. The exposure is calculated as the percent
concentration of the fragrance ingredient applied to the skin based
on the use of 20% of the fragrance mixture in the ne fragrance
consumer product (IFRA, 2007). The maximum skin level that re-
sults from the use of isoamyl alcohol in formulae that go into ne
fragrances has been reported to be 0.012% (IFRA, 2007), assuming
use of the fragrance oil at levels up to 20% in the nal product.
4. Toxicology data
4.1. Acute toxicity (see Table 2)
4.1.1. Oral studies
As a preliminary study for a mouse micronucleus test, acute oral
toxicity was evaluated with four (2/sex) animals. The NMRI mice
were treated orally with the 0.1, 0.5, 1.0, or 2.0 g/kg of isoamyl
alcohol and examined for acute toxic symptoms at intervals of
around 1, 24, 6, 24, 30, and 48 h after administration. At the high-
est dose of 2.0 g/kg bodyweight the toxic effects observed were a
reduction in spontaneous activity, eyelid closure, and rufed fur.
No mortality was observed at the highest dose which indicated
the LD
50
to be greater than 2.0 g/kg (RIFM, 2008).
The acute oral LD
50
of isoamyl alcohol in rats was reported to be
4.36 g/kg (no further details provided) (Golovinskaya, 1976).
The oral LD
50
of isoamyl alcohol in rats was reported to be 1.3 g/
kg (no further details provided) (Nishimura et al., 1994).
The acute oral (gavage) LD
50
was evaluated in groups of 4 rats
with isoamyl alcohol at a dose range of 0.3254.95 and 0.81
12.0 g/kg (concentration not reported) in polyethylene glycol 200
for male and female, respectively. Deaths in female rats occurred
4 h after high doses (4.95 and 12.0 g/kg); none died in the 10 days
after the lower doses (0.81 and 2.0 g/kg). Males receiving the high-
est doses of 4.95 g/kg and a group receiving 12.0 g/kg died within
4 h, and several at the lower doses of 0.81 and 2.0 g/kg died
15 days later. Histological examination of the liver revealed
hyperemia but very few degenerative changes. Females receiving
4.95 g/kg showed cloudy swelling and cast formation in the cortex
Table 2
Summary of acute toxicity studies.
Route Species Number
of animals/
dose group
LD
50
(g/kg) References
Oral Mice 4 >2.0 RIFM (2008)
Oral Rat N/A 4.36 Golovinskaya (1976)
Oral Rat N/A 1.3 Nishimura et al. (1994)
Oral Rat 4 1.3 (male) Purchase (1969)
4.0 (female)
Oral Rat 5 7.1 Smyth et al. (1969)
Oral Rat N/A >5.0 RIFM (1979)
Oral Rabbit 1035 3.44 Munch (1972)
Dermal Rabbit 10 >5.0 RIFM (1976a)
Dermal Rabbit 4 3.97 Smyth et al. (1969)
Dermal Rabbit 6 4.0 RIFM (1979)
Intravenous Mice N/A 0.23 Chvapil et al. (1962)
Table 3
Summary of human skin irritation studies.
Method Concentration Results References
Reactions Frequency (%)
48 h closed patch test 8% in petrolatum 0/25 0 RIFM (1976b)
5 min, occlusive patch test 75% in water 12/12 100 Wilkin and Fortner (1985a)
5 min, occlusive patch test 75% in water 3/3 100 Wilkin and Fortner (1985b)
5 min, occlusive patch test 75% in a hydrophilic ointment 12/12 100 Wilkin and Stewart (1987)
Table 4
Summary of animal irritation studies.
Method Dose (%) Species Reactions References
Single application of 5.0 g/kg 100 Rabbit Marked erythema and moderate edema RIFM (1976)
0.01 ml aliquot applied to the clipped skin 100 Rabbit Irritation observed Smyth et al. (1969)
Single application 100 Rabbit Very irritating RIFM (1979)
S104 D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S102S109
and a few pyknotic tubular cells in the medulla section of the kid-
ney. In females receiving 12.0 g/kg, the cortex showed signs of
necrosis with some tubular cells showing pyknosis. In males pyk-
nosis and hyperemia were seen in the outer zone of the medulla
in all groups, and tubular necrosis was seen in the cortex after
the two highest doses (2.0 and 4.95 g/kg). The calculated LD
50
was 4.0 g/kg (95% limits: 2.456.17 g/kg) for female and 1.3 g/kg
(95% limits: 0.672.41 g/kg) for male (Purchase, 1969).
Groups of ve Carworth-Wistar male rats were administered a
single dose of undiluted isoamyl alcohol by gavage. The oral LD
50
of was reported to be 7.1 g/kg with limits of 4.8210.4 g/kg (Smyth
et al., 1969).
Isoamyl alcohol was reported to have an LD
50
greater than 5.0 g/
kg in Sprague Dawley rats. The animals were given doses of 2.15 or
5.0 g/kg and observed for 14 days (RIFM, 1979).
The acute oral (gavage) LD
50
of isoamyl alcohol was reported to
be 39 mmol/kg (3.45 g/kg). Administration was via stomach tube
from a 50 ml syringe to groups of 1035 rabbits (Munch, 1972).
4.1.2. Dermal studies
The acute dermal LD
50
of isoamyl alcohol was evaluated in 10
rabbits. Each animal received a single dermal application of undi-
luted isoamyl alcohol at a dose of 5.0 g/kg. Clinical signs and/or
mortality were observed over a 14 day period. No deaths were ob-
served. Clinical signs included accidity, ataxia, loss of righting re-
ex and diarrhea. The LD
50
was reported to be greater than 5.0 g/kg
(RIFM, 1976a).
The acute dermal LD
50
was evaluated in groups of four male al-
bino New Zealand rabbits. Undiluted isoamyl alcohol at 0.1 ml was
applied to the clipped trunk, and kept in place beneath an imper-
vious plastic lm for 24 h (doses and skin area not provided). The
LD
50
was reported to be 3.97 g/kg with limits of 2.935.37 g/kg
(Smyth et al., 1969).
Isoamyl alcohol was reported to have a dermal LD
50
of 4 ml/kg
(4 g/kg) in rabbits. The animals were given undiluted doses of
isoamyl alcohol and observed for 8 days (RIFM, 1979).
4.1.3. Intravenous studies
The intravenous LD
50
of isoamyl alcohol in water was deter-
mined in female white H strain mice. Using an approximate gra-
phic probit method, the LD
50
was calculated to be 2.64 mmol/kg
(233 mg/kg; no further details provided) (Chvapil et al., 1962).
The hemodynamic effects of isoamyl alcohol were studied in 56
anesthetized, open chest dogs. The material was administered i.v.
at a constant rate for 40150 min. The infusion of 20 mg/kg/min
decreased heart rate, systemic arterial pressure, and myocardial
contraction force progressively and markedly. All dogs died during
the rst hour of infusion (Nakano and Kessinger, 1972).
Isoamyl alcohol was injected into the vein of cat, under a light
ether anesthesia, to determine the lethal dose. In terms of the pure
alcohol of 0.26 ml/kg (260 mg/kg) was determined to be lethal
(Macht, 1920).
4.1.4. Inhalation studies
Smyth et al. (1969) reported no death up to 8 h when concen-
trated vapors of isoamyl alcohol were exposed to rats by
inhalation.
Sensory irritation was evaluated in four Swiss male mice via
measurement of changes in respiratory rate during a 10 min expo-
sure to isoamyl alcohol. The concentration of isoamyl alcohol that
caused a 50% decrease in the respiratory rate (RD
50
) of mice was
4452 ppm with 95% condence limits of 288512,459 (Kane
et al., 1980).
Rats inhaled isoamyl alcohol as a steam vapor in an enriched
atmosphere at 20 C. After a 7 h exposure, no animals died (RIFM,
1979).
4.2. Skin irritation
4.2.1. Human studies (see Table 3)
In a pre-test for a human maximization study, a 48 h closed
patch test was conducted on the volar forearms or backs of 25 vol-
unteers with 8% isoamyl alcohol in petrolatum. No irritation was
observed (RIFM, 1976b).
Patch tests were conducted on 27 (groups of 12, 12, and 3)
healthy volunteers with 75% aqueous solution of isoamyl alcohol.
Patches were applied to the subjects forearms, and were removed
after being occluded for 5 min. Irritation reactions were observed
in all volunteers (Wilkin and Fortner, 1985a,b; Wilkin and Stewart,
1987).
4.2.2. Animal studies (see Table 4)
Irritation was evaluated during a dermal LD
50
study. A single
application of 5.0 g/kg of neat isoamyl alcohol was made to 10 rab-
bits. Marked or moderate edema were observed in 10/10 rabbits
(RIFM, 1976a).
Primary skin irritation was determined using groups of ve al-
bino rabbits. A 0.01 ml aliquot of isoamyl alcohol was applied to
the clipped skin of the animals undiluted or as a solution in water,
propylene glycol or acetone. Irritation reactions were observed
(Smyth et al., 1969).
Isoamyl alcohol was reported to be very irritating when applied
undiluted to the skin of six rabbits. Irritation resolved after 8 days
(RIFM, 1979).
4.3. Mucous membrane (eye) irritation
An eye irritation test was conducted in ve rabbits per dose. Iso-
amyl alcohol (0.5 ml aliquot) was tested undiluted or as a solution
in propylene glycol and water. Irritant effects were observed
(Smyth et al., 1969).
An eye irritation test was conducted in two rabbits with undi-
luted isoamyl alcohol. Irritation was observed up to 8 days in one
rabbit (RIFM, 1979).
4.4. Skin sensitization
4.4.1. Human studies
A maximization study was conducted on 25 (5 male, 20 female)
volunteers. Isoamyl alcohol at 8% in petrolatum was applied under
occlusion to the volar forearms or backs for ve alternate days,
48 h periods. The sites were pre-treated for 24 h with 2.5% aqueous
sodium lauryl sulfate (SLS) under occlusion. The challenge phase
was conducted after a rest period of 1014 days at sites pre-treated
for 1 h with 510% SLS. The challenge patch was removed after
48 h, and the site was read at the patch removal and 24 h after
the patch removal. No reactions were observed (RIFM, 1976b).
4.4.2. Animal studies
No data available.
4.5. Phototoxicity and photoallergy
No data available.
4.6. Absorption, distribution, and metabolism
4.6.1. Distribution
4.6.1.1. Human studies. Respiratory uptake of isoamyl alcohol was
investigated in four healthy volunteers. Test air concentration
was 25200 ppm and it was inhaled for 10 min. The mean uptake
(determined using calculations based on exhalation percentages of
isoamyl alcohol to mixed exhaled air) for the last 5 min of the test
D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S102S109 S105
respiration was 63% and the mean respiratory rate was 15.3 min
1
(Kumagai et al., 1998).
4.6.1.2. Animal studies. Groups of 10 rats per dose received 600 mg
of 20% isoamyl alcohol/l solution (either in ethanol or water) by
intraperitoneal injection in four equally divided portions of
2.5 ml/100 g of bodyweight, at 15 min intervals. Two hours after
administration, the blood concentration of isoamyl alcohol with
ethanol was maximal. It declined thereafter and was still detect-
able at 10 h but not at 12 h. When isoamyl alcohol was adminis-
tered in water, its presence in the blood was discernible 2 h after
administration but not thereafter (Greenberg, 1970).
A single dose of 2.0 g/kg of isoamyl alcohol, in an aqueous solu-
tion of 20%, was given orally to fasted six Wistar WAG rats. Blood
and urine were collected for up to 8 h for measurement of test
material levels. The blood level in mg/100 ml was 7 at 15 min, 9
at 30 min, 17 at 1 h, 8 at 1.5 h, 7 at 2 h, 3 at 4 h, and 1 at 8 h. Uri-
nary excretion was 0 (Gaillard and Derache, 1965).
After intraperitoneal administration of 1000 mg bodyweight,
the concentration of isoamyl alcohol in blood declined within 5 h
to non-detectable levels. An elimination half-life was not calcu-
lated. For isoamyl alcohol 1.2% was excreted via urine and expired
air. Compared to other amyl alcohols tested by the authors, pri-
mary alcohols were eliminated from the blood more quickly than
secondary and tertiary alcohols (Haggard et al., 1945).
4.6.2. Metabolism
4.6.2.1. Human studies. The glucuronidation of isoamyl alcohol and
other short-chained aliphatic alcohols was investigated in vitro
with human liver microsomes. The V
max
value was 3.3 nmol/min/
mg protein and the Km was determined as 13.3 mM. The glucuron-
idation increased with chain length (C
2
C
5
) of the alcohols studied
(Jurowich et al., 2004).
The rate of oxidation of isoamyl alcohol by human skin alcohol
dehydrogenase was 183.3 nM/mg protein/min (Wilkin and Stew-
art, 1987).
4.6.2.2. Animal studies. A single oral (gavage) dose of 25 mmol/3 kg
rabbit (734.6 mg/kg) of isoamyl alcohol in water was given to
three chinchilla rabbits. Increases in the urinary excretion of glucu-
ronides were monitored. Of the dose, 9% was excreted in the urine
(at 24 h) as the glucuronide. The urine did not contain aldehydes or
ketones (Kamil et al., 1953).
In isolated perfused livers of rats, 65.1 mmol isoamyl alcohol/l
were cytotoxic as evidenced by the release of liver enzymes into
the perfusate. The alcohols decreased the content of ATP in the li-
ver. The content of oxidized glutathione was increased. Lipid per-
oxidation was not observed (Strubelt et al., 1999).
Age-dependent glucuronidation activity was demonstrated
in vitro in the olfactory mucosa of 1 day, 1 week, 2 week, 3 month,
12 month, and 24 month old male Wistar rats with isoamyl alcohol
(Leclerc et al., 2002).
Oxidation to the aldehyde and glucuronidation was demon-
strated for isoamyl alcohol with microsomes from rats pre-treated
with ethanol (Iwersen and Schmoldt, 1995).
The rate of oxidative metabolism of isoamyl alcohol was about
0.1 mmol/g liver in rat liver homogenate and about 0.05 mM/g per-
fused rat liver (Hedlund and Kiessling, 1969).
The Km-values of isoamyl alcohol with alcohol dehydrogenase
from human and horse liver were 0.07 and 0.08 mM, respectively
(Pietruszko et al., 1973).
4.7. Repeated dose toxicity
4.7.1. Subchronic studies
Groups of 10 Ash/CSE rats (5/sex) were administered 500 or
1000 mg/kg of isoamyl alcohol dissolved in corn oil by gavage,
7 days a week for 6 weeks. A group of 10 controls (5/sex) were
administered corn oil alone. Observations included mortality,
behavior, bodyweight, food and water consumption, renal concen-
tration, organ weights, and gross pathology. Blood was examined
for hemoglobin content, packed cell volume, and counts of erythro-
cytes, reticulocytes, as well as total and differential leukocytes. Ser-
um was analyzed for the content of urea, glucose, total protein, and
albumin as well as activities of glutanicoxalacetic and glutamic
pyruvic trasaminases and lactic dehydrogenase. With 500 mg/kg,
a signicant increase in the hemoglobin concentration and red
blood cell count of test females was observed when compared to
the controls, but the increases were not dose-related. With
1000 mg/kg, a lower pituitary weight in males was observed, but
when expressed relative to bodyweight, the decrease was not evi-
dent. At both doses, red patches on the lungs of male and female
treated animals and control animals were found at the necropsy.
Histopathological examination of the lungs revealed lymphocyte
cufng of the bronchi, but the incidence and severity were similar
in both the test and control animals. The authors have concluded
the NOAEL to be 1000 mg/kg in females and 500 mg/kg in males
(Carpanini et al., 1973).
Groups of 20 SPF-Wistar, Chbb:THOM rats (10/sex) were
administered isoamyl alcohol in drinking water at 1000 ppm
(80 mg/kg), 4000 ppm (320 mg/kg), and 16,000 ppm
(1280 mg/kg) for 90 days. A group of 20 controls (10/sex) were
administered drinking water alone. Parameters evaluated included
bodyweight, food and water consumption, clinical signs, mortality,
hematology, clinical chemistry, gross and microscopic pathology.
The erythrocyte count was slightly elevated in males treated with
4000 ppm (320 mg/kg). With 16,000 ppm (1280 mg/kg), an in-
crease in the erythrocyte count, a decrease in the mean corpuscular
volume, and a decrease in the mean corpuscular hemoglobin con-
tent of the blood in male rats were observed. Compared to the con-
trols, a signicant deviation from the control group leukocyte
count was observed in males at 1000 ppm (80 mg/kg), and in the
prothrombin time in females treated with 4000 and 16,000 ppm
(320 and 1280 mg/kg). However, these observed effects did not ap-
pear to be relevant to the treatment. Ectopia of thymus tissue in
the region of the thyroid gland was observed in ve males treated
with 16,000 ppm (1680 mg/kg). The no-observable-adverse-effect-
level (NOAEL) of isoamyl alcohol was concluded to be 4000 ppm
(320 mg/kg) in males and 16,000 ppm (1680 mg/kg) in females
(Schilling et al., 1997; RIFM, 1991).
4.7.2. Chronic studies
Groups of 30 Ash/CSE rats (15/sex) were administered 150, 500,
and 1000 mg/kg of isoamyl alcohol dissolved in corn oil by gavage,
7 days a week for 17 weeks. A group of 30 controls (15/sex) were
administered corn oil alone. Observations included mortality,
behavior, bodyweight, food and water consumption, hematology,
serum analysis, urinalysis, renal concentration, organ weights,
and gross pathology. Microscopic pathology was examined for
the highest dose only. There were no effects associated with treat-
ment in the results of the hematological examinations, serum anal-
yses, urinary cell counts, renal concentration tests, or organ
weights. A slight reduced rate of bodyweight gain at the highest
dose level was shown to be due to a reduced food intake. Two rats
in the highest dose level died, but histopathological examination
showed that these deaths were due to dosing into the lungs and
not to any toxic effects of isoamyl alcohol. A female rat given
500 mg/kg/day developed a lipoma, which was not considered to
S106 D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S102S109
be due to treatment. The other histopathological changes seen
were related to mild infections in the animals and not to isoamyl
alcohol. The NOAEL was concluded to be 1000 mg/kg/day (Carpa-
nini et al., 1973).
Astill et al. (1996) gave 0 (water), 0 (vehicle), 50, 200, or
750 mg/kg bodyweight/day in 0.005% cremophor EL to B6C3F1
mice (50/sex). For 18 months, 5 days a week, animals were treated
with isoamyl alcohol by gavage. Increased mortality, and decreases
in bodyweight gains, and food consumption were observed at
750 mg/kg as well as fatty liver and hyperplasia of the forestomach
epithelium. A systemic NOAEL of 200 mg/kg bodyweight was
determined.
4.8. Reproductive and developmental
Groups of 25 pregnant rats were exposed to a vaporair mixture
of isoamyl alcohol at concentrations of 0.5, 2.5, and 10 mg/l, 6 h/
day from gestation day (GD) 615. In rats exposed to 10 mg/l body-
weight gain was decreased between GD 6 and 9 and increased be-
tween GD 1215, however no biologically relevant or
concentration related differences were apparent among the
groups. At 0.5 mg/l fetal examination revealed skeletal changes:
malformations of the sternebrae and/or the vertebral column. With
2.5 mg/l, the observed fetal anomalies included soft tissue changes
such as a globular shaped heart and dextrocardia, and skeletal
changes: malformations of the sternebrae and/or the vertebral col-
umn. At 10 mg/l observed fetal anomalies included external
changes such as polydactyly and skeletal changes: malformations
of the sternebrae and/or the vertebral column. With all the tested
concentrations, retardations such as incomplete or missing ossi-
cation of hyoid, skull bones, metacarpal or metatarsal bones, verte-
bral bodies, and/or sternebrae were observed. The NOAEL for dams
was 2.5 and 10 mg/l for the fetuses (Klimisch and Hellwig, 1995;
RIFM, 1990a).
As a part of the same experiment, groups of 15 pregnant Hima-
layan rabbits Chbbb:HM per dose were exposed to 0.5, 2.5, and
10 mg/l isoamyl alcohol on gestation days 719. At 10 mg/l a slight
retardation of bodyweight increase was observed throughout the
whole exposure period and was signicant on GD 710. Also, at
10 mg/l an indication of an irritant eye effect (reddish, lid closure,
or slight discharge) was also observed during the exposure period.
In fetuses pseudoankylosis and soft tissue changes such as hypo-
plasia of the gall bladder, bipartite ovary, dilated renal pelvis,
and/or separate origin of carotids were observed at all doses. How-
ever, it was noted that these ndings occurred at a similar inci-
dence rate in historical controls. Observed skeletal changes
included malformations of the sternebrae and/or the vertebral col-
umn, the sternum and the ribs. They were seen in all groups with-
out apparent dose relationships or statistically signicant
differences between the groups. The only signicant differences
of note were due to the increased incidence of two specic types
of soft tissue variation (the separated origin of carotids and traces
of interventricular foramen/septum membranaceum) which oc-
curred without a clear concentration relationship. The NOAEL for
dams was 2.5 and 10 mg/l for the fetuses (Klimisch and Hellwig,
1995; RIFM, 1990b).
4.9. Genotoxicity
4.9.1. In vitro studies
4.9.1.1. Bacterial test systems. Isoamyl alcohol was negative in a
umu test for light absorption in Salmonella typhimurium TA1535/
pSK1002 at concentrations in which growth inhibition was 650%.
However, isoamyl alcohol was positive when tested in a umu test
for luminescence with S. typhimurium TA1535/pTL210 at concen-
trations in which growth inhibition was 650% (Nakajima et al.,
2006).
4.9.1.2. Studies in mammalian cells (see Table 5). A Comet assay was
conducted on human lung carcinoma A549 cells and human
peripheral blood pB cells. Induced DNA damage was only observed
at cytotoxic concentrations of isoamyl alcohol such as 23, 46, and
91 mM (Kreja and Seidel, 2002).
An alkaline single cell gel electrophorese assay (comet assay)
was conducted on Chinese hamster V79 broblasts, and DNA dam-
age induced by isoamyl alcohol was observed at cytotoxic concen-
trations of 23, 46, and 91 mM (Kreja and Seidel, 2002).
A micronucleus assay was conducted on Chinese hamster bro-
blast V79 cells, with isoamyl alcohol at concentrations of 5, 9, and
23 mM in the presence and absence of metabolic activation (S9).
No genotoxic effects were produced at any of the tested concentra-
tions (Kreja and Seidel, 2002).
No mutagenicity was produced in a hypoxanthineguanine
phosphoribosyltransferase (HPRT) assay conducted on Chinese
hamster lung broblast cell line V79, with 51.5 mM of isoamyl
alcohol in the presence or absence of metabolic activation (S9)
(Kreja and Seidel, 2002).
4.9.2. In vivo studies
An in vivo micronucleus assay was conducted with bone mar-
row cells of NMRI mice with isoamyl alcohol at doses of 500,
1000, and 2000 mg/kg. Ten animals (5/sex) were evaluated at 24
and 48 h after a single administration for the occurrence of micro-
nuclei. There was no increase in the frequency of detected micro-
nuclei. Isoamyl alcohol was determined to be non-mutagenic in
the micronucleus assay (RIFM, 2008).
4.10. Carcinogenicity
A group of 15 Wistar rats were administered 0.1 ml/kg (0.1 g/
kg) of isoamyl alcohol by gavage, twice a week up to the time of
their spontaneous deaths. The average total dosage was 27 ml
(27 g). The 25 controls were treated with 1 ml/kg (1 g/kg) of a
0.9% NaCl solution, twice weekly. The animals were weighed at
regular intervals, and most were subjected to hematological test-
ing. At the time of spontaneous death, a necropsy, histological
examinations of all organs, vertebrae, and femur, and additional
hematological tests were conducted. The average survival time of
the control animals was 643 days. A wide spectrum of tumors
was observed from bladder carcinoma, carcinoma of the kidney
pelvis, adenocarcinoma of the proventriculum to benign tumors
such as papillomae and occasional incipient inltrative growth.
The number of malignant and benign tumors found was 0 and 3,
Table 5
Summary of studies in mammalian cells.
Test system Concentration (mM) Results References
Comet assay Human lung carcinoma A549 cells 23, 46, and 91 Not genotoxic Kreja and Seidel (2002)
Comet assay Human lung peripheral blood pB cells 46 and 91 Not genotoxic Kreja and Seidel (2002)
Comet assay Chinese hamster broblast V79 cells 23 and 91 Not genotoxic Kreja and Seidel (2002)
Micronucleus assay Chinese hamster broblast V79 cells 5, 9, and 23 Not genotoxic Kreja and Seidel (2002)
HPRT assay Chinese hamster lunch broblast V79 cells 51.5 Not genotoxic Kreja and Seidel (2002)
D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S102S109 S107
respectively. The average survival time of test animals was
527 days, and the number of malignant and benign tumors found
was 4 and 3, respectively (Gibel et al., 1975).
As a part of the same experiment group of 24 Wistar rats were
subcutaneously administered 0.04 ml/kg (0.04 g/kg) of isoamyl
alcohol, once a week up to the time of their spontaneous deaths.
The average total dosage was 3.8 ml (3.8 g/kg). The controls were
subcutaneously treated with 1 ml/kg (1 g/kg) of a 0.9% NaCl solu-
tion, twice weekly. The average survival time of the control ani-
mals was 643 days, and the number of malignant and benign
tumors found was 0 and 2, respectively. The average survival time
of test animals was 592 days, and the number of malignant and be-
nign tumors found was 10 and 5, respectively. The tumors con-
sisted of pancreas adenomas, adenomas of the proventriculus
and of suprarenal glands, spleen bromas to the benign small pap-
illomas or broadenomas (Gibel et al., 1975).
4.11. Neurotoxicity
Male albino SPF rats derived from the Wistar strain, or female
mice of the H strain were used to study the neurotoxicity of iso-
amyl alcohol. Whole body exposures were carried out in 80-l glass
chambers with 1 rat or 2 mice. In total 16 rats (4/group) or 32 mice
were exposed. Less than 1 min after removal from the exposure
box, a short electrical impulse was applied through ear electrodes
to the animals to measure the biological effect of isoamyl alcohol.
Of the six time characteristics recorded, duration of toxic extension
of hind limbs was measured, as this was considered the most sen-
sitive and reproducible response measures. All animals were given
three control tests at weekly intervals before the 1st exposure.
Most animals went through 34 exposure to each concentration,
and the interval between exposures was at least 3 weeks. The con-
centration that evoked a 30% depression in the recorded activity
(M) was determined to be 1700 ppm in rats and 950 ppm in mice
(Frantik et al., 1994).
Male SpragueDawley rats were divided into groups of four or
ve and orally administered 325 mg/kg of isoamyl alcohol. Two
hours after administration acetylcholine, 3,4-dihydroxyphenylala-
nine (DOPA), dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC),
homovanillic acid (HVA), norepinephrine, 3-methoxy-4-hydroxy-
phenylglycol (MHPG), serotonin, and 5-hydroxyindoleacetic acid
(5HIAA) contents in the small-brain regions were measured. Under
the conditions of this study, a single dose of 325 mg/kg adminis-
tered by gavage to rats resulted in increases in 5HIAA in the mid-
brain and MHPG in the medulla oblongata. Decreases occurred in
norepinephrine in the midbrain and in 5HIAA in the hypothalamus
(Kanada et al., 1994).
This individual Fragrance Material Review is not intended as a
stand-alone document. Please refer to A Safety Assessment of
Branched Chain Saturated Alcohols When Used as Fragrance Ingre-
dients (Belsito et al., 2010) for an overall assessment of this
material.
Conict of interest statement
This research was supported by the Research Institute for Fra-
grance Materials, an independent research institute that is funded
by the manufacturers of fragrances and consumer products con-
taining fragrances. The authors are all employees of the Research
Institute for Fragrance Materials.
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