910. Esters/aliphatic acyclic prim. alcohols/aliphatic linear saturated carb. acids (WHO Food Additives Series 40)

INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

WORLD HEALTH ORGANIZATION

SAFETY EVALUATION OF CERTAIN
FOOD ADDITIVES AND CONTAMINANTS

WHO FOOD ADDITIVES SERIES 40

Prepared by:
The forty-ninth meeting of the Joint FAO/WHO Expert
Committee on Food Additives (JECFA)

World Health Organization, Geneva 1998

ESTERS OF ALIPHATIC ACYCLIC PRIMARY ALCOHOLS WITH ALIPHATIC LINEAR
SATURATED CARBOXYLIC ACIDS

First draft prepared by
Dr J. Gry,
Institute of Toxicology, National Food Agency of Denmark
Ministry of Food, Agriculture and Fisheries
Soborg, Denmark

1. Evaluation
1.1 Introduction
1.2 Estimated daily per capita intake
1.3 Absorption, metabolism and elimination
1.4 Application of the Procedure for the Safety Evaluation of
Flavouring Agents
1.5 Consideration of combined intakes
1.6 Conclusions
2. Relevant background information
2.1 Explanation
2.2 Intake data
2.3 Biological data
2.3.1 Absorption and metabolism
2.3.2 Toxicological studies
2.3.2.1 Acute toxicity
2.3.2.2 Short-term toxicity
2.3.2.3 Long-term toxicity
2.3.2.4 Genotoxicity
2.3.2.5 Reproductive toxicity
2.3.2.6 Developmental toxicity
3. References

1. EVALUATION

1.1 Introduction

The Committee evaluated a group of esters of 67 aliphatic linear
and branched-chain saturated and monounsaturated primary alcohols and
aliphatic linear saturated carboxylic acids using the Procedure for
the Safety Evaluation of Flavouring Agents (the "Procedure") (see
Figure 1 and Table 1).

One member of the group, butyl acetate, was previously evaluated
at the eleventh meeting, when the Committee was unable to establish an
ADI due to a lack of data (Annex 1, reference 14).

Table 1. Summary of results of safety evaluations on esters of aliphatic acyclic primary alcohols and aliphatic linear saturated
carboxylic acids

Step 1: 2-Ethylbutyl acetate is in structural Class II, the human intake threshold of which is 540 µg per day. All of the other
substances in the group are in structural Class I, the human intake threshold of which is 1800 µg per day.
Step 2: cis-3-/trans-2-hexenyl propionate is postponed. All of the other substances in this group are metabolized to innocuous
products.

No. Substance Step A3 Step A4 Comments Conclusion based
Does intake exceed the Endogenous or on current levels
human intake threshold?¹ metabolized to of intake
Intake estimates endogenous
(µg/person per day) substances?

0117 Propyl formate No No safety concern
USA: 0.38 Europe: 5.0
0118 Butyl formate No No safety concern
USA: 0.17 Europe: 21
0119 n-Amyl formate No No safety concern
USA: 110 Europe: 29
0120 Hexyl formate No No safety concern
USA: 8.0 Europe: 8.7
0121 Heptyl formate No No safety concern
USA: 0.10 Europe: 0.00
0122 Octyl formate No No safety concern
USA: 0.95 Europe: 0.14
0123 cis-3-Hexenyl formate No No safety concern
USA: 1.7 Europe: 43
0124 Isobutyl formate No No safety concern
USA: 1.5 Europe: 4.7
0125 Methyl acetate No No safety concern
USA: 110 Europe: 460
0126 Propyl acetate No No safety concern
USA: 440 Europe: 180
0127 Butyl acetate No No safety concern
USA: 170 Europe: 1200

Table 1. Continued...

0128 Hexyl acetate Yes Yes Hexanoic acid, the metabolite No safety concern
USA: 160 Europe: 3200 of the component hexyl alcohol,
and acetic acid are endogenous
0129 Heptyl acetate No No safety concern
USA: 2.3 Europe: 56
0130 Octyl acetate No No safety concern
USA: 9.5 Europe: 83
0131 Nonyl acetate No No safety concern
USA: 2.5 Europe: 6.6
0132 Decyl acetate No No safety concern
USA: 21 Europe: 7.3
0133 Lauryl acetate No No safety concern
USA: 0.57 Europe: 9.3
0134 cis-3-Hexenyl acetate No No safety concern
USA: 57 Europe: 640
0135 trans-3-Heptenyl
acetate No No safety concern
USA: 0.76 Europe: 0.24
0136 10-Undecen-1-yl
acetate No No safety concern
USA: 0.10 Europe: 0.83
0137 Isobutyl acetate No No safety concern
USA: 1300 Europe: 1200
0138 2-Methylbutyl acetate No No safety concern
USA: 360 Europe: 130
0140 2-Ethylbutyl acetate No No safety concern
USA: 0.17 Europe: 4.0
0141 Methyl propionate No No safety concern
USA: 30 Europe: 9.3

Table 1. Continued...

0142 Propyl propionate No No safety concern
USA: 44 Europe: 9.6
0143 Butyl propionate No No safety concern
USA: 1.1 Europe: 10
0144 Hexyl propionate No No safety concern
USA: 3.0 Europe: 5.7
0145 Octyl propionate No No safety concern
USA: 0.02 Europe: 0.00
0146 Decyl propionate No No safety concern
USA: 0.95 Europe: 0.00
0147 cis-3- & trans-2-
Hexenyl propionate Postponed, pending consideration
USA: 430 Europe: 0.00 on alpha, beta-unsaturated
carbonyl compounds²
0148 Isobutyl propionate No No safety concern
USA: 6.5 Europe: 12
0149 Methyl butyrate No No safety concern
USA: 44 Europe: 220
0150 Propyl butyrate No No safety concern
USA: 38 Europe: 75
0151 Butyl butyrate No No safety concern
USA: 63 Europe: 390
0152 n-Amyl butyrate No No safety concern
USA: 200 Europe: 450
0153 Hexyl butyrate No No safety concern
USA: 27 Europe: 110
0154 Heptyl butyrate No No safety concern
USA: 3.8 Europe: 6.0
0155 Octyl butyrate No No safety concern
USA: 0.38 Europe: 16

Table 1. Continued...

0156 Decyl butyrate No No safety concern
USA: 0.08 Europe: 0.00
0157 cis-3-Hexenyl butyrate No No safety concern
USA: 4.8 Europe: 160
0158 Isobutyl butyrate No No safety concern
USA: 7.4 Europe: 47
0159 Methyl valerate No No safety concern
USA: 11 Europe: 30
0160 Butyl valerate No No safety concern
USA: 0.10 Europe: 3.7
0161 Propyl hexanoate No No safety concern
USA: 0.17 Europe: 14
0162 Butyl hexanoate No No safety concern
USA: 1.9 Europe: 15
0163 n-Amyl hexanoate No No safety concern
USA: 8.8 Europe: 8.7
0164 Hexyl hexanoate No No safety concern
USA: 13 Europe: 150
0165 cis-3-Hexenyl
hexanoate No No safety concern
USA: 1.3 Europe: 42
0166 Isobutyl hexanoate No No safety concern
USA: 1.7 Europe: 6.1
0167 Methyl heptanoate No No safety concern
USA: 0.10 Europe: 5.7
0168 Propyl heptanoate No No safety concern
USA: 0.38 Europe: 0.14
0169 Butyl heptanoate No No safety concern
USA: 4.4 Europe: 0.00

Table 1. Continued...

0170 n-Amyl heptanoate No No safety concern
USA: 0.02 Europe: 0.61
0171 Octyl heptanoate No No safety concern
USA: 0.38 Europe: 0.21
0172 Isobutyl heptanoate No No safety concern
USA: 1.9 Europe: 0.01
0173 Methyl octanoate No No safety concern
USA: 0.17 Europe: 9.7
0174 n-Amyl octanoate No No safety concern
USA: 1.9 Europe: 3.4
0175 Hexyl octanoate No No safety concern
USA: 0.95 Europe: 1.3
0176 Heptyl octanoate No No safety concern
USA: 0.95 Europe: 0.71
0177 Octyl octanoate No No safety concern
USA: 2.3 Europe: 0.03
0178 Nonyl octanoate No No safety concern
USA: 0.95 Europe: 0.14
0179 Methyl nonanoate No No safety concern
USA: 2.3 Europe: 0.86
0180 Methyl laurate No No safety concern
USA: 0.76 Europe: 5.1
0181 Butyl laurate No No safety concern
USA: 0.10 Europe: 0.00
0182 Isoamyl laurate No No safety concern
USA: 0.57 Europe: 0.14
0183 Methyl myristate No No safety concern
USA: 46 Europe: 62
0184 Butyl stearate No No safety concern
USA: 5.5 Europe: 5.1

Table 1. Continued...

¹ The human intake threshold for Class I is 1800 µg per day; 540 µg per day for Class II; and 90 µg per day for Class III
² One of the predicted main metabolites of trans-2-hexenyl propionate is trans-2-hexenol which would be oxidized to the
alpha,ß-unsaturated substance, trans-2-hexenal

1.2 Estimated daily per capita intake

The total annual volume of the 67 esters in this group is
approximately 19 tonnes in the USA and 65 tonnes in Europe. In the USA
more than 70% of the total annual volume is accounted for by five
substances, amyl butyrate, cis-3- & trans-2-hexenyl propionate,
and the acetate esters of propyl alcohol, isobutyl alcohol and
2-methylbutyl alcohol. In Europe, more than 75% of the total annual
volume is accounted for by seven substances, butyl butyrate, amyl
butyrate and the acetate esters of methyl alcohol, butyl alcohol,
hexyl alcohol, cis-3-hexenol and isobutyl alcohol. Based on the
reported annual volumes in the USA and Europe, the total estimated
daily per capita intakeof the 67 esters of aliphatic acyclic primary
alcohols and aliphatic linear saturated carboxylic acids used as
flavouring agents is 3.8 mg per capita per day in the USA and 9.2 mg
per capita per day in Europe. The use of 7 of the esters (heptyl
formate, octyl propionate, decyl propionate, decyl butyrate, butyl
heptanoate, butyl dodecanoate, cis-3- & trans-2-hexenyl
propionate) has been reported in the USA but not in Europe.

Esters of aliphatic acyclic primary alcohols and aliphatic linear
saturated carboxylic acids are principal components of alcoholic
beverages and a wide variety of fruits. Quantitative data on the
natural occurrence in food have been reported for 37 substances in the
group. In the USA, it is indicated that intake of these substances
from natural sources exceeds intake from their use as flavouring
agents.

1.3 Absorption, metabolism and elimination

In general, aliphatic linear and branched-chain esters of
aliphatic linear saturated carboxylic acids are anticipated to be
hydrolysed to their component alcohols and carboxylic acids. The
metabolism of the saturated acids and alcohols is considered in the
introduction to this chapter on flavouring agents.

The three monounsaturated alcohols in this group of esters are all
anticipated to be oxidized via their corresponding aldehydes to their
carboxylic acids, which are then metabolized in the fatty acid ß-
oxidation and other well-known metabolic pathways.

1.4 Application of the Procedure for the Safety
Evaluation of Flavouring Agents

The stepwise evaluations of the 67 esters of aliphatic acyclic
primary alcohols and linear saturated aliphatic carboxylic acids used
as flavouring substances are summarized in Table 1.

Step 1. The assignment of the structural class is the first step
in the sequence. All but one of the 67 esters of aliphatic acyclic
primary alcohols and linear saturated aliphatic carboxylic acids were
classified in structural Class I. 2-Ethylbutyl acetate contains a
sterically hindered functional group and therefore is in Class II.

Step 2. At this step evaluation of one substance, cis-3- and
trans-2-hexenyl propionate, was postponed, pending consideration of
alpha,ß-unsaturated carbonyl compounds.

The available data indicate that the esters in this group would be
hydrolysed in humans to their component alcohols and carboxylic acids.
The aliphatic acyclic primary alcohols are oxidized to their
corresponding carboxylic acids, which are either conjugated and
excreted in the urine, or undergo ß-oxidation and cleavage. The
aliphatic linear saturated carboxylic acids are endogenous in humans.
At current levels of per capita intake these esters would not be
expected to saturate the metabolic pathways. Therefore, the response
to Step 2 for each of the remaining 66 esters of aliphatic acyclic
primary alcohols and aliphatic linear saturated carboxylic acids is
"yes".

Step A3. The human intake threshold for structural Class I is 1800
µg/person per day. Sixty-four (64) of the 65 Class I esters in this
group have USA and European daily per capita intake levels less
than 1800 µg/person per day (see Table 1). Only hexyl acetate has an
intake greater than 1800 µg/person per day. 2-Ethylbutyl acetate is a
Class II substance for which intake levels in the USA and Europe are
below the intake threshold of 540 µg/person per day.

Step A4. This step must be considered only for hexyl acetate, the
only substance in this group with an estimated intake level that
exceeds the Class I threshold. The component hexyl alcohol is oxidized
to hexanoic acid which is endogenous as an intermediary metabolite in
the fatty acid pathway and acetate is a component of the tricarboxylic
acid cycle. In the opinion of the Committee the endogenous levels of
these two metabolites would not give rise to perturbations outside the
physiological range. Therefore, hexyl acetate was also determined to
be of no safety concern based on its structural class and known
metabolism.

Based on results of the safety evaluation sequence, 66 esters of
aliphatic acyclic primary alcohols and aliphatic linear saturated
carboxylic acids evaluated do not pose a safety concern when used at
current levels of intake as flavouring agents. One substance, cis-3-
& trans-2-hexenyl propionate was postponed, pending consideration on
alpha,ß-unsaturated carbonyl compounds.

1.5 Consideration of combined intakes

In the unlikely event that all foods containing all the 66 esters
evaluated were consumed simultaneously the estimated daily per
capita intake in the USA and Europe would exceed the human intake
threshold for substances in class I. All the flavouring agents in this
group of esters are expected to be metabolized via well known
biochemical pathways to innocuous metabolic and/or endogenous
substances and in the opinion of the Committee the endogenous levels
of these metabolites would not give rise to perturbations outside the

physiological range. Accordingly, even a combined theoretical intake
would be of no safety concern.

1.6 Conclusions

The Committee concluded that the substances in this group would
not present safety concerns at the current levels of intake.

No toxicity data were required for the application of the
Procedure for this group of esters. The Committee noted that the
available toxicity data were consistent with the results of the safety
evaluation using the Procedure.

2. RELEVANT BACKGROUND INFORMATION

2.1 Explanation

Ten linear saturated primary alcohols in a homologous series from
C₁ to C₁₂ are components of 51 esters in this group of 67 esters
(see Table 2). Seven esters contain four different aliphatic linear
unsaturated primary alcohols, five of which include
cis-3-hexen-1-ol. The remaining nine esters contain four different
saturated branched-chain primary alcohols, six of which include
isobutyl alcohol. Twelve aliphatic linear saturated carboxylic acids
in a homologous series from C₁ to C₁₈ are acid components of the 67
esters. There is a significant amount of structural uniformity among
the alcohol and carboxylic acid components of the 67 esters.

In the USA, the esters of aliphatic acyclic primary alcohols and
aliphatic linear saturated carboxylic acids are generally used as
flavouring substances up to average maximum levels of 200 mg/kg.
Higher levels of use (up to 3000 mg/kg) are permitted in food
categories such as chewing gum and hard candy. In Europe the upper use
levels for these flavouring substances are generally 1 to 30 mg/kg
foods and in special food categories like candy and alcoholic
beverages up to 300 mg/kg foods (CE, 1992; SCF, 1995).

2.2 Intake data

The annual volumes of the 67 esters of this group in Europe (IOFI,
1995) and in the USA (NAS, 1987) are given in Table 2.

Table 2. Most recent reported annual usage in Europe and USA

Substance Most recent Per capita intake²
annual volume¹ (kg) µg/day µg/kg bw per day

Propyl formate
USA 2.0 0.38 0.01
Europe 35 5.0 0.08

Butyl formate
USA 0.9 0.17 0.00
Europe 150 21 0.34

n-Amyl formate
USA 570 110 1.8
Europe 200 29 0.48

Hexyl formate
USA 42 8.0 0.13
Europe 61 8.7 0.15

Heptyl formate
USA 0.5 0.10 0.00
Europe 0.0 0.00 0.00

Octyl formate
USA 5.0 0.95 0.02
Europe 1.0 0.14 0.00

cis-3-Hexenyl formate
USA 9.0 1.7 0.03
Europe 300 43 0.71

Isobutyl formate
USA 8.0 1.5 0.03
Europe 33 4.7 0.08

Methyl acetate
USA 600 110 1.9
Europe 3300 460 7.7

Propyl acetate
USA 2300 440 7.4
Europe 1300 180 3.1

Butyl acetate
USA 870 170 2.8
Europe 8400 1200 20

Table 2. Continued...

Substance Most recent Per capita intake²
annual volume¹ (kg) µg/day µg/kg bw per day

Hexyl acetate
USA 840 160 2.7
Europe 23000 3200 54

Heptyl acetate
USA 12 2.3 0.04
Europe 390 56 0.93

Octyl acetate
USA 50 9.5 0.16
Europe 590 83 1.4

Nonyl acetate
USA 13 2.5 0.04
Europe 46 6.6 0.11

Decyl acetate
USA 110 21 0.35
Europe 51 7.3 0.12

Lauryl acetate
USA 3.0 0.57 0.01
Europe 65 9.3 0.15

cis-3-Hexenyl acetate
USA 300 57 0.95
Europe 4500 640 11

trans-3-Heptenyl
acetate
USA 4.0 0.76 0.01
Europe 1.7 0.24 0.00

10-Undecen-1-yl
acetate
USA 0.5 0.10 0.00
Europe 5.8 0.83 0.01

Isobutyl acetate
USA 6600 1300 21
Europe 8100 1200 19

2-Methylbutyl acetate
USA 1900 360 6.0
Europe 900 130 2.1

Table 2. Continued...

Substance Most recent Per capita intake²
annual volume¹ (kg) µg/day µg/kg bw per day

2-Ethylbutyl acetate
USA 0.9 0.17 0.00
Europe 28 4.0 0.07

Methyl propionate
USA 160 30 0.51
Europe 65 9.3 0.15

Propyl propionate
USA 230 44 0.73
Europe 67 9.6 0.16

Butyl propionate
USA 6.0 1.1 0.02
Europe 72 10 0.17

Hexyl propionate
USA 16 3.0 0.05
Europe 40 5.7 0.10

Octyl propionate
USA 0.1 0.02 0.00
Europe 0.0 0.00 0.00

Decyl propionate
USA 5.0 0.95 0.02
Europe 0.0 0.00 0.00

cis-3- & trans-2-
Hexenyl propionate
USA 2300 430 7.2
Europe 0.0 0.00 0.00

Isobutyl propionate
USA 34 6.5 0.11
Europe 86 12 0.20

Methyl butyrate
USA 230 44 0.73
Europe 1500 220 3.6

Propyl butyrate
USA 200 38 0.63
Europe 520 75 1.2

Table 2. Continued...

Substance Most recent Per capita intake²
annual volume¹ (kg) µg/day µg/kg bw per day

Butyl butyrate
USA 330 63 1.1
Europe 2700 390 6.5

n-Amyl butyrate
USA 1000 200 3.3
Europe 3100 450 7.5

Hexyl butyrate
USA 140 27 0.44
Europe 750 110 1.8

Heptyl butyrate
USA 20 3.8 0.06
Europe 42 6.0 0.10

Octyl butyrate
USA 2.0 0.38 0.01
Europe 112 16 0.27

Decyl butyrate
USA 0.4 0.08 0.00
Europe 0.0 0.00 0.00

cis-3-Hexenyl
butyrate
USA 25 4.8 0.08
Europe 1100 160 2.7

Isobutyl butyrate
USA 39 7.4 0.12
Europe 330 47 0.78

Methyl valerate
USA 60 11 0.19
Europe 210 30 0.50

Butyl valerate
USA 0.5 0.10 0.00
Europe 26 3.7 0.06

Propyl hexanoate
USA 0.9 0.17 0.00
Europe 96 14 0.23

Table 2. Continued...

Substance Most recent Per capita intake²
annual volume¹ (kg) µg/day µg/kg bw per day

Butyl hexanoate
USA 10 1.9 0.03
Europe 100 15 0.24

n-Amyl hexanoate
USA 46 8.8 0.15
Europe 61 8.7 0.15

Hexyl hexanoate
USA 70 13 0.22
Europe 1000 150 2.4

cis-3-Hexenyl
hexanoate
USA 7.0 1.3 0.02
Europe 290 42 0.69

Isobutyl hexanoate
USA 9.0 1.7 0.03
Europe 43 6.1 0.10

Methyl heptanoate
USA 0.5 0.10 0.00
Europe 40 5.7 0.10

Propyl heptanoate
USA 2.0 0.38 0.01
Europe 1.0 0.14 0.00

Butyl heptanoate
USA 23 4.4 0.07
Europe 0.0 0.00 0.00

n-Amyl heptanoate
USA 0.1 0.02 0.00
Europe 4.3 0.61 0.01

Octyl heptanoate
USA 2.0 0.38 0.01
Europe 1.5 0.21 0.00

Isobutyl heptanoate
USA 10 1.9 0.03
Europe 0.1 0.01 0.0002

Table 2. Continued...

Substance Most recent Per capita intake²
annual volume¹ (kg) µg/day µg/kg bw per day

Methyl octanoate
USA 0.9 0.17 0.003
Europe 68 9.7 0.16

n-Amyl octanoate
USA 10 1.9 0.03
Europe 24 3.4 0.06

Hexyl octanoate
USA 5.0 0.95 0.02
Europe 9.0 1.3 0.02

Heptyl octanoate
USA 5.0 0.95 0.02
Europe 5.0 0.71 0.01

Octyl octanoate
USA 12 2.3 0.04
Europe 0.2 0.03 0.00

Nonyl octanoate
USA 5.0 0.95 0.02
Europe 1.0 0.14 0.00

Methyl nonanoate
USA 12 2.3 0.04
Europe 6.0 0.86 0.01

Methyl laurate
USA 4.0 0.76 0.01
Europe 36 5.1 0.09

Butyl laurate
USA 0.5 0.10 0.00
Europe 0.0 0.00 0.00

Isoamyl laurate
USA 3.0 0.57 0.01
Europe 1.0 0.14 0.00

Methyl myristate
USA 240 46 0.76
Europe 440 62 1.0

Table 2. Continued...

Substance Most recent Per capita intake²
annual volume¹ (kg) µg/day µg/kg bw per day

Butyl stearate
USA 29 5.5 0.09
Europe 36 5.1 0.09

Total
USA 20000 3800 63
Europe 65000 9200 150

¹ USA: National Academy of Science (NAS, 1987) Evaluating the safety
of food chemicals. Washington DC. Respondants to the annual NAS survey
were requested to report annual poundages of < 1.0 lbs to two digits
past the decimal point. Europe: International Organization of the
Flavor Industry (IOFI; 1995) European inquiry on volume of use.
Private communication to FEMA.

² Intake calculated as follows: [[(annual volume, kg) x (1 x 109
µg/kg)]/[population x 0.6 x 365 days]], where population (10%, "eaters
only") = 24 x 106 for the USA and 32 x 106 for Europe; 0.6 represents
the assumption that only 60% of the flavor volume was reported in the
survey (NAS, 1987; IOFI, 1995). Intake (µg/kg bw/d) calculated as
follows: [(µg/d)/body weight], where body weight = 60 kg. Slight
variations may occur from rounding off.

2.3 Biological data

2.3.1 Absorption and metabolism

Generally, linear and branched-chain alkyl esters are hydrolysed
to their component alcohols and carboxylic acids in the intestinal
tract, blood and most tissues throughout the body, as described in the
introduction to this chapter on flavouring agents. For this group of
esters this is further supported by a series of in vitro hydrolysis
studies on butyl acetate and structurally related esters as reported
in Table 3.

Following hydrolysis the component alcohols and carboxylic acids
are metabolized as considered above (section 1.3) and in the
introduction to this chapter on flavouring agents.

Table 3. Hydrolysis data for esters of aliphatic acyclic primary alcohols with aliphatic linear saturated carboxylic acids

Ester Artificial Artificial Rat liver Rat small % Hydrolysis % Hydrolysis
gastric juice¹ pancreatic preparation¹ intestinal after 2 hours after 4 hours
t_0.5 (min) juice¹ t_0.5 (min) t_0.5 (sec) mucosa¹ t_0.5 (sec)

Butyl acetate 318 66.0 491 108 23², 72³ 41², 92³
Ethyl acetate⁸ not reported not reported not reported not reported 100⁴ not reported
Ethyl butyrate⁸ 490 5.67 not reported not reported 15², 100⁵ not reported
Ethyl hexanoate⁸ 293 3.47 0.1 0.5 not reported not reported
Ethyl heptanoate⁸ 770 9.78 0.2 0.6 10², 100³ 19²
Ethyl nonanoate⁸ 177 5.92 not reported not reported 37², 100⁵ 61²
Ethyl laurate⁸ 640 6.10 not reported not reported 12², 100⁵ 23²
Ethyl decanoate⁸ not reported not reported not reported not reported 80^6,7 not reported
Isopropyl butyrate⁸ not reported not reported not reported not reported 40^4,6 not reported
Isoamyl acetate⁸ not reported not reported not reported not reported 20⁶, 100⁴ not reported
Isoamyl butyrate⁸ 660 11.3 0.5 0.1 12², 100³ 22²
Isoamyl hexanoate⁸ 146 37.8 not reported not reported not reported not reported
Allyl hexanoate 1120 1.98 4.0 0.1 100⁷ not reported
Citronellyl acetate not reported not reported not reported not reported 100⁷ not reported

¹ Longland et al., 1977
² In artificial gastric juice. Gangolli & Shilling, 1968
³ In artificial pancreatic juice. Gangolli & Shilling, 1968
⁴ In whole homogenate of pig jejunum. Grundschober, 1977
⁵ In artificial pancreatic juice after only 1 hour. Gangolli & Shilling, 1968
⁶ By pancreatin. Leegwater & van Straten, 1974
⁷ By pancreatin. Grundschober, 1977
⁸ Structurally related ester

2.3.2 Toxicological studies

2.3.2.1 Acute toxicity

Oral acute toxicity studies have been reported for 51 of the 67
esters of aliphatic acyclic primary alcohols and aliphatic linear
saturated carboxylic acids. The very low oral acute toxicity of this
group of esters is demonstrated by oral LD₅₀ values greater than 1850
mg/kg bw (e.g., Smyth et al., 1954).

2.3.2.2 Short-term toxicity

Results of short-term toxicity studies for 6 of the 67 esters and
for some structurally related esters and selected hydrolysis products
are summarized in Table 4. Available short-term toxicity studies on
the esters and on some of their component alcohols are described in
more detail below.

a) Methyl octanoate

Methyl octanoate was diluted in cotton-seed oil and incorporated
into the diet of groups of 15 male and 15 female FDRL rats for 90
days. The dosage levels were 3.2 and 3.6 mg/kg bw per day for males
and females, respectively. Observations included food consumption,
body weight, haematology, blood chemical determinations, liver and
kidney weights and histological examination. No treatment-related
adverse effects were reported (Oser et al., 1965).

b) Methyl butyrate, octanoate and dodecanoate

In a limited 12-week study with only one dose level, groups of up
to 10 male and up to 10 female USC strain-rats were given a daily oral
dose of 100 mg methyl butyrate, methyl octanoate, methyl dodecanoate
or the structurally-related esters methyl hexanoate, methyl decanoate
and methyl tetradecanoate as part of a fat-free diet. The study was
designed to evaluate the influence of aliphatic esters on endogenous
levels of lipids and cholesterol in rats maintained on fat-free diets.
A statistically significant decrease in weight gain occurred in males
treated with methyl octanoate. A statistically significant increase
was observed in the liver cholesterol level of males given methyl
laurate, but was not accompanied by an increase in total plasma
cholesterol when compared with controls. No microscopic examination
was reported (Alfin-Slater et al., 1965).

c) Amyl butyrate, and structurally-related ethyl esters

Groups of 10 male and 10 female Osborne-Mendel rats were
maintained on diets containing either amyl butyrate or the
structurally related esters ethyl formate or ethyl pentanoate at
concentrations of 1000, 2500 or 10 000 mg/kg (equivalent to 50, 250 or
500 mg/kg bw per day) for 16-17 weeks. Additionally,

Table 4. Short-term toxicity studies for esters of aliphatic acyclic primary alcohols with aliphatic linear saturated
carboxylic acids and structurally-related substances

Substance Species, sex Route Time NOEL1 Reference
(days) (mg/kg bw per day)

Ethyl formate Rat, m & f Oral 119 >500 Hagan et al., 1967
Ethyl acetate² Rat, m & f Oral 371-392 >4³ Johannsen & Purchase, 1969
Butyl acetate Rat Oral 180 >0.5 Petrovskaya & Bul'bin, 1969
Octyl acetate Rat, m & f Gavage 91 weeks >1000⁴ Daughtrey et al., 1989a
Methyl butyrate Rat, m & f Oral 84 >300^3,5 Alfin-Slater et al., 1965
Amyl butyrate Rat Oral 112 >500 Hagan et al., 1967
Ethyl pentanoate² Rat, m & f Oral 119 >500 Hagan et al., 1967
Methyl hexanoate² Rat, m & f Oral 84 >300^3,5 Alfin-Slater et al., 1965
Ethyl heptanoate² Rat, m & f Oral 90 >500 Hagan et al., 1967
Methyl octanoate Rat, m & f Oral 84 >300 Alfin-Slater et al., 1965
Methyl octanoate Rat, m & f Oral 90 >3.6³ Oser et al., 1965
Ethyl nonanoate² Rat, m & f Oral 112 >500 Hagan et al., 1967
Ethyl nonanoate² Rat, m & f Oral 112 >1000³ FDA, 1954
Methyl decanoate² Rat, m & f Oral 84 >300^3,5 Alfin-Slater et al., 1965
Methyl laurate Rat, m & f Oral 84 >300^3,5 Alfin-Slater et al., 1965
Methyl myristate² Rat, m & f Oral 84 >300 Alfin-Slater et al., 1965
Isobutyl isobutyrate² Rats, m & f Gavage 126 >1000 Drake et al., 1978
3-Methylbutyl alcohol² Rat, m & f Gavage 119 >1000 Carpanini et al., 1973
2-Methyl-1-propanol² Rat, m & f Oral 90 >1450 BASF, 1992
Hexyl alcohol² Rat, m & f Oral 90 577⁶ Eibert, 1992
cis-3-Hexenol² Rat, m & f Oral 98 120-150 Gaunt et al., 1969

¹ A NOEL reported in this table as "greater than" (>) indicates that no adverse effects were observed at the highest dose
level in the study, and therefore an actual NOEL was not obtained.
² A structurally related substance to the group
³ Only one dose level
⁴ Increased liver weights in high-dose (1000 mg/kg bw) and intermediate-dose (500 mg/kg bw) groups and mild nephropathy
in the high-dose males were judged by the authors to be of minimal toxicological significance.
⁵ No histopathology reported
⁶ No statistical analysis of data
⁷ Only 2 males and 2 females per dose.

ethyl heptanoate was tested at concentrations of 1000 and 10 000 mg/kg
diet for 13 weeks, and ethyl nonanoate was tested for 16 weeks at 10
000 mg/kg diet in groups of 5 males and 5 females. There were no
effects on growth or haematology in any of the groups, and no
macroscopic abnormalities at any dose level. Microscopic examination
was performed on tissues from the 10 000 mg/kg groups which revealed
no changes (Hagan et al., 1967).

d) Butyl acetate

Butyl acetate was orally administered to 40 white rats at dose
levels of 0, 0.005, 0.05 and 0.5 mg/kg bw per day for six months.
Animals in the control group, and eight animals in the high-dose group
underwent pathomorphological examination at the end of the study. No
changes in the internal organs of the animals were reported
(Petrovskaya & Bul'bin, 1969).

e) Octyl acetate

Groups of 20 male and 20 female Sprague-Dawley rats received
undiluted octyl acetate by gavage at doses of 100, 500 or 1000 mg/kg
bw per day, 5 days per week, for 13 weeks. Control rats received
distilled water at a dose of 1000 mg/kg bw per day. After 45 days of
dosing, five animals per group were sacrificed and necropsied. There
were no statistically significant differences in mean haematology
values between the test and control animals. Serum chemistry values
showed no evidence of any treatment-related effects. Gross necropsy
showed no indication of any significant treatment-related effects.

After 13 weeks, the remaining animals were sacrificed and
necropsied. Body weights were slightly lower for high-dose male and
female rats as compared to controls, but were generally not
statistically significant. This was therefore considered by the
authors to be a borderline treatment-related effect. Similarly, mean
food consumption values for high-dose males and females were slightly
lower than controls but, in general, were not statistically
significant. This finding paralleled the changes in body weight.

In the high-dose group, there was an increase in the relative
liver and kidney weights in males and females. An increase in the
relative liver weight was also evident in the mid-dose group in both
sexes. All other organ weights were normal. The increased liver
weights of rats were not associated with liver pathology or
hepatotoxicity as reflected by microscopic examination and serum
enzyme parameters, respectively. The authors attributed the effect to
a compensatory response of the liver to an increased metabolic load
from the exogenous octyl acetate and not a reflection of true
hepatotoxicity. This type of compensatory response to exogenous
substances was reported previously by Golberg (Golberg, 1966). The
increased liver weights in the high-dose and intermediate-dose animals
were judged by the authors to be of minimal toxicological
significance.

Mild tubular nephropathy was reported in the kidneys of high-dose
males only. The specific findings consisted of increased incidence of
dilated renal tubules in the cortical-medullary zone, containing
granular casts and regenerative hyper-plasia in proximal convoluted
tubules. This effect has been observed with aliphatic hydrocarbons in
male rats and has been found to be associated with a minimal change in
kidney function (Alden et al., 1984; Halder et al., 1984; Phillips
& Cockrell, 1984; Phillips & Egan, 1984a,b). Therefore, the finding of
nephropathy in the high-dose group of male rats was not believed by
the authors to have significant toxicological implications for humans
(Daughtrey et al., 1989a).

f) Hexyl alcohol

Two groups of 10 male and 10 female rats were fed hexyl alcohol
for 13 weeks at dietary levels of 0.25 or 0.50%; a third group was fed
1% for weeks 1-10 and 2%, 4% and 6% for weeks 11, 12 and 13,
respectively. Decreased food consumption was observed in females at
the high-dose level, but body weights for all animals were normal. No
significant haematological changes or differences in urine analyses
were observed for the test or control groups. Gross pathology and
microscopic evaluation were performed and revealed no
treatment-related effects. The 1% level was reported to be equivalent
to an intake of 577 mg/kg bw per day (Eibert, 1992).

Three groups of 2 male and 2 female pure bred beagle dogs were fed
hexyl alcohol for 13 weeks at levels of 0.5%, 1% or 1000 mg/kg bw per
day (high-dose group) via gelatin capsules. A fourth group of 4 males
and 4 females served as controls. Body weight, organ weight and food
consumption for the treated animals did not differ from controls. All
animals in the high-dose group displayed gross signs of toxicity
intermittently after treatment, including salivation, excitation,
ataxia, tremors and anaesthesia. The animals generally returned to
normal within 4 hours of treatment. One female dog in the high-dose
group died on the first day of treatment and was replaced by another
female. Three of the four remaining animals in the high-dose group
died during the study. No signs of toxicity were observed in the other
test animals. Haematology, serum chemistry and urinalysis showed no
significant difference as compared to controls. Animals in the
high-dose group exhibited gastrointestinal inflammation and congestion
of other visceral organs. Some gastric irritation was observed in the
mid-dose group. Both males treated at the 1000 mg/kg bw per day level
exhibited significant testicular atrophy. Effects on the testes and
other reproductive tissue have been observed with other aliphatic
alcohols at high-dose levels (Lington & Bevan, 1994). A finding of
nodules on the lung surface of some animals was reported to be non-
treatment-related. The NOEL was 1% in the diet, equal to 230 to 695
mg/kg bw per day (Eibert, 1992).

g) cis-3-Hexenol

Groups of 15 male and 15 female weaning rats were given
drinking-water containing 0, 310, 1250 or 5000 mg/litre

cis-3-hexenol for 98 days. A statistically significant reduction in
water intake was reported in male rats in the high-dose group only.
Tissues from all rats in the high-dose group and from 50% of the
controls were examined microscopically. Statistically significant
increases in relative kidney and adrenal gland weights were observed
in males only at the 5000 mg/litre level, but were not accompanied by
any evidence of histopathology. No other treatment-related
abnormalities were reported. The NOEL was 1250 mg/litre, which
corresponds to an intake level of 150 mg/kg bw per day (Gaunt et
al., 1969).

h) 2-Methyl-1-propanol (isobutyl alcohol)

Groups of 10 male and 10 female Wistar rats were given 2-methyl-1-
propanol in their drinking-water for 3 months. The test substance was
administered at concentrations of 0, 1000, 4000 or 16 000 mg/kg diet,
which was reported to correspond to approximate dose levels of 0, 60,
340 or 1450 mg/kg bw per day.

Food and drinking-water consumption, body weight gain, haematology
and clinical chemistry parameters revealed no treatment-related
adverse effects. Gross pathology and histopathological examinations
were normal. The authors concluded that results of this study
demonstrated a lack of toxicity associated with administra-tion of 2-
methyl-1-propanol in the drinking-water of rats, and that the NOEL was
1450 mg/kg bw per day the top dose (BASF, 1992).

i) 3-Methylbutyl alcohol (isoamyl alcohol)

3-Methylbutyl alcohol was administered to groups of 15 male and 15
female Ash/CSE rats in corn oil by gavage, providing daily dose levels
of 0, 150, 500 or 1000 mg/kg bw per day for 17 weeks. Examination of
haematology, serum analyses, urinalysis, renal concentration tests and
organ weights revealed no treatment-related effects. The animals were
examined for macroscopic abnormalities, and the major organs were
weighed. Microscopic examination was performed on the major organs and
several tissues of the control and high-dose animals. No treatment-
related abnormalities were observed (Carpanini et al., 1973).

2.3.2.3 Long-term toxicity

Butyl stearate was administered to groups of 16 male rats at
dietary concentrations of 0.01, 0.05, 0.25, 1.25 or 6.25% for 2 years.
Two additional groups of male rats were fed a control diet. No adverse
effects on growth or survival were observed. Haematology studies did
not reveal any significant changes. At the end of one year, necropsies
were performed on 3 animals from each group and revealed no
treatment-related effects. Gross pathology and detailed histopathology
studies on the control groups, and animals in the 1.25 and 6.25%
groups (equivalent to 625 and 3125 mg/kg bw per day) revealed no
treatment-related effects (Smith, 1953).

2.3.2.4 Genotoxicity

Genotoxicity studies have been performed in vitro using the
following esters of aliphatic acyclic primary alcohols and aliphatic
linear saturated carboxylic acids: methyl acetate, butyl acetate,
butyl stearate and the structurally related isoamyl formate (Table 5)
and demonstrates that these substances are not genotoxic.

Blood samples from male Swedish industrial workers, 13 of whom
were exposed to butyl acetate at a median concentration of 12 mg/m³
and 8 of whom were exposed to methyl acetate at a median concentration
of 14 mg/m³, were cultured for 72 hours and examined for sister
chromatid exchanges (SCE). There was no difference in the frequencies
of SCE between the exposed group and the matched reference group
(Haglung et al., 1980).

2.3.2.5 Reproductive toxicity

a) Butyl acetate

In a limited reproductive toxicity study, 48 adult white rats were
given a 0.1 ml "oil"solution containing 2 mg butyl acetate by gavage
on alternating days for 8 months. The animals were given total doses
of 24, 84 and 208 mg prior to the first, second and third generations,
respectively. The first offspring also received 15 mg before mating.
The administration of butyl acetate produced no statistically
significant changes on the number of pregnant females, the number of
born offspring, the number of viable offspring, the birth weight of
the offspring, or the weight of the offspring after 7 and 21 days
(Sporn et al., 1963).

b) Butyl stearate

Groups of 20 male and 20 female rats received diets providing
6.25% butyl stearate (equivalent to 3125 mg/kg bw per day) for 10
weeks prior to mating. A group of 12 male and 12 female rats of the
same age were fed a control diet for 10 weeks prior to mating. No
adverse effects on fertility, litter size or survival of offspring
were observed, but significantly reduced growth during preweaning and
postweaning periods was reported. Litters were weaned 21 days
post-partum, and their weights determined. Twenty-four male and 24
female weanlings from each group were fed the test diet for 12 days.
After 21 days, the rats were sacrificed and necropsied. No gross
pathological changes were reported (Smith, 1953).

2.3.2.6 Developmental toxicity

Octyl acetate

In a teratogenicity study, groups of pregnant Sprague-Dawley rats
were given octyl acetate by gavage on gestation days 6-15 providing
dose levels of 0, 100, 500 or 1000 mg/kg bw per day. Statistically

significant reductions in body weight gain and food consumption were
observed in dams in the mid- and high-dose groups. No statistically
significant effects on embryo-fetal lethality or fetal growth were
observed for any treatment group. In the high-dose group only, the
incidence of litters with at least one malformed fetus and the mean
percentage of the litter malformed was significantly elevated
(P<0.05). These observations occurred only at a dose level that was
maternally toxic. The results demonstrate that octyl acetate does not
exhibit developmental toxicity in rats under the study conditions
(Daughtrey et al., 1989b).

Table 5. Mutagenicity/genotoxicity studies for esters of saturated aliphatic acyclic primary alcohols with linear aliphatic acyclic acids

Substance name Test system Test object Concentration of Results Reference
in vitro substance

Isoamyl formate Rec assay B. subtilis up to 18 µg/disk Negative Oda et al., 1978
Rec assay B. subtilis 20 µl/disk in DMSO Negative¹ Yoo, 1986
Chromosomal aberration Chinese hamster fibroblast up to 2 mg/ml in DMSO Negative² Ishidate et al., 1984
test cells
Ames test S. typhimurium TA92, TA1535, up to 10 mg/plate in DMSO Negative¹ Ishidate et al., 1984
TA100, TA1537, TA94, TA98,
TA2637

Methyl acetate Ames test S. typhimurium TA97, TA98,
TA102, TA104, TA1535,TA1538 up to 10 mg/plate Negative¹ Zeiger et al., 1992

Butyl acetate Chromosomal aberration Chinese hamster fibroblast
test cells 2 mg/ml in DMSO Negative² Ishidate et al., 1984

Ames test S. typhimurium TA97, TA98,
TA102, TA104, TA1535,TA1538 up to 10 mg/plate in DMSO Negative¹ Zeiger et al., 1992

Ames test S. typhimurium TA92, TA94, up to 10 mg/plate in DMSO Negative¹ Ishidate et al., 1984
TA98, TA100, TA153,TA1535,
TA2637

Modified Ames test S. typhimurium TA98, TA100, 1-5000 µg/plate Negative¹ Shimizu et al., 1985
TA1535,TA1537, TA1538
E. coli WP2 uvrA

Butyl stearate Reversion assay TA 97, TA98, TA100, TA102, 100-5000 µg/plate in Negative¹ Hachiya, 1987
TA1537, WP2/pKM102 acetone with Tween 80

¹ Both with and without S-9 activation
² Without S-9 activation

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    See Also:
       Toxicological Abbreviations