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
SATURATED ALIPHATIC ACYCLIC LINEAR PRIMARY ALCOHOLS, ALDEHYDES,
AND ACIDS
First draft prepared by
Antonia Mattia, Ph.D.
Division of Product Policy, Office of PreMarket Approval (HFS-206)
Center for Food Safety and Applied Nutrition
US Food and Drug Administration
Washington, D.C., USA
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 from use as flavouring
agents
1.6 Conclusions
2. Relevant background information
2.1 Intake data
2.2 Toxicological studies
2.2.1 Acute toxicity
2.2.2 Short-term and long-term toxicity
and carcinogenicity
2.2.2.1 Acetaldehyde
2.2.2.2 Propyl alcohol
2.2.2.3 Butyl alcohol
2.2.2.4 Butyric acid
2.2.2.5 Amyl alcohol
2.2.2.6 Valeric acid
2.2.2.7 Hexyl alcohol
2.2.2.8 Hexanal
2.2.2.9 Hexanoic acid
2.2.2.10 Heptyl alcohol
2.2.2.11 1-Octanol
2.2.2.12 Octanoic acid
2.2.2.13 Nonyl alcohol
2.2.2.14 Decanoic acid
2.2.2.15 Undecanoic acid
2.2.2.16 Myristaldehyde
2.2.2.17 1-Hexadecanol
2.2.3 Genotoxicity
2.2.4 Reproductive and developmental toxicity
2.2.4.1 Propionic acid
2.2.4.2 Butyric acid
2.2.4.3 Valeric acid
3. References
1. EVALUATION
1.1 Introduction
The Committee evaluated a group of 38 flavouring agents that
includes selected saturated aliphatic acyclic linear primary alcohols,
aldehydes and acids of chain length C1-18 using the Procedure for the
Safety Evaluation of Flavouring Agents (the "Procedure") (see Figure 1
in the Introduction to the section on Substances Evaluated Using the
Procedure for the Safety Evaluation of Flavouring Agents and Table 1
in this section).
Several substances in the group had been evaluated previously by
the Committee. At the seventeenth meeting a group ADI "not limited"
was allocated to acetic acid and its potassium and sodium salts, an
ADI "not limited" was allocated to propionic acid, and a group ADI of
0-3 mg/kg bw was allocated to formic acid and ethyl formate (Annex 1,
reference 32). A group ADI of 0-0.1 mg/kg bw was established for
ocatanal and nonanal, singly or in combination, at the twenty-eighth
meeting (Annex 1, reference 66). At the twenty-ninth meeting, ADIs
"not specified" were allocated to the aluminium, ammonium, calcium,
magnesium, potassium, and sodium salts of lauric, myristic, palmitic,
and stearic acids (Annex 1, reference 70). At that meeting, the
Committee did not establish ADIs for myristic, palmitic or stearic
acids owing to lack of information on the manufacture or use of the
food-grade material, but noted that these substances are normal
constituents of coconut oil, butter and other edible oils. ADIs have
not been allocated to butyl alcohol, decanal or propyl alcohol because
the data were considered to be inadequate (Annex 1, references 38, 14,
and 56, respectively).
One substance structurally related to the group, ethyl alcohol,
was evaluated as a flavouring agent at the forty-sixth meeting of the
Committee (reference Annex 122). The Committee determined that ethyl
alcohol posed no safety concern at its current level of intake when
used as a flavouring agent.
1.2 Estimated daily per capita intake
The total annual production volume of the 38 substances from
their use as flavouring substances is approximately 2100 tonnes in the
USA (NAS, 1987). In the USA, approximately 90% of the total volume
(NAS, 1987) is accounted for by acetic acid, which includes uses
(aciduvant or solvent) in food other than flavour use. Data are not
available on the specific flavour use of acetic acid in Europe.
Disregarding the annual volume of acetic acid, the total reported
annual volume of the remaining 37 aliphatic substances is
approximately 200 tonnes from use as flavouring substances in the USA
(NAS, 1987) and 300 tonnes in Europe (IOFI, 1995). In the unlikely
event that all of the substances in this group were simultaneously
consumed on a daily basis, the estimated daily per capita intakes in
Europe and the USA would be approximately 40 mg per day and 30 mg per
day, respectively (excluding acetic acid and propionic acid which have
ADIs "not limited"). According to the European and USA production
statistics and derived intakes, acetaldehyde, butyl alcohol and
butyric acid are the major flavouring substances in this group.
Acetaldehyde and butyl alcohol constitute about 46% of the daily
per capita intake of flavouring agents in this group in the USA and
acetaldehyde and butyric acid constitute about 50% of the daily intake
in Europe. Other flavouring agents in this group that are used at
higher intake levels (i.e., >1800 µg per day) include butyric acid,
propionic acid, propyl alcohol and stearic acid in the USA and
octanoic acid, hexanoic acid, valeraldehyde, butyl alcohol and hexyl
alcohol in Europe (Table 1).
Linear saturated aliphatic alcohols, aldehydes and acids are
ubiquitous in nature. Low molecular weight alcohols and acids have
been detected in almost every known fruit and vegetable (CIVO-TNO,
1996). However, there are relatively few reports for the natural
occurrence of the corresponding aldehydes. In the USA, the available
quantitative data indicate that the dietary consumption of saturated
linear aliphatic alcohols, aldehydes and acids from naturally
occurring sources exceeds the consumption from their use as flavouring
substances (Stofberg & Kirschman, 1985; Stofberg & Grundschober,
1987).
1.3 Absorption, metabolism and elimination
Linear aliphatic acyclic alcohols (Lington & Bevan, 1994),
aldehydes (Brabec, 1993) and carboxylic acids (von Oettingen, 1960;
Dawson et al., 1964; Katz & Guest, 1994) are absorbed through the
gastrointestinal tract. Plasma half-lives are difficult to measure
since many low molecular weight alcohols (e.g., ethanol), aldehydes
and carboxylic acids (e.g., acetate and propionate) are endogenous in
humans (Lington & Bevan, 1994). Acetaldehyde has been detected in
whole blood (<0.2 mg/litre) and acetate is a blood buffer (Tietz,
1986).
The flavouring agents in this group of selected saturated
aliphatic linear alcohols, aldehydes and acids are all metabolized via
fatty acid and tricarboxylic acid pathways. Additional information can
be found in introduction to this chapter on flavouring agents.
1.4 Application of the procedure for the safety
evaluation of flavouring agents
Step 1. All of the flavouring agents in this group were
classified in structural class I (Cramer et al., 1978).
Step 2. All of the flavouring agents in this group are known or
can be readily predicted to be efficiently metabolized to substances
harmless to humans at the estimated intakes of the flavouring agents.
Step A3. Twenty-seven substances in this group fall below the
human intake threshold for class I (i.e., 1800 µg per day) at their
current levels of intake; therefore, these substances were determined
to be of no safety concern on the basis of their structural class and
low levels of estimated intake.
Step A4. Eleven substances in this group exceeded the human
intake threshold for class I. In all cases, the substances can be
predicted to undergo complete metabolism to endogenous products via
the fatty acid and tricarboxylic acid pathways. In the opinion of the
Committee the endogenous levels of metabolites from these substances
would not give rise to perturbations outside the physiological range.
Therefore, these 11 substances were also determined to be of no safety
concern based on their structural class and known metabolism.
Table 1 summarizes the evaluation of the 38 saturated aliphatic,
acyclic linear primary alcohols, aldehydes and acids using the
Procedure.
Table 1. Summary of results of safety evaluations of saturated aliphatic acyclic linear primary alcohols, aldehydes and acids.
Step 1: All of the substances in the group are in structural class I, the human intake threshold of which is 1800 µg per dayay.
Step 2: All of the substances in this group are metabolized to innocuous products.
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 substances?
(µg per person per day)
Formic acid No N/R Formic acid is produced endogenously and it No safety concern
USA: 160 is a normal component of intermediate
Europe: 800 metabolism.
Acetaldehyde Yes Yes Acetaldehyde is oxidized to acetate which No safety concern
USA: 9 700 is metabolized via the citric acid cycle;
Europe: 11 000 acetaldehyde can also be reduced to ethanol.
Acetic acid Yes Yes Acetic acid is metabolized to CO2; it No safety concern
USA: 360 000 acetylates amines and can be incorporated
Europe: N/D2 into proteins.
Propyl alcohol Yes Yes Propyl alcohol is oxidized to propionaldehyde No safety concern
USA: 2700 which yields propionate; propionate undergoes
Europe: 420 metabolism in the citric acid cycle.
Propionaldehyde No N/R See propyl alcohol. No safety concern
USA: 140
Europe: 33
Propionic acid Yes Yes See propyl alcohol. No safety concern
USA: 5200
Europe: 1100
Butyl alcohol Yes Yes Butyl alcohol is oxidized to its No safety concern
USA: 8100 corresponding aldehyde, which is oxidized to
Europe: 1900 the acid; metabolism via fatty acid and
tricarboxylic acid pathways.
Table 1. Continued...
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 substances?
(µg per person per day)
Butyraldehyde No N/R See butyl alcohol. No safety concern
USA: 17
Europe: 26
Butyric acid Yes Yes See butyl alcohol. No safety concern
USA: 5 900
Europe: 10 000
Amyl alcohol No N/R Amyl alcohol is oxidized to its corresponding No safety concern
USA: 44 aldehyde, which is rapidly oxidized to the
Europe: 97 acid; metabolism via fatty acid and
tricarboxylic acid pathways.
Valeraldehyde Yes Yes See amyl alcohol. No safety concern
USA: 8.8
Europe: 3000
Valeric acid No N/R See amyl alcohol. No safety concern
USA: 850
Europe: 140
Hexyl alcohol Yes Yes Hexyl alcohol is oxidized to its No safety concern
USA: 800 corresponding aldehyde, which is rapidly
Europe: 1900 oxidized to the acid; metabolism via fatty
acid and tricarboxylic acid pathways.
Hexanal No N/R See hexyl alcohol. No safety concern
USA: 260
Europe: 780
Hexanoic acid Yes Yes See hexyl alcohol. No safety concern
USA: 1300
Europe: 3500
Table 1. Continued...
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 substances?
(µg per person per day)
Heptyl alcohol No N/R Heptyl alcohol is oxidized to its No safety concern
USA: 7 corresponding aldehyde, which is rapidly
Europe: 12 oxidized to the acid; metabolism via fatty
acid and tricarboxylic acid pathways.
Heptanal No N/R See heptyl alcohol. No safety concern
USA: 3.2
Europe: 200
Heptanoic acid No N/R See heptyl alcohol. No safety concern
USA: 5.3
Europe: 170
1-Octanol No N/R 1-Octanol is oxidized to its corresponding No safety concern
USA: 32 aldehyde, which is rapidly oxidized to the
Europe: 230 acid; metabolism via fatty acid and
tricarboxylic acid pathways.
Octanal No N/R See 1-octanol. No safety concern
USA: 90
Europe: 170
Octanoic acid Yes Yes See 1-octanol. No safety concern
USA: 650
Europe: 3800
Nonyl alcohol No N/R Nonyl alcohol is oxidized to its No safety concern
USA: 2.1 corresponding aldehyde, which is rapidly
Europe: 8.1 oxidized to the acid; metabolism via fatty
acid and tricarboxylic acid pathways.
Table 1. Continued...
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 substances?
(µg per person per day)
Nonanal No N/R See nonyl alcohol. No safety concern
USA: 17
Europe: 130
Nonanoic acid No N/R See nonyl alcohol. No safety concern
USA: 63
Europe: 64
1-Decanol No N/R 1-Decanol is oxidized to its No safety
USA: 7 corresponding aldehyde, which is rapidly
Europe: 290 oxidized to the acid; metabolism via fatty
acid pathways and tricarboxylic acid
pathways.
Decanal No N/R See 1-decanol. No safety concern
USA: 61
Europe: 288
Decanoic acid No Yes See 1-decanol; at high concentrations, No safety concern
USA: 980 decanoic acid undergoes omega-oxidation.
Europe: 1400
Undecyl alcohol No N/R Undecyl alcohol is oxidized to its No safety concern
USA: 11 corresponding aldehyde, which is rapidly
Europe: 0.9 oxidized to the acid; metabolism via fatty
acid and tricarboxylic acid pathways.
Undecanal No N/R See undecyl alcohol. No safety concern
USA: 1.5
Europe: 480
Table 1. Continued...
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 substances?
(µg per person per day)
Undecanoic acid No N/R See undecyl alcohol. No safety concern
USA: 8.8
Europe: 4.6
Lauryl alcohol No N/R Lauryl alcohol is oxidized to its No safety concern
USA: 80 corresponding aldehyde, which is rapidly
Europe: 170 oxidized to the acid; metabolism via fatty
acid and tricarboxylic acid pathways.
Lauric aldehyde No N/R See lauryl alcohol. No safety concern
USA: 21
Europe: 52
Lauric acid No N/R See lauryl alcohol. No safety concern
USA: 1200
Europe: 590
Myristaldehyde No N/R Myristaldehyde is rapidly oxidized to its No safety concern
USA: 25 corresponding acid; metabolism via fatty
Europe: 9.4 acid and tricarboxylic acid pathways.
Myristic acid No N/R See myristaldehyde. No safety concern
USA: 72
Europe: 160
1-Hexadecanol No Yes 1-Hexadecanol is oxidized to its No safety concern
USA: 0.2 corresponding aldehyde, which is rapidly
Europe: 3.6 oxidized to the acid; metabolism via fatty
acid and tricarboxylic acid pathways.
Table 1. Continued...
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 substances?
(µg per person per day)
Palmitic acid No N/R beta-Oxidation of palmitic acid yields No safety concern
USA: 234 2-carbon units that enter the tricarboxylic
Europe: 89 acid cycle.
Stearic acid Yes Yes beta-Oxidation of stearic acid yields No safety concern
USA: 1900 2-carbon units that enter the tricarboxylic
Europe: 58 acid cycle.
1 N/R: Not required for evaluation because consumption of the substance was determined to be of no safety concern at Step A3 of the Procedure.
2 N/D: No intake data reported.
1.5 Consideration of combined intakes from use as flavouring agents
In the unlikely event that all of the substances in this group of
flavouring agents were simultaneously consumed on a daily basis, the
estimated daily per capita intake in Europe and the USA would exceed
the human intake threshold for substances in class I. All of the
substances in this group and their metabolites are innocuous and
endogenous, and their combined intake was judged by the Committee not
to give rise to perturbations outside the physiological range.
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. The Committee noted that the available toxicity data were
consistent with the results of the safety evaluation using the
Procedure. In cases where ADIs were previously established, these
ADIs were maintained at the present meeting.
2. RELEVANT BACKGROUND INFORMATION
2.1 Intake data
The most recent data on the annual production volumes of the
flavouring agents in this group in the USA and in Europe are given in
Table 2. The estimates of intake were calculated assuming
under-reporting of the production data and consumption by 10% of the
population, as indicated in the footnote to Table 2.
Table 2. Annual production and estimated per capita intake of saturated
aliphatic acyclic linear primary alcohols, aldehydes and acids in the USA
and Europe
Substance Most recent annual Daily Per Capita Intake2
production volume1 ("eaters only")
tonnes
µg/day µg/kg bw/day
1. Formic acid
USA 0.84 160 2.7
Europe 5.6 800 13
2. Acetaldehyde
USA 51 9700 160
Europe 78 11 000 180
Table 2. Continued...
Substance Most recent annual Daily Per Capita Intake2
production volume1 ("eaters only")
tonnes
µg/day µg/kg bw/day
3. Acetic acid
USA3 1910 360 000 6000
Europe 0 0 0
4. Propyl alcohol
USA 14 2700 45
Europe 2.9 420 6.9
5. Propionaldehyde
USA 0.72 140 2.3
Europe 2.29 330 5.5
6. Propionic acid
USA 27 5200 86
Europe 8.0 1100 19
7. Butyl alcohol
USA 43 8100 140
Europe 13 1900 32
8. Butyraldehyde
USA 0.09 17 0.29
Europe 0.19 26 0.44
9. Butyric acid
USA 31 5900 98
Europe 73 10 000 170
10. Amyl alcohol
USA 0.23 43 0.73
Europe 0.68 96 1.6
11. Valeraldhyde
USA 0.046 8.7 0.15
Europe 21 3000 50
12. Valeric acid
USA 4.4 850 14
Europe 0.97 140 2.3
13. Hexyl alcohol
USA 4.3 810 14
Europe 13 1900 31
Table 2. Continued...
Substance Most recent annual Daily Per Capita Intake2
production volume1 ("eaters only")
tonnes
µg/day µg/kg bw/day
14. Hexanal
USA 1.4 260 4.3
Europe 5.4 780 13
15. Hexanoic acid
USA 6.8 1300 22
Europe 25 3500 59
16. Heptyl alcohol
USA 0.037 7.0 0.12
Europe 0.081 11 0.19
17. Heptanal
USA 0.017 3.2 0.05
Europe 1.5 210 3.5
18. Heptanoic acid
USA 0.028 5.3 0.09
Europe 1.2 170 2.9
19. 1-Octanol
USA 0.17 32 0.54
Europe 1.6 230 3.9
20. Octanal
USA 0.47 90 1.5
Europe 1.2 170 2.8
21. Octanoic acid
USA 3.43 650 11
Europe 27 3800 63
22. Nonyl alcohol
USA 0.011 2.1 0.03
Europe 0.057 8.1 0.14
23. Nonanal
USA 0.09 17 0.29
Europe 0.91 130 2.2
24. Nonanoic acid
USA 0.33 63 1.0
Europe 0.45 64 1.1
Table 2. Continued...
Substance Most recent annual Daily Per Capita Intake2
production volume1 ("eaters only")
tonnes
µg/day µg/kg bw/day
25. 1-Decanol
USA 0.037 7.0 0.12
Europe 0.2 28 0.48
26. Decanal
USA 0.32 61 1.0
Europe 2.0 290 4.9
27. Decanoic acid
USA 5.1 980 16
Europe 9.9 1400 24
28. Undecyl alcohol
USA 0.06 11 0.19
Europe 0.006 0.86 0.01
29. Undecanal
USA 0.008 1.5 0.03
Europe 3.4 480 8.0
30. Undecanoic acid
USA 0.046 8.7 0.15
Europe 0.032 4.6 0.08
31. Lauryl alcohol
USA 0.42 80 1.3
Europe 1.2 170 2.8
32. Lauric aldehyde
USA 0.011 21 0.35
Europe 0.36 52 0.86
33. Lauric acid
USA 6.5 1200 21
Europe 4.2 590 9.9
34. Myristaldehyde
USA 0.13 25 0.41
Europe 0.066 9.4 0.16
35. Myristic acid
USA 0.38 72 1.2
Europe 1.1 150 2.6
Table 2. Continued...
Substance Most recent annual Daily Per Capita Intake2
production volume1 ("eaters only")
tonnes
µg/day µg/kg bw/day
36. 1-Hexadecanol
USA 0.0009 0.17 0.003
Europe 0.025 3.6 0.06
37. Palmitic acid
USA 1.2 230 3.9
Europe 0.63 89 1.5
38. Stearic acid
USA 9.9 1900 31
Europe 0.41 58 0.97
Totals
USA 2110 400 000 6700
Europe 300 43 000 720
Total excluding acetic acid
USA 200 38 000 640
1 USA: National Academy of Science (NAS, 1987) Evaluating the safety of
food chemicals. Washington, DC. Europe: International Organization of the
Flavour 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 flavour volume was reported in the survey [NAS, 1987;
IOFI, 1995]. Intake (µg/kg bw/day) calculated as follows: [µg/day/body
weight], where body weight = 60 kg. Slight variations may occur from
rounding off.
3 The USA production volume reported for acetic acid includes use of acetic
acid as a solvent by the flavour and food industries.
2.2 Toxicological studies
2.2.1 Acute toxicity
Linear aliphatic alcohols, aldehydes and carboxylic acids exhibit
low acute toxicity. For this group of saturated, aliphatic, acyclic,
linear primary alcohols, aldehydes and acids used as flavouring
agents, studies in rodents indicate LD50 values typically > 1 g/kg
bw for 36 of the 38 substances. Generally, LD50 values of aldehydes
and carboxylic acids having a carbon chain length greater than 3 are
>2500 mg/kg bw. LD50 values were not available for undecanoic acid
and palmitic acid. The acute toxicity studies that were available are
summarized in Table 3.
Table 3. Acute toxicity studies for Saturated Aliphatic Acyclic Linear Primary Alcohols, Aldehydes and Acids
Substance Species Sex1 Route LD50 (mg/kg bw) Reference
Formic acid mouse NR oral 1100 Malorny, 1969
Acetic acid mouse NR gavage 4960 Woodard et al., 1941
rat NR gavage 3310 Woodard et al., 1941
rat NR oral 3530 Smyth et al., 1951
Propionic acid rat male gavage 4290 Smyth et al., 1962
Butyric acid rat male & female oral 8790 Smyth et al., 1954
rat NR oral 2940 Smyth et al., 1951
Valeric acid rat NR oral 1844 Smyth et al., 1969a
Hexanoic acid rat male gavage 6440 Smyth et al., 1962
rat male gavage 3000 Lewis, 1989
Heptanoic acid rat NR oral 7000 Guest et al., 1982
Octanoic acid rat male gavage 1283 Smyth et al., 1962
rat male & female gavage 10 080 Jenner et al., 1964
Nonanoic acid rat NR oral 3200 Fassett, 1963
Decanoic acid rat male gavage 3301 Smyth et al., 1962
Lauric acid mouse NR oral 1238 Schafer & Bowles, 1985
Myristic acid rat NR oral >5000 Moreno, 1977
Stearic acid rat NR oral >5000 Moreno, 1977
Acetaldehyde rat NR oral 1930 Smyth et al., 1951
Propionaldehyde rat NR oral 1110 Smyth et al., 1951
Butyraldehyde rat NR oral 5890 Smyth et al., 1951
Valeraldehyde rat male gavage 3000-6400 Smyth et al., 1962, 1969a
Hexanal rat male gavage 7740 Smyth et al., 1962
rat male & female oral 4890 Smyth et al., 1954
Heptanal rat NR oral >5000 Moreno, 1974
Octanal rat male gavage 4600 Smyth et al., 1962
Nonanal rat male & female gavage >5000 Shelanski & Moldovan, 1971
Decanal mouse NR gavage >4175 Jenner et al., 1964
rat male & female gavage >3332 Jenner et al., 1964
Undecanal rat male & female gavage >5000 Shelanski & Moldovan, 1971
Lauric aldehyde rat male & female gavage >23 100 Calandra, 1971
Table 3. Continued...
Substance Species Sex1 Route LD50 (mg/kg bw) Reference
Myristaldehyde rat male & female gavage >4000 Lynch, 1971
rat NR oral 4500 Smyth et al., 1962
Propyl alcohol rat male & female gavage 6500 Jenner et al., 1964
rat male & female gavage 6500 Taylor et al., 1964
rat NR oral 5000 Levenstein, 1976
rat male & female oral 1870 Smyth et al., 1954
rat NR oral 5400 Rinehart et al., 1967
Butyl alcohol rat male & female gavage 2510 Jenner et al., 1964
rat male & female gavage 790 (female);
2020 (male) Purchase, 1969
rat NR oral 4360 Smyth et al., 1951
Amyl alcohol rat male & female gavage 3030 Jenner et al., 1964
rat NR oral 5730 Carpanini et al., 1973
Hexyl alcohol rat male & female gavage 720 (female);
1800 (male) Purchase, 1969
rat NR oral 4590 Smyth et al., 1954
Heptyl mouse NR oral 4300 Yegorov & Adrianov, 1961a
1-Octanol rat NR oral 4135 Levenstein & Wolven, 1972
Nonyl alcohol mouse NR oral 19 000 Yegorov & Adrainov, 1961a
1-Decanol rat NR oral 9800 Smyth et al., 1951
Undecyl alcohol rat male gavage 3000 Smyth & Carpenter, 1944
Lauryl alcohol rat male & female oral 1280 Lewis, 1989
1-Hexadecanol rat NR oral 8400 Coopersmith & Rutowski, 1965
1 NR = not reported.
2.2.2 Short-term and long-term toxicity and carcinogenicity
Although toxicity studies were not required to apply the Procedure
to this group of flavouring agents, multiple dose toxicity studies
lasting more than 21 days in were available for approximately half of
the 38 substances in the group (see Table 4). The lowest NOELs
derived from these studies were 50-60 mg/kg bw per day, reported for
heptyl alcohol and propyl alcohol. Few multiple dose studies are
available for aldehydes due to their volatility and reactivity. Not
all of these studies were designed to provide comprehensive
toxicological assessments of the substances tested; however,
consideration of these studies did not raise concerns regarding the
safe use of the substances in this group as flavouring agents.
Several studies were conducted to evaluate the irritant effects of
alcohols and acids on the forestomach of the rat. There are several
substances in this group for which data indicate that high doses given
to rats cause lesions of the forestomach. These effects are not
considered to be relevant to the human ingestion of these substances
as flavouring agents in foods.
A brief summary of the available data on substances not previously
evaluated by the Committee is given below.
2.2.2.1 Acetaldehyde
A NOEL of 125 mg/kg bw per day was reported for acetaldehyde added
to the drinking-water of male and female rats for 4 weeks at level of
0, 25, 125 or 625 mg/kg bw per day (Til et al., 1988); the only
treatment-related effect was hyperkeratosis of the forestomach at 625
mg/kg bw per day. No adverse effects were seen when acetaldehyde in
drinking-water at a daily intake level of 0.5 mg/kg bw was given to
rats (Amirkanova & Latypova, 1967).
2.2.2.2 Propyl alcohol
No adverse effects on the liver were observed when male rats were
give 1 or 2 M solutions of propyl alcohol (approximately 60 or 120
mg/kg bw per day) as a drinking-water substitute for 6 or 2 months,
respectively. Mallory bodies were reported in some animals (Hillbom
et al., 1974a). In groups of rats given a 1 M solution of propyl
alcohol as their sole source of drinking-water for 4 months, a lower
ratio of weight gain to caloric intake compared to controls was
observed, but there were no effects on the liver. A NOEL of 60 mg/kg
bw per day was determined in this study (Hillbom et al., 1974b).
In a study of the factors affecting the distribution of propionic
acid in the forestomach of rats, no adverse effects on the forestomach
mucosa were reported when male rats were fed a pellet diet containing
0 or 2-3% propionic acid (about 3800-5800 mg/kg bw per day) for 12
weeks (Bueld & Netter, 1993).
Table 4. Short-term and long-term toxicity studies for saturated aliphatic acyclic linear primary alcohols, aldehydes and acids
Substance Species, sex Route Time NOEL1 Reference
(mg/kg/bw per day)
Formic acid rat, male & female oral 2 years >400 Malorny, 1969
Acetic acid rat, male oral 63 days 350 Pardoe, 1952
Propionic acid rat, male oral 24 weeks 3800 Bueld & Netter, 1993
Butyric acid rat oral up to 500 days 500 Mori, 1953
Hexanoic acid rat, male diet 3 weeks 2000 Moody & Reddy, 1978
Decanoic acid rat diet 150 days >5000 Mori, 1953
Lauric acid rat, male diet 18 weeks >6000 Fitzhugh et al., 1960
10-Undecenoic acid2 rat gavage 6-9 months >400 Tislow et al., 1950
Palmitic acid rats diet 150 days >5000 Mori, 1953
Stearic acid mice oral 3 weeks >15 000 Tove, 1964
Acetaldehyde rats, male & female oral 4 weeks 125 Til et al., 1988
Hexanal rat, male & female oral 28 days >125 Komsta et al., 1988
Myristaldehyde mice diet 130 days >166 Galea et al., 1965
Propyl alcohol rat, male oral 4 months 60 Hillbom et al., 1974b
Butyl alcohol rat, male oral 28 days 940 Bio-Fax, 1969
Amyl alcohol rat, male & female oral 13 weeks >1000 Butterworth et al., 1978
Hexyl alcohol dog, male & female oral 13 weeks 230 Eibert, 1992
Heptyl alcohol rabbit gavage 6 months >50 Voskovofnikova, 1966
1-Octanol mice gavage one month >179 Voskovofnikova, 1966
Nonyl alcohol rabbit diet 67 days >148 Treon, 1963
1-Hexadecanol rat, male & female diet 13 weeks 577 Eibert, 1992
1 A NOEL (no-observed-effect level) 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.
2.2.2.3 Butyl alcohol
No adverse effects were observed when 6.9% butyl alcohol and 25%
sucrose (about 5.6 mg/kg bw per day butyl alcohol) were added to the
drinking-water of male rats for 13 weeks (Wakabayashi et al., 1984).
In rats given control diets or diets with 0.69, 1.38, 2.75 or 5.5%
butyl alcohol (equivalent to 690-5500 mg/kg bw), a statistically
significant increase in the ratio of liver-to-body weight was reported
in males at all but the lowest dose tested and in females only at the
highest dose (PPG, 1991a).
In a 28-day study on male rats fed diets containing 0, 1000, 3500
or 10 000 mg butyl alcohol kg feed (about 90-940 mg/kg bw per day) in
2% corn oil, no deaths, gross lesions at necropsy or differences in
liver and kidney weights were reported; there was a statistically
significant increase in the ratio of adrenals-to-body weight at all
doses compared to controls (Bio-Fax, 1969).
2.2.2.4 Butyric acid
In a study of the development of gastric lesions with diets
containing fatty acids, rats fed a rice diet with 1% butyric acid
(equivalent to 500 mg/kg bw per day) that was gradually increase to
10% (equivalent to 5000 mg/kg bw per day) over a period of 500 days
had forestomach lesions with prominent keratin cysts after being fed
the diet for more than 50 days. No lesions were observed in the
glandular stomach (Mori, 1953).
2.2.2.5 Amyl alcohol
Amyl alcohol given to rats by gavage for 13 weeks at a dose level
of 1000 mg/kg bw per day produced no effects on body weight gain, food
or water consumption, haematological values, serum and urine analyses,
renal function, organ weight or histopathology (Butterworth et al.,
1978).
2.2.2.6 Valeric acid
Rats fed 5% valeric acid (about 2500 mg/kg bw per day) in a rice
diet for 115-150 days had papillomatous growths in the forestomach
(Mori, 1953).
2.2.2.7 Hexyl alcohol
Two groups of male and female rats were fed hexyl alcohol at
dietary levels of 0.25 and 0.50% for 13 weeks; a third group was fed
1% (reported to be equivalent to 577 mg/kg bw per day) for weeks 1-10,
then 2, 4 and 6% for weeks 11, 12 and 13, respectively. Food
consumption was decreased in the high-dose females, but no significant
haematological changes, differences in urine analyses or
histopathological effects were observed (Eibert, 1992).
In a 13-week study, hexyl alcohol at levels of 0.5 and 1% in the
diet, or at a dose level of 1000 mg/kg bw per day in gelatin capsules,
was given to dogs. At a dose of 1000 mg/kg bw per day, 4 out of 5 dogs
died. Haematology, serum chemistry and urine analyses revealed no
differences in treated dogs relative to controls. There was
gastrointestinal inflammation in the mid- and high-dose groups.
Congestion of the viscera and testicular atrophy were observed at the
high dose. A NOAEL of 1%, which corresponds to a daily intake of
230-695 mg/kg bw, was determined from this study (Eibert, 1992).
2.2.2.8 Hexanal
No adverse effects were reported when hexanal was given to rats in
drinking-water at concentrations of 1, 10, 100 and 1000 mg/litre
(calculated to provide doses of about 0.1, 1.2, 12.6 and 124.7 mg/kg
bw per day) for 4 weeks (Komsta et al., 1988).
2.2.2.9 Hexanoic acid
No effects on hepatic peroxisomes or peroxisomal enzymes were
induced in male rats fed hexanoic acid in the diet at a level of 2%
for 3 weeks (Moody & Reddy, 1978).
In rats fed 10% (about 5000 mg/kg bw per day) hexanoic acid for
150 days, no changes in the glandular stomach or forestomach were
observed (Mori, 1953).
2.2.2.10 Heptyl alcohol
Heptyl alcohol, administered intragastrically to mice, in the form
of a solution or suspension over a one-month period, showed no
cumulative effects at a dose of 150 mg/kg bw per day (Voskoboinikova,
1966). The NOEL in rabbits given 0, 1.4, 14 or 50 mg/kg bw per day
heptyl alcohol by gavage in sunflower oil for 6 months was 50 mg/kg bw
per day (Voskoboinikova, 1966).
2.2.2.11 1-Octanol
No cumulative effects were observed in a study in which 1-octanol
was administered intragastrically to mice in the form of a solution or
suspension over a one-month period at a dose of 180 mg/kg bw per day
(Voskoboinikova, 1966).
2.2.2.12 Octanoic acid
Rats gavaged on gestation days 6-15 with octanoic acid in corn oil
at dose levels of 0, 1125 or 1500 mg/kg bw per day exhibited maternal
toxicity and maternal mortality. There was an decrease in the number
of live pups on post-gestational day 6, but no developmental toxicity
was reported (Narotsky et al., 1994).
2.2.2.13 Nonyl alcohol
No adverse effects were reported when an isomeric mixture of nonyl
alcohol, 2-methyl-1-octanol and 3-methyl-1-octanol, calculated to
provide a daily intake level of 148 mg/kg bw, was added to the diet of
rabbits for 67 days of an 83-day period (Treon, 1963).
2.2.2.14 Decanoic acid
In a study of gastric lesions, 10% decanoic acid (about 5000 mg/kg
bw per day) in the diet of rats for 150 days resulted in no observable
changes in the forestomach or glandular stomach (Mori, 1953).
2.2.2.15 Undecanoic acid
In a study with undecanoic acid, there was a marked inhibitory
effect on growth in rats give 2.5% (about 1250 mg/kg bw per day) for 8
weeks (Newell et al., 1949).
2.2.2.16 Myristaldehyde
No adverse effects on mortality and body and organ weights were
reported when myristaldehyde was fed to mice at a level of 166 mg/kg
bw per day for 130 days (Galea et al., 1965).
2.2.2.17 1-Hexadecanol
Two groups of male and female rats were fed 1-hexadecanol for 13
weeks at dietary levels of 1 or 2.5%; a third group was fed 5% for
weeks 1-10, 7.5% for week 11, and 10% for weeks 12 and 13. Decreased
food consumption (in females at the intermediate and high dose) and/or
body weights (in males and females at the high dose and in females
only at the intermediate dose) were observed at various times in rats
in the intermediate and high-dose groups. No significant
haematological findings, changes in urinalyses or pathological effects
were reported between control and treated animals. A NOAEL of 1%
(equal to 577 mg/kg bw per day) was determined from this study
(Eibert, 1992).
In a 13-week study in dogs, at levels of 0, 0.5, 1 or 3%, no
effects on body weight, organ weight or food consumption were
reported. No significant haematological findings, changes in
urinalyses or gross pathological effects were reported between control
and treated animals; however, serum glutamate oxaloacetate
transaminase levels were elevated at all three doses. A NOAEL of 3%
(equal to 807 mg/kg bw per day) was determined from this study
(Eibert, 1992).
In addition to the multiple dose studies described above, the
Committee was aware of the results of a long-term inhalation study in
which hamsters that were administered acetaldehyde developed an excess
of upper respiratory tract tumours (Kruysse et al., 1975). Respiratory
lesions were also observed in 2-week and 13-week whole body
inhalation studies on formic acid (National Toxicology Program, 1992).
No systemic effects resulted, but the NTP recommended caution in
extrapolating the results of these studies to man because humans do
not metabolize formate to CO2 as rapidly as rodents. The Committee
considered that, under conditions of use of acetaldehyde and formic
acid as flavouring agents, these observations were not predictive of a
response in humans because these substances are endogenous and oral
ingestion from their use as flavouring agents is low.
2.2.3 Genotoxicity
In vitro and in vivo genotoxicity studies for the flavouring
agents in this group are listed in Tables 5 and 6. Saturated aliphatic
acyclic linear primary alcohols, aldehydes, and carboxylic acids
generally exhibited consistent negative results in the Ames assay, the
unscheduled DNA synthesis test, and the in vitro or in vivo mouse
micronucleus test. However, genotoxic activity has been reported for
some low molecular weight alcohols, carboxylic acids and aldehydes in
varied assays, including the sister chromatid exchange (SCE) assay,
the chromosomal aberration test and the forward mutation assays with
mouse lymphoma and Chinese hamster lung cells.
The positive results in in vitro genotoxicity assays for
aliphatic aldehydes is not surprising in light of the recognized
reactivity of the aldehyde functional group. Acetaldehyde induced an
increase in SCE in adult human lymphocytes (He & Lambert, 1985) and
human peripheral lymphocytes (Helander & Lindahl-Kiessling, 1991).
Acetaldehyde and propionaldehyde induced an increase in SCE in Chinese
hamster embryonic diploid cells (Furnus et al., 1990). However,
aldehydes exhibit a short plasma half-life and are efficiently
oxidized to the corresponding acids, which are metabolized in the
fatty acid or citric acid pathways. These are important in vivo
conditions that are difficult to establish in the above-mentioned
in vitro assays. In one in vivo test, there was no evidence of an
increase in micronucleated polychromatic erythrocytes in the bone
marrow cells of B6C3F1 mice given a single intraperitoneal injection
of 95 or 100 mg acetaldehyde/kg bw. Dose levels of 190 mg/kg bw
(approximately 50% of the subcutaneous LD50 value) or more did
increase the number of mouse micronuclei (Ozawa et al., 1994).
Administration via intraperitoneal injection, however, bypasses the
liver, where 80% of the acetaldehyde from the portal circulation is
converted to acetate.
Table 5. In vitro mutagenicity/genotoxicity studies for saturated aliphatic acyclic linear primary alcohols, aldehydes and acids
Substance name Test system Test cells Concentration Results Reference
Formic acid modified Ames test S. typhmiurium TA97, TA98, TA100, 10-3333 µg/plate negative1 Zeiger et al, 1992
(preincubation method) TA1535, Chinese hamster ovary cells
Chromosomal aberration test (CHO) K1 8-14 mM positive1 Morita et al, 1990
Chromosomal aberration test Chinese hamster ovary cells (CHO) K1 12-14 mM negative1 Morita et al, 1990
Acetic acid modified Ames test S. typhmiurium strains TA97, TA98, 100-1000 µg/plate negative1 Zeiger et al, 1992
(preincubation method) T100, TA1535, Chinese hamster
Chromosomal aberration test 10-14 mM negative1 Morita et al, 1990
Chromosomal aberration test Chinese hamster ovary K1 cells 4-10 mM positive1 Morita et al, 1990
Sister chromatid exchange Adult human lymphocytes 2.5-10 mM positive Sipi et al., 1992
Propionic acid Modified Ames test S. typhmiurium TA97, TA98, TA1535, 100-10 000 µg/plate negative1 Zeiger et al, 1992
(preincubation method) and TA1537
DNA repair test (spot test) E. coli strains WP2, WP67, polA-, 125 µl/plate positive Basler et al., 1987
uvrA-, CM871
SOS chromotest E. coli PQ37 0.01-10 mM negative Basler et al., 1987
Ames test S. typhmiurium TA98, TA100, TA1535, 0.01-10 µl/plate negative Basler et al., 1987
TA1537
Sister chromatid exchange Adult human lymphocyte cells 2.5 mM positive4 Sipi et al., 1992
Sister chromatid exchange Chinese hamster V79 cells 0.1-33.3 mM negative1 Basler et al, 1987
Butyric acid Chromosomal aberration test Chinese hamster fibroblast cells up to 1 mg/ml negative1 Ishidate et al.,
1984
Table 5. Continued...
Substance name Test system Test cells Concentration Results Reference
Ames test S. typhmiurium TA92, TA1535, TA100, up to 10 mg/plate negative1 Ishidate et al.,
TA1537, TA94, TA98 1984
Hexanoic acid Mouse lymphoma assay mouse lymphoma L5178Y TK+/- 700 µg/ml positive3 Heck et al., 1989
1000 µg/ml negative2
Unscheduled DNA synthesis Rat hepatocytes 1000 nl/ml negative Heck et al., 1989
Ames test (plate
incorporation assay) S. typhmiurium TA98, TA100, TA1538, 75 mg/plate negative1 Heck et al., 1989
TA1535 and TA1537
Heptanoic acid Mouse lymphoma assay Mouse lymphoma L5178Y TK +/- 900 µg/ml negative2 Heck et al., 1989
600 µg/ml positive3
Unscheduled DNA synthesis Rat hepatocytes 1000 nl/ml negative Heck et al., 1989
assay
Ames test (plate incorporation S. typhmiurium TA98, TA100, 150 mg/plate negative1 Heck et al., 1989
assay) TA1538, TA1535 and TA1537
Modified Ames test S. typhmiurium TA97, TA98, TA100, 10 mg/plate negative Zeiger et al., 1992
(preincubation method) TA104, TA1535 and TA1537
Octanoic acid Plate and suspension assays S. typhmiurium TA1535, TA1537 at 0.0000625- negative1 FDA, 1976
and TA1538 0.00025%
Nonactivation suspension test Saccharomyces cerevisiae D4 0.000325-0.001300% negative FDA, 1976
Unscheduled DNA synthesis Rat hepatocytes 300 nl/ml negative Heck et al., 1989
Ames test (plate S. typhmiurium TA98, TA100, TA1538, 50 mg/plate negative1 Heck et al., 1989
incorporation assay) TA1535 and TA1537
Table 5. Continued...
Substance name Test system Test cells Concentration Results Reference
Decanoic acid Rec assay B. subtilis strains H17 and M45 18 µg/disk negative Oda et al., 1978
Modified Ames test S. typhimurium TA98, TA100, TA1535, up to 666 µg/plate negative1 Zeiger et al.,
(preincubation method) TA97 and TA1537 1988
Lauric acid Modified Ames test S. typhimurium TA98, TA100, TA1535, up to 666 µg/plate negative1 Zeiger et al, 1988
(preincubation method) TA97 and TA1537
Myristic acid Cell mutagenesis assay Mouse lymphoma L5178Y TK+/- 62.5 µg/ml negative2 Heck et al., 1989
125 µg/ml negative3
Ames test (plate S. typhimurium TA98, TA100, TA1535, 10 mg/plate negative1 Heck et al., 1989
incorporation assay) TA1537 and TA1538
Modified Ames test S. typhmiurium TA97, TA98, TA100, up to 3333 µg/plate negative Zeiger et al., 1988
(preincubation method) TA1535 and TA1537
Stearic acid Modified Ames test S. typhmiurium TA98, TA100, TA1535, 1-1000 µg/plate negative1 Shimizu et al.,
(preincubation method) TA1537 and TA1538 1985
Ames test S. typhmiurium TA98, TA100, TA1535, 50 µg/plate negative1 Blevins & Taylor,
TA1537 and TA1538 1982
Acetaldehyde Sister chromatid exchange Adult human lymphocytes 0.1-2.4 mM positive He & Lambert, 1985
Forward mutation assay L5178y mouse lymphoma TK+/- 0.004-0.008 positive2 Wangenheim &
mol/litre Bolcsfoldi, 1988
Ames test S. typhmiurium TA100, TA102 and TA104 Not reported negative1 Dillon et al, 1992
Chromosomal aberration test Chinese hamster embryonic 0.002% positive Furnus et al., 1990
diploid cells
Sister chromatid exchange Adult human peripheral lymphocytes 100-400 µM positive Helander & Lindahl-
Kiessling, 1991
Table 5. Continued...
Substance name Test system Test cells Concentration Results Reference
Propionaldehyde Ames test S. typhmiurium TA98, TA100 and TA102 0.13 nmol to 0.13 negative1 Aeschbacher et
mmol/plate al., 1989
Forward mutation assay V79 Chinese hamster lung cells 1-90 mM positive2 Brambrilla et al,
1989
Ames test S. typhmiurium TA100, TA102 and TA104 not reported negative3 Dillon et al, 1992
Unscheduled DNA synthesis Adult human hepatocytes 10-100 mM negative Martelli et al.,
assay 1994
Chromosomal aberration test Chinese hamster embryonic diploid 0.0005-0.002% positive Furnus et al., 1990
cells
Butyraldehyde Ames test S. typhmiurium TA100, TA102 and TA104 not reported negative1 Dillon et al, 1992
Unscheduled DNA synthesis Adult human hepatocytes 10-30 mM negative Martelli et al.,
assay 1994
Forward mutation assay V79 Chinese hamster lung cells 1-30 mM positive2 Brambrilla et al.,
1989
Sister chromatid exchange Chinese hamster ovary cells 9-90 µg/ml positive1 Galloway et al.,
1987
Chromosome aberration test Chinese hamster ovary cells 59-135 µg/ml negative1 Galloway et al.,
1987
Sister chromatid exchange Adult human lymphocytes 0.002% negative Obe & Beek, 1979
Valeraldehyde Forward mutation assay V79 Chinese hamster lung cells 3-30 mM positive2 Brambilla et al.,
1989
Unscheduled DNA synthesis Adult human and rat hepatocytes 3-100 mM negative Martelli et al.,
assay 1994
Rec assay B. subtilis strains H17 and M45 0.6 ml/plate negative1 Matsui et al, 1989
Table 5. Continued...
Substance name Test system Test cells Concentration Results Reference
Hexanal Forward mutation assay V79 Chinese hamster lung cells 3-30 mM positive2 Brambrilla et al.,
1989
Unscheduled DNA synthesis Adult human and rat hepatocytes 3-100 mM negative Martelli et al.,
assay 1994
Ames test S. typhmiurium TA102 and TA104 up to 1 mg/plate negative Marnett et al.,
1985
Ames test (spot test) S. typhmiurium TA98, TA100, TA1535 3 µmol/plate negative1 Florin et al, 1980
and TA1537
Heptanal Ames test (spot test) S. typhmiurium TA98, TA100, TA1535 3 µmol/plate negative1 Florin et al, 1980
and TA1537
Ames test S. typhmiurium TA97, TA98, TA100, 1-3333 µg/plate negative1 Zeiger et al, 1992
TA1535 and TA1537
Octanal Ames test (spot test) S. typhmiurium TA98, TA100, TA1535 3 µmol/plate negative1 Florin et al, 1980
and TA1537
Nonanal Sister chromatid exchange Rat (female Fischer 344 animals) 0.1-100 µM positive Eckl et al., 1993
hepatocytes
Unscheduled DNA synthesis Adult human and rat hepatocytes 3-100 mM negative Martelli et al.,
assay 1994
Forward mutation assay V79 Chinese hamster lung cells 0.1-0.3 mM positive2 Brambrilla et al.,
1989
Modified Ames test S. typhmiurium TA98, TA100 and TA1535 1-666 µg/plate negative1 Mortelmans et al.,
(preincubation method) 1986
Ames test S. typhmiurium TA102 and TA104 up to 1 mg/plate negative Marnett et al.,
1985
Chromosomal aberration test Rat hepatocytes 0.4 µg/ml negative Eckl et al., 1993
Table 5. Continued...
Substance name Test system Test cells Concentration Results Reference
Decanal Rec assay B. subtilis strains H17 and M45 5 µl per disk positive Yoo, 1986
Rec assay E. coli WP2, uvrA 0.005-0.04 mg/plate negative Yoo, 1986
Chromosomal aberration test Chinese hamster fibroblast cells 0.125 mg/ml negative Ishidate et al.,
1984
Ames test S. typhmiurium TA92, TA1535, TA100, up to 1 mg/plate negative1 Ishidate et al.,
TA1537, TA94 and TA98 1984
Undecanal Ames test (spot test) S. typhmiurium TA98, TA100, TA1535 3 µmol/plate negative1 Florin et al, 1980
and 1537
Propyl alcohol Ames test S. typhmiurium TA100 up to 100 µmol/plate negative1 Stolzenberg &
Hine, 1979
Sister chromatid exchange V79 Chinese hamster lung fibroblasts 3.3-100 mM negative2 Von der Hude et
al., 1987
Sister chromatid exchange Chinese hamster ovary cells 0.01% negative Obe & Ristow, 1977
Micronucleus test Chinese hamster lung fibroblast cells 50 µl/ml negative1 Lasne et al., 1984
Butyl alcohol Ames test S. typhimurium TA102 up to 5000 µg/plate negative1 Muller et al, 1993
Sister chromatid exchange Chinese hamster ovary cells 0.01% negative Obe & Ristow, 1977
Forward mutation assay Chinese hamster ovary cells 0.2-1.6 µl/ml positive PPG, 1991b
1-Octanol Cell mutagenesis assay Mouse lymphoma L5178Y TK+/- 100 µg/ml negative1 Heck et al., 1989
Ames test S. typhmiurium TA1535, TA1537, TA1538, 2000 nl/plate negative1 Heck et al., 1989
TA98 and TA100
1-Decanol Rec assay B. subtilis strains H17 and M45 17 µg/disk negative Oda et al., 1978
Table 5. Continued...
Substance name Test system Test cells Concentration Results Reference
Undecyl alcohol Rec assay B. subtilis strains H17 and M45 20 µg/disk positive Yoo, 1986
Rec assay E. coli WP2 uvrA 0.005-0.04 mg/plate negative Yoo, 1986
Lauryl alcohol Modified Ames test S. typhmiurium TA98, TA100, TA1535, 0.01-0.50 µg/plate negative1 Shimizu
(preincubation method) TA1537 and TA1538 et al., 1985
1-Hexadecanol Ames test S. typhmiurium TA98, TA100, TA1535, 50 µg/plate negative1 Blevins & Taylor,
TA1537 and TA1538 1982
1 Both with and without metabolic activation.
2 Without metabolic activation
3 With metabolic activation
4 Positive only at middle dose (2.5 mM), negative at lower (1.25 mM) and higher doses (5 mM); no dose-response relationship
Table 6. Mutagenicity/genotoxicity studies for saturated aliphatic acyclic linear primary alcohols, aldehydes and acids
Substance name Test system Test organism Concentration Results Reference
Propionic acid Micronucleus test, Chinese hamster cells 5 ml/kg bw negative Basler et al., 1987
intraperitoneal injection
Acetaldehyde Mouse bone marrow Mouse 95-400 mg/kg bw positive Ozawa et al., 1994
micronucleus test,
intraperitoneal injection
In mutation assays with mammalian cell lines, hexanoic acid and
heptanoic acid exhibited an increase in the frequency of mutations in
mouse lymphoma L5178Y cells with S9 metabolic activation at
concentrations greater than 600 µg/ml. The authors noted that culture
conditions of low pH and high osmolality, which may occur upon
incubation with acidic substances, have been shown to produce
false-positive results in this and other assays (Heck et al., 1989).
Therefore, these results must be cautiously interpreted. Formic acid
and acetic acid, which initially gave an increase in SCE in Chinese
hamster ovary cells, were later shown to be negative when tested at
physiological pH (Morita et al., 1990). In a forward mutation assay,
butyl alcohol tested at concentrations of 0.2 to 1.6 µl/ml was
mutagenic when incubated with Chinese hamster ovary cells (PPG,
1991b). This result is also probably due to perturbations in the pH of
the test medium.
2.2.4 Reproductive and developmental toxicity
Reproductive and developmental toxicity studies on low molecular
weight aliphatic alcohols (propyl alcohol and butyl alcohol) via
inhalation at high concentrations have been associated with
developmental effects in the presence of maternal toxicity (Nelson
et al., 1990). When butyric acid, valeric acid and octanoic acid
were given daily by tracheal intubation on days 6 to 15 of gestation,
only fetotoxicity was reported at the highest dose level (1500 mg/kg
bw per day) with octanoic acid; no other evidence of fetotoxicity,
developmental toxicity or teratogenicity associated with these three
carboxylic acids was observed (Narotsky et al., 1994). There is no
evidence to conclude that, when ingested as flavouring substances,
intake of any of the substances in the group of linear saturated
aliphatic substances would be associated with reproductive or
developmental toxicity.
2.2.4.1 Propionic Acid
Fetal abnormalities or effects on survival were not observed when
the calcium salt of propionic acid was fed to pregnant rodents (up to
300 mg/kg bw per day for 10 days, hamsters (up to 400 mg/kg bw per day
for 5 days) and rabbits (up to 400 mg/kg bw per day for 13 days)
(FDRL, 1972).
2.2.4.2 Butyric Acid
Maternal weight loss and respiratory effects were observed in
female rats given 100 or 133 mg/kg bw per day of butyric acid by
tracheal intubation on days 6 to 15 of gestation (Narotsky et al.,
1994). In dams with peripartum respiratory symptoms, reduced pup
weight and decreased progeny viability were reported, but no signs of
significant development toxicity were reported at either dose. Gastric
irritation was noted at necropsy.
2.2.4.3 Valeric Acid
Female rats given 0, 75 or 100 mg/kg bw per day valeric acid by
gavage on days 6 to 15 of gestation exhibited signs of maternal
toxicity including respiratory effects and decreased body weight, but
no significant developmental toxicity at either dose. In Segment II of
this study, valeric acid was associated with maternal toxicity and
reduced fetal weights at dose levels from 50 to 200 mg/kg bw per day.
No fetal skeletal malformations were reported, except for sternebrae
variations. Gastric irritation was noted at necropsy (Narotsky
et al., 1994).
3. REFERENCES
Aeschbacher, H.U., Wolleb, U., Loliger, J., Spadone, J.C., & Liardon,
R. (1989) Contribution of coffee aroma constituents to the
mutagenicity of coffee. Food Chem. Toxicol., 27(4): 227-232.
Amirkhanova, G.F. & Latypova, Z.V. (1967) Toxicity of acetaldehyde
in peroral administration to animals. Nauch. Tr. Kazan. Med. Inst.,
24: 26-27.
Basler, A., Von der Hude, W., & Scheutwinkel, M. (1987) Screening of
the food additive propionic acid for genotoxic properties. Food
Chem. Toxicol., 25(4): 287-290.
Blevins, R.D. & Taylor, D.E. (1982) Mutagenicity screening of
twenty-five cosmetic ingredients with the Salmonella/microsome test.
J. Environ. Sci. Health, A17(2): 217-239.
Bio-Fax Industrial Bio-test Lab. Inc. (1969) Data Sheet No. 2-5/69:
n-Butyl alcohol. Bio-Fax Industrial Bio-test Lab. Inc., Northbrook,
Illinois, USA.
Brabec, M. J. (1993) Aldehydes and acetals. In: Clayton, G.D. &
Clayton, F.E. ed. Patty's industrial hygiene and toxicology, 3rd rev.
ed. John Wiley & Sons, Inc., New York, Vol. IIB, pp. 2629-2669.
Brambrilla, G., Cagelli, E., Canonero, R., Martelli, A., & Marinari,
U.M. (1989) Mutagenicity in V79 Chinese hamster cells of n-alkanals
produced by lipid peroxidation. Mutagenesis, 4(4): 277-279.
Bueld, J. E. & Netter, K. J. (1993) Factors affecting the distribution
of ingested propionic acid in the rat forestomach. Food Chem.
Toxicol., 31: 169-176.
Butterworth, K. R., Gaunt, I. F., Heading, C. E., Grasso, P., &
Gangolli, S. D. (1978) Short-term toxicity of n-amyl alcohol in
rats. Food Cosmet. Toxicol., 16: 203-207.
Calandra, J.C. (1971) Private communication to FEMA.
Carpanini, F.M.B., Gaunt, I.F., Kiss, I.S., Grasso, P., & Ganqolli,
S.D. (1973) Short-term toxicity of isoamyl alcohol in rats.
Food Cosmet. Toxicol., 11: 713-724.
CIVO-TNO (1994) In: Maarse, H & Visscher C.A. ed. Volatile components
in food: Qualitative and quantitative data - Vol. III, 7th ed.
Centraal Instituut Voor Voedingsonderzoek TNO, Zeist, The Netherlands.
Coopersmith, I.M. & Rutkowski, A.J. (1965) Hexadecyl alcohol. Drug
Cosmet Ind., 96: 630-631, 732, 735.
Cramer, G.M.,Ford, R.A., & Hall, R.L. (1978) Estimation of toxic
hazard-decision tree approach. Food Cosmet. Toxicol., 16: 255-276.
Dawson, A.M., Holdsworth, C.D., & Webb, J. (1964) Absorption of short
chain fatty acids in man. Proc. Soc. Exp. Biol. Med,. 117: 97-100.
Dillon, D.M., McGregor, D.B., Combes, R.D., & Zeiger, E. (1992)
Detection of mutagenicity in Salmonella of some aldehydes and
peroxides. Environ. Mol. Mutagen., 19(Suppl. 20): 15.
Eckfeldt, J. H. & Yonetani, Y. (1982) Isoenzymes of aldehyde
dehydrogenase from horse liver. In: Wood, W.A. ed. Methods in
enzymology. Academic Press, New York, pp. 474-479.
Eckl, P.M., Ortner, A., & Esterbauer, H. (1993) Genotoxic properties
of 4-hydroxyalkenals and analogous aldehydes. Mutat. Res., 290(2):
183-192.
Eibert, J.J. (1992) Private communication to FEMA.
Expert Panel of the Cosmetic Ingredient Review (EPCIR) (1987) Final
report on the safety assessment of oleic acid, lauric acid, palmitic
acid, myristic acid, and stearic acid. J. Am. Coll. Toxicol., 6:
321-401.
Fassett, D.W. (1963) Private communication cited in Patty's industrial
hygiene and toxicology, 2nd ed. Wiley Interscience, New York, Vol.
II, pp. 1788.
Feldman, R.I. & Weiner, H. (1972) Horse liver aldehyde dehydrogenase:
I. Purification and characterization. J. Biol. Chem., 247: 260-266.
Fitzhugh, O.G., Schouboe, P.J., & Nelson, A.A. (1960) Oral toxicities
of lauric acid and certain lauric acid derivatives. Toxicol. Appl.
Pharmacol., 2: 59-67.
Florin, I., Rutberg, L., Curvall, M., & Enzell, C.R. (1980) Screening
of tobacco smoke constituents for mutagenicity using the Ames' test.
Toxicology, 15: 219-232.
Food and Drug Administration (1976) Mutagenic evaluation of compound.
FDA 75-38. 000124-07-2, caprylic acid, 98%. Food and Drug
Administration, Washington, DC, USA.
Food and Drug Research Laboratories (FDRL) (1972) Teratologic
evaluation of FDA 71-36 (calcium propionate) in mice, rats, hamsters,
and rabbits. Final report prepared under DHEW contract no. FDA
71-260. Maspeth, New York. Cited in National Technical Information
Service (NTIS) No. PB80-104599, "Evaluation of the health aspects of
propionic acid, calcium propionate, sodium propionate, dilauryl
thiodipropionate, and thiodipropionic acid as food ingredients."
Federation of American Societies for Experimental Biology, Bethesda,
Maryland (Prepared for the Food and Drug Administration, 1979).
Furnus, C.C., Ulrich, M.A., Terreros, M.C., & Dulout, F.N. (1990)
The induction of aneuploidy in cultured Chinese hamster cells by
propionaldehyde and chloral hydrate. Mutagenesis, 5(4): 323-326.
Galea, V., Zugravu, E., Suciu, D., & Buraga, S. (1965) Toxicity of
C14-C20 aldehydes. Igiena 14: 203-208.
Galloway, S.M., Armstrong, M.J., Reuben, C., Colman, S., Brown, B.,
Cannon, C., & Bloom, A.D. (1987) Chromosome aberrations and sister
chromatid exchanges in Chinese hamster ovary cells. Environ.
Mol. Mutagen., 10(10): 1-175.
Gibel, W.K., Lohs, K., & Wildner, G.P. (1975) Carcinogenic activity of
propanol, 2-methyl-1-propanol, and 3-methyl-1-butanol. Arch.
Geschwulstforsch., 45: 19-24.
Graham, W.D., Teed, H., & Grice, H.C. (1954) Chronic toxicity of bread
additives to rats. J. Pharm. Pharmacol., 6: 534-545.
He S.M. & Lambert B. (1985) Induction and persistence of SCE-inducing
damage in human lymphocytes exposed to vinyl acetate and aldehyde
in vitro. Mutat. Res., 158(3): 201-208.
Heck J.D., Vollmuth, T.A., Cifone, M.A., Jagannath, D.R., Myhr, B., &
Curren, R.D. (1989) An evaluation of food flavoring ingredients in a
genetic toxicity screening battery. Toxicologist , 9(1): 257.
Helander, A. & Lindahl-Kiessling, K. (1991) Increased frequency of
acetaldehyde-induced sister-chromatid exchanges in human lymphocytes
treated with an aldehyde dehydrogenase inhibitor. Mutat. Res.,
264(3): 103-107.
Hillbom, M.E., Franssila, K., & Forsand, O.A. (1974a) Effects of
chronic ingestion of some lower aliphatic alcohols in rats. J. Jpn.
Stud. Alcohol, 9: 101-108.
Hillbom, M.E., Franssila, K., & Forsand, O.A. (1974b) Effects of
chronic ingestion of some lower aliphatic alcohols in rats. Res.
Commun. Chem. Pathol. Pharmacol., 9: 177-180.
International Organization of the Flavor Industry (IOFI) (1995)
European inquiry on volume of use. Private communication to FEMA.
Ishidate, M. Jr., Sofuni, T., Yoshikawa, K., Hayashi, M., Nohmi, T.,
Sawada, M., & Matsu, A. (1984) Primary mutagenicity screening of food
additives currently used in Japan. Food Cosmet. Toxicol., 27(8):
623-636.
Jenner, P.M., Hagan, E.C., Taylor, J.M., Cook, E.L., & Fitzhugh, O.G.
(1964) Food flavorings and compounds of related structure I. Acute
oral toxicity. Food Cosmet. Toxicol., 2: 327-343.
Katz, G. & Guest, D. (1994) Aliphatic carboxylic acids. In: Patty's
industrial hygiene and toxicology, 4th rev. ed. John Wiley & Sons,
New York, Vol. IIE, Chapter 36, pp. 3523-3671.
Komsta, E.I.C, Secours, V.E., Valli, V.E., & Villeneuve, D.C. (1988)
Results of a short-term toxicity study for three organic chemicals
found in Niagara River drinking water. Bull. Environ. Contam.
Toxicol., 41: 515-522.
Kruysse, A., Feron, V.J., & Til, H.P. (1975) Repeated exposure to
acetaldehyde vapor. Studies in Syrian golden hamsters. Arch.
Environ. Health, 30: 449-452.
Lange, L.G., Stykowski, A.J., & Vallee, B.L. (1976) Human liver
alcohol dehydrogenase: Purification, composition and catalytic
features. Biochemistry, 15: 4687.
Lasne, C., Gu, Z.W., Venegas, W., & Chouroulinkov, I. (1984) The
in vitro micronucleus assay for detection of cytogenetic effects
induced by mutagen-carcinogens: Comparison with the in vitro
sister-chromatid exchange assay. Mutat. Res., 130: 273-282.
Lehninger, A. L. (1993) Principles of biochemistry. Worth
Publishers, Inc., New York.
Levenstein, M. (1976) Private communication to FEMA.
Levenstein, I. & Wolven, A.M. (1972) Private communication to FEMA.
Lewis, R.J. (1989) Food additives handbook. Van Nostrand Reinhold, New
York.
Lington, A.W. & Bevan, C. (1994) Alcohols. In: Patty's industrial
hygiene and toxicology, 4th rev. ed. John Wiley & Sons, New York,
Vol. IID, Chapter 30, pp. 2585-2760.
Lynch, T.A. (1971) Private communication to FEMA.
McMartin, K.E., Ambre, J.J., & Tephly, T.R. (1980) Methanol poisoning
in human subjects: Role of formic acid accumulation in metabolic
acidosis. Am. J. Med., 68: 414-418.
Malorny, G. (1969) Acute and chronic toxicity of formic acid and
formates. Z Ernaehrungswiss., 9: 332-339.
Mankes, R.F., Lefevre, R., Renak, V., Fiesher, J., & Abraham, R.
(1985) Reproductive effects of some solvent alcohols with differing
partition coefficients. Teratology, 31: 67A.
Marnett, L.J., Hurd, H.K., Hollstein, M.C., Levin, D.E., Esterbauer,
H., & Ames, B.N. (1985) Naturally occurring carbonyl compounds are
mutagens in Salmonella tester strain TA104. Mutat. Res., 148:
25-34.
Martelli, A., Canonero, R., Cavanna, M., Ceradelli, M., & Marinari,
U.M. (1994) Cytotoxic and genotoxic effects of five n-alkanals in
primary cultures of rat and human hepatocytes. Mutat. Res., 323(3):
121-126.
Matsui, S., Yamamoto, R., & Yamada, H. (1989a) The Bacillus
subtilis/ microsome rec-assay for the detection of DNA damaging
substances which may occur in chlorinated and ozonated waters.
Water Sci. Technol., 21: 875-887.
Moody, D.E. & Reddy, J.K. (1978) Hepatic peroxisome (microbody)
proliferation in rats fed plasticizers and related compounds.
Toxicol. Appl. Pharmacol., 45: 497-504.
Moreno, O.M. (1974) Private communication to FEMA.
Moreno, O.M. (1977) Private communication to FEMA.
Mori, K. (1952) Production of gastric lesions in the rat by acetic
acid feeding. Gann, 43: 443-446.
Mori, K. (1953) Production of gastric lesions in the rat by the diet
containing fatty acids. Jpn. J. Cancer Res., 44: 421-427.
Morita, T., Takeda, K., & Okumura, K. (1990) Evaluation of
clastogenicity of formic acid, acetic acid and lactic acid on cultured
mammalian cells. Mutat. Res., 240(3): 195-202.
Mortelmans, K., Haworth, S., Lawlor, T., Speck, W., Tainer, B., &
Zeiger, E. (1986) Salmonella mutagenicity tests: II Results from the
testing of 270 chemicals. Environ. Mutagen., 8(7): 1-119.
Muller, W., Engelhart, G., Herbold, B., Jackh, R., & Jung, R. (1993)
Evaluation of mutagenicity testing with Salmonella typhimurium TA102
in three different laboratories. Environ. Health Perspect.,
101(Suppl. 3): 33-36.
Nakayasu, H., Mihara, K., & Sato, R. (1978) Purification and
characterization of a membrane-bound aldehyde dehydrogenase from rat
liver microsomes. Biochem. Biophys. Res. Commun., 83: 697-703.
Narotsky, M.G., Francis, E.Z., & Kavlock, R.J. (1994) Developmental
toxicity and structure-activity relationships of aliphatic acids,
including dose-response assessment of valproic acid in mice and rats.
Fundam. Appl. Toxicol., 22: 251-265.
National Academy of Sciences (1987) Evaluating the safety of food
chemicals. Washington, DC.
National Toxicology Program (NTP) (1992) NTP report on toxicity
studies of formic acid (CAS No.: 64-18-6) administered by inhalation
to F344/N rats and B6C3F1 mice. Research Triangle Park, NC, USA (NTP
Tox 19, NIH Publication No. 92-3342).
Nelson, B., Brightwell, W., Khan, A., Krieg, E., & Hoberman, A. (1990)
Developmental toxicology assessment of 1-octanol, 1-nonanol and 1-
decanol administered by inhalation to rats. J. Am. Coll. Toxicol.,
9: 93-97.
Newell, G.W., Petretti, A.D., & Reiner, L. (1949) Studies of the acute
and chronic toxicity of undecylenic acid. J. Invest. Dermatol.,
13:145-149.
Obe, G. & Beek, B. (1979) Mutagenic activity of aldehydes. Drug
Alcohol Depend., 4: 91-94.
Obe, G. & Ristow, H. (1977) Acetaldehyde, but not ethanol, induced
sister chromatid exchanges in Chinese hamster cells in vitro.
Mutat. Res., 56(2): 211-213.
Oda, Y., Hamono, Y., Inoue, K., Yamamoto, H., Hiihara, T., & Kunita,
N. (1978) Mutagenicity of food flavours in bacteria (1st report) (in
Japanese, no English summary).
Ozawa, S., Kimura, Y., & Hitotosumachi, S. (1994) Acetaldehyde
induces micronuclei in mice administered intraperitoneally. Mammal
Mutagenesis. Study Group Community. Mutagenicity, 2(1): 33-34.
Pardoe, S.U. (1952) Renal functioning in lead poisoning. Br. J.
Pharmacol., 7: 349-357.
PPG Industries Inc. (1991a) 14-Day dietary inclusion study on DSM 848.
Submission to EPA. Unpublished document.
PPG Industries Inc. (1991b) Mutagenicity test on AP6 and AP7 in the
CHO/HGPRT forward mutation assay. Unpublished journal.
Purchase, I.F.H. (1969) Studies in kaffir corn malting and brewing.
XXII. The acute toxicity of some fusel oils found in Bantu beer.
S. Afr. Med. J., 43: 795-798.
Rinehart, W.E., Kaschak, M., & Pfitzer, E.A. (1967) Range finding
toxicity data for 43 compounds. Ind. Hyg. Found. Am. Chem.
Toxicol., 6: 1-8.
Rodwell, D.E., Mercieca, M.D., Rusch, G.M., & Tasker, E.J. (1988) A
teratology screening study in rats with N-hexanol. Toxicologist, 11:
213 (abstract 848)
Schafer, E.W. Jr. & Bowles, W.A. Jr. (1985) Acute oral toxicity and
repellency of 933 chemicals to house and deer mice. Arch. Environ.
Contam. Toxicol., 14: 111.
Shelanski, M.V. & Moldovan, M. (1971) Private communication to FEMA.
Shimizu, H., Suzuki, Y., Takemura, N., Goto, S., & Matsushita, H.
(1985) The results of microbial mutation test for forty-three
industrial chemicals. Jpn. J. Ind. Health, 27: 400-419.
Sipi, P., Jarventaus, H., & Norppa, H. (1992) Sister-chromatid
exchanges induced by vinyl esters and respective carboxylic acids in
cultured human lymphocytes. Mutat. Res., 279: 75-82.
Smyth, H.F. Jr. & Carpenter, C.P. (1944) The place of the range of
finding test in the industrial toxicology laboratory. J. Ind. Hyg.
Toxicol., 26: 269-273.
Smyth, H.F. Jr., Carpenter, C.P., & Weil, C.S. (1951) Range finding
toxicity data: List IV. Arch. Ind. Hyg. Occup. Med., 4: 119-122.
Smyth, H.F. Jr., Carpenter, C.P., Weil, C.S., & Pozzani, U.C. (1954)
Range finding toxicity data: List V. Arch. Ind. Hyg. Occup. Med.,
10: 61-68.
Smyth, H.F. Jr., Carpenter, C.P., Weil, C.S., Pozzani, U.C., &
Striegel, J.A. (1962) Range finding toxicity data: List VI. Am.
Ind. Hyg. Ass. J., 23: 95-107.
Smyth, H.F. Jr., Weil, C.S., West, J.S., & Carpenter, C.P. (1969a)
Exploration of joint toxic action: twenty-seven industrial chemicals
intubated in rats in all possible pairs. Toxicol. Appl. Pharmacol.,
14: 340-347.
Stofberg, J. & Grundschober, F. (1987) The consumption ratio and food
predominance of flavoring materials. Perfum. Flavor., 12: 27-56.
Stofberg, J. & Kirschman, J.C. (1985) The consumption ratio of
flavoring materials: A mechanism for setting priorities for safety
evaluation. Food Chem. Toxicol., 23: 857-860.
Stolzenberg, S.J. & Hine, C.H. (1979) Mutagenicity of halogenated and
oxygenated three-carbon compounds. J. Toxicol. Environ. Health, 5:
1149-1158.
Taylor, J.M., Jenner, P.M., & Jones, W.I. (1964) A comparison of the
toxicity of some allyl, propenyl, and propyl compounds in the rat.
Toxicol. Appl. Pharmacol., 6(4): 378-387.
Tephly, T.R. (1991) The toxicity of methanol. Life Sci., 48:
1031-1041.
Tietz, N. (1986) Textbook of clinical chemistry. W.B. Saunders
Company, Philadelphia, PA.
Til, H.P., Woutersen, R.A., Feron, V.J., & Clary, J.J. (1988)
Evaluation of the oral toxicity of acetaldehyde and formaldehyde in a
4-week drinking-water study in rats. Food Chem. Toxicol., 26:
447-452.
Tislow, R., Margolin, S., Foley, E.J., & Lee, S.W. (1950) Toxicity
of undecylenic acid. J. Pharmacol. Exp. Ther., 98: 31-32.
Tove, S.B. (1964) Toxicity of saturated fat. J. Nutr., 84: 237-243.
Treon, J.F. (1963) Alcohols. In: Patty's industrial hygiene and
toxicology, 2nd rev. ed. Wiley Interscience, New York, Vol. II,
Chapter 34, p. 1466.
Von der Hude, W., Scheutwinkel, M., Gramlich, U., Fibler, B., &
Basler, A. (1987) Genotoxicity of three carbon compounds evaluated in
the SCE test in vitro. Environ. Mutagen., 9: 401-410.
von Oettingen, W.F. (1960) The aliphatic acids and their esters:
Toxicity and potential dangers: The saturated monobasic aliphatic
acids and their esters. Am. Med. Assoc. Arch. Ind. Health, 21:
28-65.
Voskoboinikova, V.B. (1966) Substantiation of the maximum permissible
concentration of the flotation reagent IM-68 and its component
alcohols (hexyl, heptyl and octyl alcohol) in bodies of water.
Gig. i. Sanit., 31: 310-316.
Wakabayashi, T., Horiuchi, M., Sakaguchi, M., Onda, H. & Lijima, M.
(1984) Induction of megamitochondria in the rat liver by n-propyl
alcohol and n-butyl alcohol. Acta Pathol. Jpn., 34: 471-480.
Waltman, R., Tricomi, V., Shabanah, E., & Arenas, R.A. (1978)
Prolongation of rat gestation time by unsaturated fatty acids.
Am. J. Obstet. Gynecol., 131: 735-738.
Wangenheim, J. & Bolcsfoldi, G. (1988) Mouse lymphoma L5178Y thymidine
kinase locus assay of 50 compounds. Mutagenesis, 3(3): 193-205.
Woodard, G., Lange, S.W., Nelson, K.W., & Calvery, H.O. (1941) The
acute oral toxicity of acetic, chlor acetic, dichloracetic and
trichloracetic acids. J. Ind. Hyg. Toxicol., 23: 78-82.
Yegorov, Y.L. & Andrianov, L.A. (1961a) Toxicity of heptyl, nonyl and
decyl alcohols. Uch. Zap. Mosk. Nauchn.-Isslad. Inst. G.
Yoo, Y.S. (1986) Mutagenic and antimutagenic activities of flavoring
agents used in foodstuffs. J. Osaka City Med. Center, 34(3-4):
267-288.
Zeiger, E., Anderson, B., Haworth, S., Lawlor, & Mortelmans, K. (1988)
Salmonella mutagenicity test: IV. Results from the testing of 300
chemicals. Environ. Mol. Mutagen., 11(Suppl. 12): 1-158.
Zeiger, E., Anderson, B., Haworth, S., Lawlor, & Mortelmans, K. (1992)
Salmonella mutagenicity test: V. Results from the testing of 311
chemicals. Environ. Mol. Mutagen., 19(Suppl. 21): 2-141.