METHYL ANTHRANILATE
Explanation
Methyl anthranilate was reviewed at the eleventh meeting of the
Joint FAO/WHO Expert Committee on Food Additives, specifications were
prepared, and a conditional acceptable daily intake for man (ADI) of
0-1.5 mg/kg bw was established (FAO/WHO, 1967; FAO/WHO, 1968).
Since this previous review, new data has become available and is
included in this monograph.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
Substantial evidence has accumulated showing that many esters
readily undergo enzymatic hydrolysis into their component alcohols and
acids (F.E.M.A., 1974; Longland et al., 1977; Grundschober, 1977). In
the case of methyl anthranilate, there is direct experimental evidence
showing that this ester, while only slowly hydrolysed by artificial
gastric or pancreatic juice, was readily hydrolysed in rat liver
homogenate (50% in 26.6 minutes) and rapidly hydrolysed in a
homogenate of rat small intestine mucosa (50% in 2.5 minutes)
(Longland et al., 1977). Methyl anthranilate has also been shown to be
completely hydrolysed (>99% in two hours) in pig liver homogenate;
but was more resistant to hydrolysis in pig jejunum homogenate and
completely unhydrolysed by a pancreatin preparation (Grundschober,
1977).
The hydrolysis products of methyl anthranilate are, of course,
methyl alcohol and anthranilic acid. Methyl alcohol is readily
metabolized via well-known pathways to carbon dioxide and water
(Williams, 1959; Harger, 1967). Anthranilic acid is a normal
metabolite in man and is excreted in the urine, primarily, as
o-aminohippuric acid and to a lesser extent as anthranilic acid
glucuronide. Data are also available on other species (rat, rabbit,
cat, dog) (Charconnet-Harding et al., 1953; Price et al., 1956; Brown
& Price, 1956; Williams, 1959).
TOXICOLOGICAL STUDIES
Special studies on carcinogenicity
There was no increase in the incidence of primary lung tumours in
A/He mice (20 females per group), over a period of 24 weeks, that
received a total dose of methyl anthranilate of 2.25 or 11.2 g/kg bw
(repeated i.p. injections three times a week for a total of 24
injections). Methyl anthranilate was not considered to be a carcinogen
under the conditions of this test (Stoner et al., 1973).
A recent bioassay of anthranilic acid for possible
carcinogenicity has shown that, under the conditions of the test,
anthranilic acid was not carcinogenic for either Fisher 344 rats or
B6C3F1 mice (DHEW, 1978).
Acute toxicity
LD50
Animal Route mg/kg bw References
Mouse oral 3 900 Jenner et al., 1964
Rat oral 2 910 Jenner et al., 1964
Rat oral 3 000 Dow, 1967
Guinea-pig oral 2 780 Jenner et al., 1964
Guinea-pig oral 4 000 Dow, 1967
Rabbit Dermal 5 000 Opdyke, 1974
Short-term studies
Rat
Groups of 10 male and 10 female rats were maintained for 13 weeks
on diets containing methyl anthranilate at levels of 0, 1000 and
10 000 ppm (approximately equivalent to 50 and 500 mg/kg bw). No
adverse effects were observed on body weights, appearance, food
intake, haematology, organ weights, macroscopic or microscopic (at
highest dietary level) examination of the major organs (Hagan et al.,
1967).
Groups of 10 male and 10 female weanling rats were maintained for
a period of 115 days on diets containing methyl anthranilate at levels
of 0, 3000 and 10 000 ppm (approximately equivalent to 150-300 and
500-1000 mg/kg bw). There was no evidence of adverse effects at the
3000 ppm level as judged by appearance, behaviour, growth, mortality,
terminal haematological examination, final body weights, organ
weights, and gross and microscopic examination. The only observable
effects noted at the 10 000 ppm level were increases in the average
weights of the liver and kidneys, and slight (minimal) histological
changes in the kidneys (Dow, 1967).
Groups of 35 male and 35 female rats received doses of 1.5 and
3.0% of anthranilic acid in the diet for 78 weeks. There was a matched
control group of 15 males and 15 females, which was part of a pooled
control group of 30 males and 30 females.
No increases in tumours were noted, nor were there any abnormal
or dose-related non-neoplastic lesions. There was a slight dose-
related depression of weight gain, but there were no unusual clinical
signs, nor was there any effect on survival.
Groups of 35 male and 35 female mice received doses of 2.5 and
5.0% of anthranilic acid in the diet for 78 weeks. As in the rat
experiment, there were matched and pooled control groups of 15 and 30
of each sex.
No increases in tumours were noted, nor were there abnormal or
dose-related non-neoplastic lesions. Except for low-dose males, there
was a slight dose-related depression of weight gain. There were no
unusual clinical signs and there was no effect on survival (DHEW,
1978).
Comments
The evaluation of methyl anthranilate is based on short-term
toxicity studies and on data demonstrating the conversion of methyl
anthranilate to methyl alcohol and anthranilic acid.
Data from long-term studies in rats and mice with anthranilic
acid show that there is no increase in tumour incidence in test
animals compared with the controls. The previous conditional ADI was
converted into an ADI. A monograph was prepared.
EVALUATION
Level causing no toxicological effect
Rat: 3000 ppm (0.3%) in the diet equivalent to 150 mg/kg bw.
Estimate of acceptable daily intake for man (ADI)
0-1.5 mg/kg bw.
REFERENCES
Brown, R. R. & Price, J. M. (1956) Quantitative studies on metabolites
of tryptophan in the urine of the dog, cat, rat, and man, J.
Biol. Chem., 219, 985-997
Charconnet-Harding, F., Dalgliesh, C. E. & Newberger, A. (1953) The
relation between riboflavin and tryptophan metabolism, studied in
the rat, Biochem. J., 53, 513-521
DHEW (1978) Bioassay of anthranilic acid for possible carcinogenicity,
US Department of Health, Education, and Welfare, DHEW Publication
No. (National Institute of Health) 78-836
Dow (1967) Toxicity of methyl anthranilate. Unpublished report from
the Dow Chemical Company, Midland, Michigan, USA
FAO/WHO (1967) Toxicological evaluation of some flavouring substances
and non-nutritive sweetening agents, FAO Nutrition Meetings
Report Series No. 44a; WHO/Food Add./68.33
FAO/WHO (1968) Specifications for the identity and purity of food
additives and their toxicological evaluation: some flavouring
substances and non-nutritive sweetening agents, Eleventh Report
of the Joint FAO/WHO Expert Committee on Food Additives, FAO
Nutrition Meetings Report Series No. 44; World Health
Organization Technical Report Series No. 383
F.E.M.A. (1974) Scientific literature review of aliphatic primary
alcohols, aldehydes, esters, and acids in flavor usage.
Published by the National Information Services under contract
with the Food and Drug Administration
F.E.M.A. (1978) Scientific literature review of anthranilates in
flavor usage. Published by the National Information Services
under contract with the Food and Drug Administration
Grundschober, F. (1977) Toxicological assessment of flavouring
esters, Toxicology, 8, 387-390
Hagan, E. C. et al. (1967) Food flavourings and compounds of related
structure: II. Subacute and chronic toxicity, Food Cosmet.
Toxicol., 5, 141-157
Harger, R. N. (1967) Aliphatic alcohols, Prog. Chem. Tox., 3, 1-61
Jenner, P. M. et al. (1964) Food flavourings and compounds of related
structure. I. Acute oral toxicity, Food Cosmet. Toxicol., 2,
327-343
Longland, R. C., Shilling, W. H. & Gangolli, S. D. (1977) The
hydrolysis of flavouring esters by artificial gastrointestinal
juices and rat tissue preparations, Toxicology, 8, 197-204
Opdyke, D. L. J. (1974) Fragrance raw materials monographs, Food
Cosmet. Toxicol., 12, 935-936
Price, J. M., Brown, R. R. & Ellis, M. E. (1956) Quantitative studies
on the urinary excretion of tryptophan metabolites by humans
ingesting a constant diet, J. Nutr., 60, 323-333
Stoner, G. D. et al. (1973) Test for carcinogenicity of food additives
and chemotherapeutic agents by the pulmonary tumor response in
strain A mice, Cancer Res., 33, 3069-3085
Williams, R. T. (1959) Detoxication mechanisms, The metabolism and
detoxication of drugs, toxic substances and other compounds,
London, Chapman & Hall Ltd, 2nd ed.
See Also:
Toxicological Abbreviations
Methyl anthranilate (FAO Nutrition Meetings Report Series 44a)
METHYL ANTHRANILATE (JECFA Evaluation)