METHYL-N-METHYLANTHRANILATE
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
Metabolism
Single adult rats were each given orally by gavage a 1.0, 5.0 or
50 g dose of methyl N-methylanthranilate. Analysis of the 24-hour
urine revealed unspecified amounts of N-methylanthranilic acid and
anthranilic acid in a ratio of approximately 20:1. It was concluded
that ingestion of methyl N-methylanthranilate is followed promptly by
de-esterification with the urinary elimination principally of the
N-methylated acid (FDRL, 1963).
Although methyl-N-methyl anthranilate was not hydrolysed in
artificial intestinal fluid, 20% was hydrolysed in two hours by pig
jejunum preparations and more than 90% was hydrolysed in two hours by
pig liver preparations (Grundschober, 1977). This is in general
agreement with guinea-pig studies in which an ester solution at 25 ppm
in saline was completely hydrolysed whereas at 270 ppm significant
quantities of ester were detected in the portal blood (Pelling et
al.).
TOXICOLOGICAL STUDIES
Special studies on dermal toxicity
No irritation occurred when methyl N-methyl anthranilate was
tested at full strength on rabbit skin for 24 hours nor at 10% in
petrolatum on two human subjects. It produced two (out of a possible
25) questionable sensitization reactions in humans at 10% in
petrolatum but no reactions when retested on a new group of 25
subjects (Opdyke et al., 1975).
Special studies on mutagenicity
Studies by Sakai et al. (1978) indicated that methyl N-methyl-
anthranilate was non-mutagenic in a Salmonella test system.
Acute toxicity
Species Route of LD50
administration mg/kg bw References
Rat oral 3 700 Opdyke, 1975
Rat (female) oral Between 2250 and Gaunt et al.,
3380 (100% death 1970
at high level)
Rabbit dermal 5 000 Opdyke, 1975
LC50 - larvae of Tribolium destructior - 0.1151 mg/cm2
Vasechko et al.
1970
Short-term studies
Bar & Griepentrog (1967) administered daily to rats for 12 weeks
a 20.3 mg/kg dose of methyl N-methyl anthranilate by gavage. No toxic
effects were noted and the no-effect level was reported as 20.3 mg/kg.
Methyl N-methylanthranilate was added to the diet of rats at
levels calculated to result in approximate daily intakes of 19.9 mg/kg
for males and 22.2 mg/kg for females for 90 days. Measurement of body
weight and food consumption revealed no significant differences
between test and control rats. Haematological examinations and blood-
chemical determinations conducted at weeks 6 and 12 revealed normal
values. Liver and kidney weights at autopsy were normal, and
histopathology revealed no dose-related lesions (Oser et al., 1965).
Methyl-N-methylanthranilate was added to the diet of rats at
levels of either 300, 1200 or 3600 ppm (approximately equivalent to a
daily intake of 15, 60 or 180 mg/kg) for 90 days. Measurement of body
weight and food intakes showed no significant differences between test
and control animals. Haematological examination revealed a slight but
significant leucocytopaenia and anaemia in animals receiving 1200 and
3600 ppm at week 6, but not at 90 days. The results of urinalysis
conducted at week 6 and blood biochemistry examinations at week 13
were within normal limits. Measurements of organ weights revealed a
statistically significant increase in the kidney weights in males
receiving 1200 and 3600 ppm. Gross findings showed no evidence of
agent-related lesions (Gaunt et al., 1970).
Long-term studies
No data available.
OBSERVATIONS IN MAN
One human volunteer was given orally a single 150 mg dose of
methyl N-methylanthranilate and urine was collected at seven hours
following treatment. Analysis revealed unspecified amounts of
N-methylanthranilic acid and anthranilic acid in a ratio of
approximately 20:1. The authors concluded that ingestion of methyl
N-methylanthranilate is followed promptly by de-esterification with
the urinary elimination principally of the N-methylated acid (FDRL,
1963).
The maximum possible daily intake in man has been calculated to
be 12.6 mg/day (0.21 mg/kg/day) for a 60 kg adult in the United
Kingdom (Gaunt et al., 1970) and 80 mg/kg/day in the United States of
America. This large difference is likely to be the result of the large
quantity of methyl N-methylanthranilate permitted in chewing gum in
the United States of America.
Comments
Methyl N-methylanthranilate appears to be of low toxicity in man
and rats and is rapidly hydrolysed to N-methylanthranilic and
anthranilic acid. In a short-term study in rats a no-effect level of
300 ppm was found. Relevant data for anthranilic acid is discussed
under methylanthranilate.
EVALUATION
Estimate of acceptable daily intake for man
0-0.2 mg/kg bw.
REFERENCES
FDRL (Food and Drug Research Laboratory) (1963) Unpublished report
Grundschober, F. (1977) Toxicology, 8, 370-381
Pelling, D. et al. (?) Unpublished report
Opdyke, D. L. J. (1975) RIFM monographs on fragrance materials,
Food and Cosmet. Toxicol., 13, 791
Sakai, A. et al. (1978) Shokuhin Elseigaku Zasshi, 19, 85-90
Gaunt, I. F. et al. (1970) Food Cosmet. Toxicol., 8 (4), 359-368
Vasechko, G. I. et al. (1970) Akad. Ukc. RSR B, 32, 275
Bar, F. U. & Griepentrog, F. (1967) Medizin Ernahr, 8, 244
Oser, B. L., Carson, S. & Oser, M. (1965) Food Cosmet. Toxicol., 3, 563