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
See Also: Toxicological Abbreviations