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    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