FAO Meeting Report No. PL/1965/10/1
    WHO/Food Add./27.65

    EVALUATION OF THE TOXICITY OF PESTICIDE RESIDUES IN FOOD

    The content of this document is the result of the deliberations of the
    Joint Meeting of the FAO Committee on Pesticides in Agriculture and
    the WHO Expert Committee on Pesticide Residues, which met in Rome,
    15-22 March 19651

    Food and Agriculture Organization of the United Nations
    World Health Organization
    1965

                
    1 Report of the second joint meeting of the FAO Committee on
    Pesticides in Agriculture and the WHO Expert Committee on Pesticide
    Residues, FAO Meeting Report No. PL/1965/10; WHO/Food Add./26.65

    AZINPHOS-METHYL

    Chemical name

         O,O-dimethyl-S-(4-oxo-1,2,3,-benzotriazin-3,
    (4H)-yl-methyl)-phosphoro-dithioate; [S-(3,4-dihydro-4-oxobenzo-[-d]
    (1,2,3) triazin-3-yl-methyl]-dimethyl phosphoro-thiolothionate.

    Synonyms

         Guthion, Gusathion

    Empirical formula

         C10H12O3N3PS2

    Structural formula

    

    BIOLOGICAL DATA

    Biochemical aspects

         Azinphos-methyl is activated to gutoxon, a highly potent
    cholinesterase inhibitor. The molar I50 in rat brain is 2.99 × 10-8
    (Schrader, 1963).

    Acute toxicity

                                                                    
    Animal             Route      LD50 mg/kg     References
                                  body-weight
                                                                    

    Rat                Oral         11-25         DuBois et al., 1957;
                                                  Gaines, 1960

    Rat           Intraperitoneal    5-11.6       DuBois et al., 1957

    Mouse              Oral             8.0*      Sato, 1959

    Guinea-pig         Oral            80.0       Dubois et al., 1957

    Guinea-pig    Intraperitoneal      40.0       DuBois et al., 1957
                                                                    

    * Given as azinphos-methyl emulsion.

    Short-term studies

         Rat. The addition of azinphos-methyl to the diet of groups,
    each 10 young male and 10 young female rats, at levels of 2, 5 and 20
    ppm did not markedly alter the growth-rate over 60 days. The
    body-weight of the male rats fed 20 ppm was about 4% less than that of
    the controls. In the rats fed 2 and 5 ppm for 120 days, cholinesterase
    activity was unaffected, but at 20 ppm there was inhibition in the
    brain (10%) and in serum and erythrocytes (about 30%). After 120 days
    no appreciable changes in the gross and microscopic appearance of
    brain, heart, liver, spleen, adrenals, stomach, intestines, skeletal
    muscle and bone marrow were found. There was no evidence of
    demyelination in the nervous system (DuBois, 1956).

         When weanling male rats were fed diets containing 50 and 100 ppm
    of azinphos-methyl for 16 weeks, approximately half of each group
    died. All animals receiving azinphos-methyl in the diet showed marked
    cholinergic effects, including diarrhoea, salivation, lacrimation,
    muscular tremors and fasciculations. These symptoms were most marked
    during the first month on the diets. The rats fed 50 ppm of
    azinphos-methyl weighed about 10% less and the rats fed 10 ppm, 18%
    less than rats fed a normal diet. The cholinesterase activity of the
    serum, brain, erythrocytes and submaxillary glands of rats fed 50 and
    100 ppm was markedly inhibited. The inhibition was most marked in the
    erythrocytes and brain and the animals did not fully recover from
    these effects during a 3-week period on a normal diet.

         Both gross and microscopic examination failed to indicate any
    evidence of testicular atrophy due to the presence of the high levels
    of azinphos-methyl in the diet (Doull et al., 1951).

         Dog. Groups of 2 dogs, 1 male and 1 female, given 5, 10, 20 and
    50 ppm of azinphos-methyl did not show any loss of weight nor any
    symptoms of azinphos-methyl poisoning during a 12-week period. At
    dietary levels of 5, 10 and 20 ppm there was no significant decrease
    but at 50 ppm there was a 25% decrease in serum cholinesterase
    activity at the end of the 12-week period. The erythrocyte
    cholinesterase of the 1 male and 1 female dog began to be inhibited at
    10 ppm in the diet (DuBois, 1957).

    Long-term studies

         No data available.

    Comments on experimental studies reported

         Satisfactory studies have been carried out in rats but in the
    studies in dogs only a very small number of animals was used.

    EVALUATION

    Level causing no significant toxicological effect in rat

         5 ppm in the diet, equivalent to 0.25 mg/kg body-weight per day.

    Estimate of acceptable daily intake for man

         0-0.0025 mg/kg body-weight per day.

    Further work desirable

         Chemical composition and toxicity of the residues. Observations
    on the effect in man. Reproduction studies in the rat.

    REFERENCES

    Doull, J., Amido, P. & DuBois, K. P. (1951) Unpublished report, 5 June

    DuBois, K. P. (1956) University of Chicago. Unpublished final report,
    3 May

    DuBois, K. P. (1957) University of Chicago. Unpublished final report,
    1 June

    DuBois, K. P., Thursh, D. R. & Murphy, S. D. (1957) J. Pharmacol.
    exp. Ther., 119, 208

    Gaines, Th. B. (1960) Toxicol. Appl. Pharmacol., 2, 88

    Sato, J. (1959) Kumamoto med. J., 12, 312 (from Chemical
    Abstracts, 1960, 54, 21473)

    Schrader, G. (1963) Die Entwicklung neuer insektizider
    Phosphorsäure-Ester, Verlag Chemie Weinheim
    

    See Also:
       Toxicological Abbreviations
       Azinphos-methyl (ICSC)
       Azinphos-methyl (FAO/PL:1968/M/9/1)
       Azinphos-methyl (WHO Pesticide Residues Series 2)
       Azinphos-methyl (WHO Pesticide Residues Series 3)
       Azinphos-methyl (WHO Pesticide Residues Series 4)
       Azinphos-methyl (Pesticide residues in food: 1991 evaluations Part II Toxicology)