This pesticide was evaluated for acceptable daily intake by the
    Joint Meetings of the FAO Committee on Pesticides in Agriculture and
    the WHO Expert Committee on Pesticide Residues (FAO/WHO, 1965;
    FAO/WHO, 1968). At the latter meeting it was considered desirable for
    studies to be made available on cholinesterase inhibition of plasma
    and erythrocytes in man, on the metabolism of the pesticide by man and
    on the identification and toxicology of metabolites. The present
    monograph addendum summarizes further relevant studies that have
    become available.


    Biochemical aspects

    Absorption, distribution and excretion

         A preliminary study showed that, following oral or
    intraperitoneal administration of 0.1-0.2 mg/kg bw of 14C-labelled
    azinphos-methyl to rats, about two-thirds of the activity was excreted
    in urine and one-quarter in faeces within 48 hours. Over 90% of orally
    administered compound is absorbed and activity is eliminated from the
    body with a halflife of eight to nine hours. Following intravenous
    administration, biliary excretion accounts for about one-third of
    activity eliminated. Less than 0.1% of activity appeared as carbon
    dioxide, indicating that the benzotriazine ring is not degraded
    extensively. An equivalent of only 0.1 mg/kg azinphos-methyl tissue
    remained in the tissues 48 hours after oral administration of 2 mg/kg
    bw of the compound (Anon, 1973).


         The in vitro metabolism of methoxy-14C- and 32P-azinphos-methyl
    by subcellular fractions from mouse liver was investigated.
    Degradation occurred mainly in microsomal and soluble fractions.
    Dimethylphosphorothioic and dimethylphosphoric acids were formed by
    microsomal dearylation. The microsomal system also caused oxidative
    desulfuration, resulting in the formation of the oxygen analogue.
    Examination of the degradative activity of the soluble fraction
    suggested that glutathione alkyltranferase catalysed the conjugation
    of azinphos-methyl and glutathione, the only products found being
    S-methyl glutathione and desmethyl azinphos-methyl.  The enzyme showed
    little activity against the oxygen analogue of azinphos-methyl
    (Motoyama and Dauterman, 1972).


    Special studies on mutagenicity

         Groups of 12 male mice received a single intraperitoneal
    injection of 0, 0.125 or 0.25 mg/kg bw of azinphos-methyl as a
    solution in corn oil. Each mouse was mated with a group of three
    virgin females. At the end of one week they were replaced by a further
    group and this procedure was repeated for six weeks. Female animals
    were examined to determine the number of implantation and resorption
    sites and the number of embryos produced. The fertility of male
    animals and the number of implantation and embryos were unaffected by
    treatment and the number of deciduomata were not increased (Arnold et
    al., 1971).

    Observations in man

         Two male subjects each received 16 mg azinphos-methyl orally
    daily for 30 days. The daily urinary output of azinphos-methyl related
    compounds, estimated by a method which converted them to anthranilic
    acid, was determined before, during and after cessation of treatment.
    The amount of anthranilic acid excreted in urine was increased on the
    day following the start of treatment and remained at a high level
    during treatment with azinphos-methyl; it returned to a normal level
    on the day following cessation of treatment. Neither subject showed a
    depression of blood cholinesterase levels during treatment (Thornton,

         Groups of five male subjects received 10, 12, 14 or 16 mg
    azinphos-methyl by mouth daily for 30 days. Plasma and erythrocyte
    cholinesterase levels were measured before and during treatment. No
    significant inhibition of enzyme activity was found (Rider et al.,

         Further groups of five male subjects received daily doses of 18
    or 20 mg for an unspecified period with depression of serum or
    erythrocyte cholinesterase activity (Rider et al., 1972).


         Azinphos-methyl is readily absorbed from the gastrointestinal
    tract although some of it or its metabolites are returned to the gut
    by biliary secretion. The benzotriazin moiety is rapidly excreted in
    animals and man and concentration in particular organs does not occur.
    Dimethylphosphorothioic and dimethylphosphoric acids, desmethyl
    azinphos-methyl and the oxygen analogue of azinphos-methyl have been
    demonstrated as metabolites in in vitro studies using mouse tissues.

         The results of a dominant lethal test in mice were negative.

         Plasma and erythrocyte cholinesterase activities were not
    depressed in human subjects receiving up to 16 mg azinphosmethyl daily
    for 30 days. Full details of the investigation, however, are not
    available and the meeting was unable to use these data in estimating
    the acceptable daily intake for the compound. The previous estimate
    based on the results of experimental studies on animals was confirmed.


    Level causing no significant toxicological effects

         Rat: 2.5 ppm (0.00025%) in diet, equivalent to 0.125 mg/kg bw

         Dog: about 5 ppm (0.0005%) in dry diet, equivalent to 0.125 mg/kg 

    Estimate of acceptable daily intake in man

         0-0.0025 mg/kg bw



    1.   Identification and toxicity of metabolites.

    2.   Residue data for other crops including grapes, for which
         insufficient data were available to establish or amend tolerances
         at the 1973 meeting.


    Anon. Pharmacokinetic studies with 14C-labelled Gusathion A
    1973                and Gusathion M (Provisional results). Unpublished
                        report from Isotopen-Institut submitted by
                        Chemagro Corporation

    Arnold, D., Keplinger, M. L. and Faucher, O. E, Mutagenic
    1971                Study with Guthion in Albino Mice. Unpublished
                        report from Industrial Biotest Laboratories, Inc.
                        submitted by Chemagro Corporation

    Motoyama, N. and Dauterman, W. C. The in vitro metabolism of
    1972                azinphos-methyl by mouse liver. Pesticide
                        Biochemistry and Physiology, 2: 170-177

    Rider, J. A., Swader, J. I. and Puletti, E. J.
    1971                Anticholinesterase toxicity studies with methyl
                        parathion, guthion and phosdrin in human subjects.
                        Federation Proceedings, 30: H.2

    Rider, J. A., Swader, J. I. and Puletti, E. J.
    1972                Anticholinesterase toxicity studies with guthion,
                        phosdrin, di-syston and trithion in human
                        Subjects. Fed. Proc,, Fed. Amer, Sec. Exp. Biol.
                        31: 520

    Thornton, J. S. Analysis of urine samples from human subjects
    1971                treated orally with guthion. Unpublished report
                        from Chemagro Corporation, Research and
                        Development Department


    See Also:
       Toxicological Abbreviations
       Azinphos-methyl (ICSC)
       Azinphos-Methyl (FAO Meeting Report PL/1965/10/1)
       Azinphos-methyl (FAO/PL:1968/M/9/1)
       Azinphos-methyl (WHO Pesticide Residues Series 2)
       Azinphos-methyl (WHO Pesticide Residues Series 4)
       Azinphos-methyl (Pesticide residues in food: 1991 evaluations Part II Toxicology)