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    TRIAZOPHOS

    EXPLANATION

         Triazophos was evaluated for acceptable daily intake by the 1982
    Joint Meeting (Annex 1, FAO/WHO, 1983a), at which time a temporary ADI
    of 0 - 0.0002 mg/kg b.w. was established. A toxicological monograph
    was published after that Meeting (Annex 1, FAO/WHO, 1983b). Additional
    studies required to complete the toxicological data base were a
    carcinogenicity study, a teratogenicity study in at least 1 mammalian
    species, metabolism studies in additional mammalian species (to
    explain species differences in acute toxicity studies, and additional
    mutagenicity studies. The results of the additional studies that were
    submitted to the present Meeting are summarized in this monograph
    addendum.

    EVALUATION FOR ACCEPTABLE INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Rats

         The metabolic fate of triazophos was studied in Wistar WIDK f SPF
    rats. 14C-Radiolabelled triazophos (labelled at the 3-position of
    the triazophos ring; 98% radiochemical purity) was administered by
    single oral gavage at about 5 mg/kg b.w. Pooled urine and faecal
    samples were collected after 24, 48, and 96 hours. Blood samples
    were also taken at 0, 0.5, 2, 4, 6, 8, 24, and 48 hours after
    administration. Maximal blood concentrations were attained after
    about 4 hours. The recovery rate of 98% after 96 hours indicates
    that excretion was relatively complete. The predominant route of
    excretion of radioactivity was urinary, with greater than 90% of the
    administered radioactivity excreted in 48 hours. Faecal elimination of
    administered radioactivity amounted to 4.6% after 48 hours. Residual
    tissue radioactivity concentrations were highest in the kidney and
    liver but were, nevertheless, relatively low at less than 0.004 ppm.

         Pooled rat urine contained 3 identifiable metabolites, as shown
    in Figure 1, 1-phenyl-3-hydroxy-(1H)-1,2,4-triazole (43%) and its
    glucuronide (36%) and sulfate conjugates (13%). Unchanged triazophos
    was not detected in the urine or faeces (Schwalbe-Fehl et al.,
    1986).

    Dogs

         The metabolic fate of triazophos was also examined in beagle dogs
    using the same treatment and sampling regime as for rats. Two female
    dogs were treated by gavage with 14C-radiolabelled triazophos
    (5 mg/kg b.w.) in sesame oil. Urinary excretion predominated,
    averaging 85% of administered dose after 24 hours and 92% after
    48 hours. Faecal elimination accounted for 0.3% and 7.5% of the
    administered dose after 24 and 48 hours, respectively. Maximal blood
    concentrations were attained after 2 hours; after 48 hours,
    radioactivity was not detectable in the blood.

         Residual tissue levels in the dogs were not determined.
    Qualitatively, the metabolic fate of triazophos in dogs was similar to
    that established in rats (see Figure 1). The urine contained the same
    three metabolites as in rats and in comparable amounts, namely
    1-phenyl-3-hydroxy-(1H)-1,2,4-triazole (49%) and its glucuronide (39%)
    and sulfate (5%) conjugates. Unchanged triazophos was not detected. In
    each case, the glucuronide metabolite underwent spontaneous conversion
    to the intermediate trazole metabolite (Schwalbe-Fehl et al., 1986).

    FIGURE 2

    Toxicological studies

    Special studies on mutagenicity

         Triazophos was without mutagenic activity in a number of
    in vitro and in vivo assays (see Table 1).

    Special study on acute toxicity

         The acute oral toxicity of the principal metabolite of
    triazophos, 1-phenyl-3-hydroxy-(1H)-1,2,4-triazole, was greater than
    5000 mg/kg b.w. (Diehl & Leist, 1986).

    Special studies on teratogenicity

    Rats

         Triazophos was fed in the diet to groups of 20 - 23 pregnant
    Hoe:WISK(SPF71) Wistar rats from day 6 to day 15 of gestation at
    approximate daily doses of 0.87, 4.2, or 22 mg/kg b.w. Dams were
    sacrificed at day 21 and the fetuses were examined for developmental
    abnormalities. There were no treatment-related effects on food
    consumption or body-weight gain. The number of fetal resorptions and
    viable fetuses, fetal weights, crown-rump lengths, and sex ratios did
    not differ significantly between treated and control groups. Placentas
    and placental weights were unaffected by treatment. No visceral or
    skeletal abnormalities were associated with treatment. No significant
    macroscopic changes were observed in the viscera of the dams at post
    mortem. Accordingly, the no-observed-effect level in this study
    exceeded 22 mg/kg b.w./day (Baeder et al., 1976).

    Rabbits

         The effects of repeated oral administration of triazophos on the
    progress and outcome of pregnancy were studied in the rabbit. As a
    previously conducted dose-ranging study had demonstrated that
    triazophos produced maternal toxicity at daily doses above 10 mg/kg
    b.w./day (Tesh et al., 1985a), groups of 18 artificially inseminated
    New Zealand white rabbits received 0, 2, 4, or 8 mg/kg b.w./day
    triazophos (92.1% pure) in sesame oil by gavage from day 6 to day 19
    of treatment, inclusively. The animals were sacrificed on day 19 and
    the uterine contents were removed and necropsied. Only the females
    receiving the highest dose exhibited a significant reduction of food
    intake and body-weight gain during the first third of the treatment
    period, although there was a tendency for the body-weight gain of all
    treated groups to lag behind that of controls. There were no
    dose-related influences of treatment on the numbers of early or late
    resorptions or on pre- or post-implantation losses. The number of
    viable young, their sex ratios, and fetal and placental weights were

    also unaffected. One dam in the highest-treatment group aborted, while
    another exhibited total litter resorption. No treatment-related
    effects on the morphogenesis of fetal viscera or skeletons were
    detected at necropsy of the viable young. Accordingly, the
    no-observed-effect level in this study was 4 mg/kg b.w./day
    (Tesh et al., 1985b).

        Table 1:  Results of mutagenicity studies on triazophos
                                                                                                             

    Test system              Test object             Concentration of       Results         Reference
                                                                                                             
                                                     triazophos
    Ames test                S. typhimurium          0, 0.2, 20,            Negative        Gerick & Wagner,
                             TA98, TA100,            50, & 500                              1977
                             TA1535, TA15371         /plate

    Gene conversion          Saccharomyces           1000, 2000,            Negative        Mondino, 1980a
                             cerevisiae D41          & 4000 g/1

    Forward mutation         Schizosacchromyces      1000, 2000,            Negative        Mondino, 1980b
                             pombe1                  & 4000 g/1

    Chromosome aberration    Human lymphocytes1      0.05, 0.5,             Negative        Mondino, 1981
                                                     5, & 50 g/1

    Micronucleus test        NMRI mice               0, 0.2, 2,             Negative        Mayer, et al.,
                                                     & 20 mg/kg                             1980
                                                                                                             

    1    metabolic activation (S-9)
        COMMENTS

         Comparative metabolism studies of triazophos in female rats and
    dogs did not reveal any significant qualitative differences. In each
    case the only significant urinary metabolites were 14C-1-phenyl-
    3-hydroxy-(1H)-1,2,4-triazole and its glucuronide and sulfate
    conjugates. This finding contrasts with the previous metabolism study
    in rats in which 14C-urea was the predominant urinary metabolite.
    The similarity observed in the present study of the metabolic fate
    and the excretion profiles in rats and dogs suggests that the relative
    differences in acute toxicity in these species noted by the 1982 Joint
    Meeting may have been due to other factors, such as the nature of the
    test vehicle employed in acute toxicity testing (viz., starch
    suspension and sesame oil), or to differences in species suscep-
    tibility to inhibition of acetylcholinesterase.

         Triazophos was apparently not embryotoxic or teratogenic in rats
    or in rabbits. It provided no evidence of mutagenicity in a series of
    short-term assays.

         Owing to the continuing absence of a carcinogenicity study, the
    Meeting extended the temporary ADI.

    TOXICOLOGICAL EVALUATION

    LEVEL CAUSING NO TOXICOLOGICAL EFFECT

         Rat:      10 ppm in the diet, equivalent to 0.5 /kg b.w./day.
         Dog:      1 ppm in the diet, equivalent to 0.025 mg/kg b.w./day.

    ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR MAN

         0 - 0.0002 mg/kg b.w.

    STUDIES WITHOUT WHICH THE DETERMINATION OF AN ADI IS IMPRACTICABLE,
    TO BE SUBMITTED BY 1990:

         Results of the ongoing carcinogenicity study in mice. [Note: This
    is a correction of the 1986 Joint Meeting report, in which this was
    incorrectly listed as a rat study.]

    STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE FOR THE CONTINUED
    EVALUATION OF THE COMPOUND

         1.   An appropriate delayed neurotoxicity study in hens.
         2.   Acute oral toxicity data on any metabolites of triazophos
              that are found in food crops.

    REFERENCES

    Baeder, C., Weigand, W., & Kramer, M.. Report on the embryotoxicity
    1976      study of triazophos in Wistar rats after oral administration
              in the feed. Unpublished Hoechst report No. 43676. Submitted
              to WHO by Hoechst AG, Frankfurt, FRG.

    Diehl & Leist. Hoe 014622 - Technical substance (Code Hoe 014622
    1986      Ut 2C99 0001): Test of the acute oral toxicity in male and
              female Wistar rats. Unpublished Hoechst Report No. 860771.
              Submitted to WHO by Hoechst AG, Frankfurt, FRG.

    Gericke, D. & Wagner, H.H. Test for mutagenicity in bacteria strains
    1977      in the absence and presence of a liver preparation.
              Unpublished Hoechst report No. 12/77. Submitted to WHO by
              Hoechst AG, Frankfurt, FRG.

    Mayer, D., Kramer, M., & Weigan, W. Test report on the mutagenicity of
    1980      HOE 02960 - active ingredient (Code - Hoe 02960 OI AS204)
              after oral administration to NMRI - Mice micronucleus test.
              Unpublished Hoechst Report No. 381/80. Submitted to WHO by
              Hoechst AG, Frankfurt, FRG

    Mondino, A. Study of the mutagenic activity of the compound HOE 02960
    1980a     with Saccharomyces cerevisiae. Unpublished report from
              Instituto Di Richerche Biomediche "Antoine Marxer" S.P.A.,
              Ivrea, Italy. Submitted to WHO by Hoechst AG,
              Frankfurt, FRG.

    Mondino, A. Study of the mutagenic activity in vitro of the compound
    1980b     HOE 02960 with Schizosaccharomyces pombe. Unpublished
              report from Instituto Di Richerche Biomediche "Antoine
              Marxer" S.P.A., Ivrea, Italy. Submitted to WHO by Hoechst
              AG, Frankfurt, FRG.

    Mondino, A. In vitro study of chromosome aberration induced by the
    1981      test article HOE 02960 OF AS 204 in cultured human
              lymphocytes. Unpublished report from Instituto Di Richerche
              Biomediche "Antoine Marxer" S.P.A., Ivrea, Italy. Submitted
              to WHO by Hoechst AG, Frankfurt, FRG.

    Schwalbe-Fehl, M., Schmidt, E., Kellner, H.M., & Eckert, H.H.
    1986      HOE 02960-14C, Triazophos, comparative metabolism
              study in rats and dogs. Unpublished Hoechst Analytical and
              Radiochemical Laboratories Report No. CM0481/85. Submitted
              to WHO by Hoechst AG, Frankfurt, FRG.

    Tesh, J.M., Ross, F.W. & Wightman, T.J. Triazophos. Active ingredient
    1985a     technical (Code: HOE 02960 OI ZD 002): Embryotoxicity study
              in rabbits, range-finding study. Unpublished report
              No. 84/HAG091/303 from Life Science Research, Eye,
              Suffolk, UK. Submitted to WHO by Hoechst AG, Frankfurt, FRG.

    Tesh, J.M., Ross, F.W., Wightman, T.J., & Wilby, O.K. Triazophos.
    1985b     Active ingredient technical (Code; HOE 02960 OI ZD 002):
              Embryotoxicity in rabbits. Unpublished report No. 84/HAG092/
              549 from Life Science Research, Eye, Suffolk, UK. Submitted
              to WHO by Hoechst AG, Frankfurt, FRG.
    


    See Also:
       Toxicological Abbreviations
       Triazophos (JMPR Evaluations 2002 Part II Toxicological)
       Triazophos (Pesticide residues in food: 1982 evaluations)
       Triazophos (Pesticide residues in food: 1983 evaluations)
       Triazophos (Pesticide residues in food: 1991 evaluations Part II Toxicology)
       Triazophos (Pesticide residues in food: 1993 evaluations Part II Toxicology)