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    PESTICIDE RESIDUES IN FOOD - 1982


    Sponsored jointly by FAO and WHO






    EVALUATIONS 1982





    Data and recommendations of the joint meeting
    of the FAO Panel of Experts on Pesticide Residues
    in Food and the Environment and the
    WHO Expert Group on Pesticide Residues
    Rome, 23 November - 2 December 1982

    Food and Agriculture Organization of the United Nations
    Rome 1983


    PIRIMICARB

    CHEMICAL STRUCTURE 1

    Explanation

         Pirimicarb was evaluated by the Joint Meeting in 1976 and 1978
    (FAO/WHO 1977 and 1979)1. The temporary ADI established in 1976 was
    re-assessed in 1978 and 0-0.01 mg/kg bw was recommended. The Joint
    Meeting concluded that, although it was not unduly concerned about the
    carcinogenic potential of pirimicarb, it wished to see a further
    carcinogenicity study undertaken in an appropriate mammalian species
    using a current accepted protocol. A mouse oncogenicity study was
    performed and is reviewed in this monograph addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    TOXICOLOGICAL STUDIES

    Special Study for Carcinogenicity

         Groups of Alderley Park Swiss derived mice (60/sex/group) were
    fed diets containing pirimicarb at levels of 0 (2 groups), 200, 400
    and 1 600 ppm for up to 96 weeks. Animals were examined throughout the
    study for abnormal clinical or behavioural conditions, body weights
    were determined and food consumption was measured at regular
    intervals. Complete histopathology, including bone marrow smears, were
    performed on all animals. There was no evidence of bacterial, viral or
    parasitic infections in any of the animals examined during the study.

         Body weights of the 1 600 ppm male and female rats were
    significantly decreased (p <0.01) throughout the study. Food
    consumption and food utilization were variably decreased throughout
    the test, as well as increased food wastage, primarily in the high
    dose group animals. Mortality rates for males were comparable among
    all treatment and control groups, whereas, mortality was significantly
    increased for high dose females. There was a significant increase in
    the finding of lymphosarcoma among the high dose females during weeks
    27-52, but the incidence of lymphosarcoma overall was comparable among
    all treatment and control groups.

              

    1  See Annex 2 for WHO and FAO documentation.

         The incidence of pulmonary tumours (pulmonary adenomas) in the
    high dose males and females is not biologically significant when
    compared with historical control data and the considerations from the
    first mouse study (Palmer and Samuels 1974).

         Hepatocellular nodules, classed as Type A or Type B, were
    significantly increased in the high dose group when compared to
    controls. No consistent trend in either Type A or B nodule was
    determined, and therefore, total incidence of liver nodules, per se,
    was evaluated. The incidence of these tumours was not significantly
    increased among groups through week 78 of the study, as determined by
    intercurrent deaths, but became significantly different from week 79
    to termination. There was no clear dose response, the mortality rate
    was increased for low and high dose males from weeks 76 to
    termination, and there was no previous identification of liver
    involvement or target organ toxicity to the liver. These support the
    conslusion that pirimicarb was not oncogenic in mice under the
    conditions of this study (Litchfield  et al 1980).

    Special Studies on Mutagenicity

    Rat - cytogenetic study

         Six-week-old, Wistar-derived outbreed male rats (180-220 g) were
    administered pirimicarb dissolved in maize oil (10, 50 and 100 mg/kg)
    by oral gavage. There were five experimental groups with eight
    animals/group. The negative and positive (EMS) control groups
    consisted of a total of 12 animals at each dosing regime. Six or 24
    hours after a single dose and 6 hours after the five consecutive daily
    doses of the test compound, animals were given a single IP treatment
    of 3 mg/kg colchicine and sacrificed two hours later by cervical
    dislocation. Chromosome slides were prepared and 50 cells from each
    animal were examined and scored for chromatid or chromosome gaps,
    chromatid breaks, fragments and other complex abnormalities.

         Pirimicarb did not induce chromosomal alterations in bone marrow
    cells of Wistar-derived outbred male rats when administered via oral
    gavage (Anderson  et al 1980).

     Salmonella/microsome reverse mutations

         Pirimicarb, dissolved in DMSO at five concentrations (4, 20, 100,
    500 and 2 500 g/plate), was evaluated in two separate studies for
    mutagenic activity by the plate-incorporation method of the Ames
     Salmonella reverse mutation test, in the presence and absence of
    mammalian metabolic activation from rat liver enzymes. Five histidine-
    requiring strains of  Salmonella typhimurium for detecting base-pair
    substitution, (TA 100, TA 1535) and frameshift mutation (TA 98, TA
    1537 and TA 1538) were used in the histidine-reversion assay. The

     in vitro mammalian metabolic activation system consisted of liver
    homogenate fraction "S-9" from Aroclor 1254 treated Sprague-Dawley
    albino rats and the co-factor solution described by Ames.

         Pirimicarb did not demonstrate a dose-related increase in the
    number of histidine-independent colonies, failed to induce any
    biologically significant change in the reversion frequency to
    histidine independence with or without the addition of metabolic
    activation preparation in the study, and thus, was not mutagenic at
    the dose levels tested (4 through 2 500 g/plate) (Trueman 1980;
    Longstaff 1978).

    COMMENTS

         Pirimicarb was last evaluated by the JMPR in 1978, when the
    Meeting expressed concern for the previously conducted rat and mouse
    oncogenicity studies. An additional long-term evaluation was requested
    and has been submitted and reviewed. It was concluded that pirimicarb
    was not carcinogenic in the rodent species tested, under the
    conditions of the study.

         Pirimicarb was also evaluated for mutagenic activity in a battery
    of  in vivo and  in vitro studies and all results were negative. In
    the absence of positive findings in the mutagenicity and
    carcinogenicity studies, the concerns previously expressed have been
    resolved and an ADI has been established.

    TOXICOLOGICAL EVALUATION

    Level Causing no Toxicological Effect

         Monkey : 2 mg/kg bw/day,

         Rat : 175 ppm in the diet, equivalent to 9 mg/kg bw

         Dog : 1.8 mg/kg bw/day.

    Estimate of Acceptable Daily Intake for Man

         0 - 0.02 mg/kg bw.

    REFERENCES

    Anderson, D., Richardson, C.R., Howard, C.A., Bradbrook, C., Salt,
    1980      M.J. and Cook S.K. Pirimicarb: a cytogenetic study in the
              rat. Report by ICI Central Toxicology Laboratory No.
              CTL/P/525, submitted by ICI to WHO. (Unpublished)

    Litchfield, M.H., Sotherson, M.F. and Jackson, D.G. Pirimicarb:
    1980      Lifetime feeding study in the mouse. CTL Study No. PM 0002,
              submitted by ICI to WHO.

    Longstaff, E. Pirimicarb; short-term predictive tests for
    1978      carcinogenicity results from the  Salmonella/microsome
              reverse mutation test. Report by ICI Central Toxicology
              Laboratory, No. CTL/P/428, submitted by ICI to WHO.
              (Unpublished)

    Palmer, S.M. and Samuels, D.M. Pirimicarb: 80-week carcinogenic study
    1974      in mice. CTL Study No. HO/CTL/P121/B, submitted by ICI to
              WHO.

    Trueman, R.W. An examination of pirimicarb for potential mutagenicity
    1980      using the  Salmonella/microsome reverse mutation assay. CTL
              Report No. Y00032/001/002, submitted by ICI to WHO.


    See Also:
       Toxicological Abbreviations
       Pirimicarb (Pesticide residues in food: 1976 evaluations)
       Pirimicarb (Pesticide residues in food: 1978 evaluations)
       Pirimicarb (Pesticide residues in food: 1979 evaluations)
       Pirimicarb (Pesticide residues in food: 1981 evaluations)