VINCLOZOLIN

    EXPLANATION

         Vinclozolin was reviewed by the JMPR in 1986 (FAO/WHO 1987a) and
    a Temporary ADI of 0-0.04 mg/kg bw was estimated. "Metabolite T" was
    identified as a major plant metabolite which had not been fully
    evaluated with respect to toxicity. Additional testing of metabolite T
    was determined necessary before an ADI could be allocated. These data
    have been submitted and are reviewed in this monograph addendum.

    EVALUATION FOR ACCEPTABLE INTAKE

    BIOLOGICAL DATA

    Toxicological Studies

    Acute toxicity

    Rats

         Metabolite T (3,5-dichlorophenylcarbamoyl-2-propionic acid)
    (purity >98%) was administered via oral savage in aqueous
    carboxymethyl cellulose to Wistar rats. Single oral doses of 1000,
    1780, 2610 and 3830 mg/kg bw were given to 5 male and 5 female rats
    per dose group. Each group was observed for 14 days. An LD50 =
    2740 mg/kg bw in males. The significance of cageside observations
    increased with doses of 1780 mg/kg bw and included the following:
    dyspnea, abnormal position, staggering, atonia, paresis, piloerection
    and poor general state (Kirsch, 1986a).

    Mice

         In an identical protocol to the rat acute study, NMRI mice were
    orally gavaged with metabolite T at doses of 500, 1000 and 2000 mg/kg
    bw. There were 5 male and 5 female mice per dose group. The LD50 was
    greater than 2000 mg/kg bw. Cageside observations included: dyspnea,
    staggering, piloerection and poor general state (Kirsch, 1986b).

    Special studies on mutagenicity

         Metabolite T was negative in a number of acceptable mutagenicity
    studies, which included assessments of gene mutations and chromosomal
    aberration. Summary results are presented in Table 1.

    COMMENTS

         "Metabolite T", 3,5-dichlorophenylcarbamoyl-2-propionic acid, was
    evaluated for acute toxicity in rats and mice, and for mutagenic
    activity in the Ames test, Rec assay and an in vitro cytogenetic
    assay in Chinese hamster ovary cells. These studies indicate that
    metabolite T is not mutagenic in the test systems analyzed. Although
    the acute oral toxicity studies demonstrate that metabolite T is more
    acutely toxic to rats and mice than vinclozolin, the 1986 Residue
    Evaluations indicate that it is a transient residue (also found in
    conjugated form) in only two commodities and is therefore not a
    residue of concern. The Meeting therefore estimated an ADI for
    vinclozolin.

        Table 1. Results of mutagenicity studies on "Metabolite T"
                                                                                                             

    Test system        Test object         Concentration of        Purity      Results        Reference
                                           Vinclozolin             (%)
                                                                                                             

    Ames assay 1/      S. typhimurium      0, 20, 100, 500,        >98         Negative       Gelbke, 1986
                       TA-98, 100,         2500, 5000 µg/plate                 2/
                       TA-1535, 1537

    Rec assay 1/       Bacillus            0, 10, 100, 500,        >98         Negative       Hoorn, 1987
                       subtills            1000, 2500, 5000,                   2/
                       strains H17         10000 µg/plate

    CHO/HGPRT 1/       Chinese             5-500 µg/ml, and        >98         Negative       Taalman, 1986
    Chromosome         hamster             250-1500 µg/ml                      2/
    aberration         ovary cells
                                                                                                             

    1/   With and without activation.
    2/   The positive controls gave the expected positive response.
    
    TOXICOLOGICAL EVALUATION

    LEVEL CAUSING NO TOXICOLOGICAL EFFECT

         Mouse:    486 ppm in the diet, equal to 86.8 mg/kg bw/day
         Rat:      486 ppm in the diet, equal to 27.2 mg/kg bw/day
         Dog:      100 ppm in the diet, equal to 7.19 mg/kg bw/day

    ESTIMATE FOR ACCEPTABLE DAILY INTAKE FOR MAN

         0-0.07 mg/kg bw

    REFERENCES

    Gelbke, P. 1986. Report on the study of Vinclozolin - Metabolite "T"
    BF 352-42 in the Ames test. Report No. 861398. Submitted to WHO by
    BASF Aktiengesellschaft, Ludwigshafen/ Rhein FRG.

    Hoorn, A. 1987. Report on the mutagenic evaluation of Winclozolin
    Metabolite "T" in the Rec assay with Bacillus subtilis. Report
    No. 87/028. Submitted to WHO by BASF Aktiengesellschaft,
    Ludwigshafen/Rhein FRG.

    Kirsch, P. 1986a. Report on the study of the acute oral toxicity
    on the rat based on OECD and EPA (FIFRA) of Vinclozolin Metabolite
    BF 352-42. Report No. 86/402. Submitted to WHO by BASF
    Aktiengesellschaft, Ludwigshafen/Rhein FRG.

    Kirsch, P. 1986b. Report on the study of the acute oral toxicity on
    the mouse based on OECD and EPA (FIFRA) of Vinclozolin Metabolite
    BF 352-42. Report No. 86/403. Submitted to WHO by BASF
    Aktiengesellschaft, Ludwigshafen/Rhein FRG.

    Taalman, R. 1986. Report on the clastogenic evaluation of Vinclozolin
    Metabolite "T" on an in vitro cytogenetic assay measuring chromosome
    aberration frequency in Chinese hamster ovary (CHO) cells. Report
    No. 86/418. Submitted to WHO by BASF Aktiengesellschaft,
    Ludwisshafen/Rhein FRG.
    

    See Also:
       Toxicological Abbreviations
       Vinclozolin (Pesticide residues in food: 1986 evaluations Part II Toxicology)
       Vinclozolin (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental)