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    SUMMARY OF BENZIMIDAZOLES

         The benzimidazoles produce a variety of toxic effects in
    experimental biological systems, some of which may be due to the
    well-established binding affinity of 2-substituted benzimidazoles
    for tubulin, an important component of the cytoskeleton, including
    the spindle apparatus of dividing cells. Toxicity is frequently
    observed in haematopoietic tissues, liver, and testis, and there is
    evidence of embryotoxicity, carcinogenicity, and genotoxicity for
    certain benzimidazoles other than those considered by the Committee.

         Leukopenia and anaemia accompanying hypocellularity of bone
    marrow, spleen, and thymus have been described in a variety of
    species given febantel, fenbendazole, or oxfendazole; however, in
    the case of fenbendazole the effect was limited to leukopenia in
    pigs. Testicular hypoplasia was observed only with febantel in dogs
    and with oxfendazole in mice and rats. No such testicular effects
    were reported for fenbendazole. Embryotoxicity and/or fetotoxicity
    was observed with all three compounds. Evidence of teratogenicity
    was found only after the administration of oxfendazole to sheep,
    although the possibility of a similar effect in rabbits could not be
    excluded because of the very low doses of oxfendazole used.

         Hepatotoxicity was a finding common to the three compounds in
    several species. A small increase in hepatocellular carcinomas was
    observed only in female rats treated orally with a high dose of
    fenbendazole. The absence of similar evidence in experiments with
    febantel and oxfendazole could be related to the lower administered
    dose levels of these compounds. It is well known that even a
    two-fold difference in the dose level is important in the induction
    of significant responses in rodent carcinogenicity tests.

         In tests for genotoxicity, none of these compounds, or
    2-amino-5-phenylsulfinyl-2-benzimidazole (a metabolite of
    oxfendazole) was active in the Ames test or, where tested, in the
    primary rat hepatocyte DNA repair assay, in  in vivo assays for
    chromosomal aberrations, and the micronucleus test. Significant
    responses were obtained in the dominant lethal test in male mice
    with febantel and in the mouse lymphoma  tk-locus genotoxicity
    assay with fenbendazole and its 2-amino metabolite. Fenbendazole was
    also shown to inhibit mitosis in HeLa cells, a finding that may be
    important in the interpretation of the significant responses in the
    genotoxicity tests. Given the generally nongenotoxic properties of
    these compounds, any hepatocarcinogenic responses are likely to show
    dose-threshold effects.

         Metabolism of febantel, fenbendazole, and oxfendazole results
    in the presence of a combination of fenbendazole, oxfendazole and
    their metabolites (see Figure on page 23). However, insufficient
    data were available on the kinetics of the pathways involved and on

    the degree of absorption from the gastrointestinal tract to allow
    the Committee to make direct comparisons of the toxicity of each of
    the compounds on a molar basis after oral administration. The
    limited quantitative data available on the absorption of these three
    compounds in the oral carcinogenicity studies in rats suggested that
    both febantel and oxfendazole were tested at relatively low doses as
    compared with fenbendazole.

         Although no information was presented to identify the causal
    agent(s) responsible for the range of effects seen with the three
    compounds, oxfendazole appears to be the most toxic. The Committee
    therefore considered that an ADI based on the NOEL for oxfendazole
    would provide the most appropriate basis for proposing MRLs that
    would fully protect consumers of food containing residues resulting
    from the administration of any of the three compounds.



    See Also:
       Toxicological Abbreviations