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.