Benomyl, a
benzimidazole fungicide, produced ocular and craniocerebral malformations in fetal rats when administered to the dams by gavage in a dose of 62.4 mg/kg of maternal
body weight/day on days 7-21 of gestation. Ocular anomalies included
retinal dysplasia,
cataracts,
microphthalmia, and
anophthalmia. These anomalies occurred in 43.3% of fetuses exposed to
benomyl and a normal
protein diet but increased to 62.5% when
benomyl administration was combined with a
protein deficient (8%
casein) diet. Microscopic examination of the malformed eyes revealed that the most common abnormality,
retinal dysplasia, consisted of rosettes of
retinal cells and
retinal infolding. The majority of rosettes had a single layer and a limiting membrane. Rosettes with two or three layers were also observed, particularly in fetuses exposed both to
protein deficiency and
benomyl. Although
anophthalmia was identified macroscopically in five fetuses, only a single instance of true
anophthalmia was found microscopically. These data support the results of previous investigators that
benomyl induces ocular malformation and that
protein deficiency enhances the teratogenic effects of
benomyl. The disorderly proliferation of
retinal cells and rosette formation resembled the periventricular cell masses that accumulate in brains exposed to
benomyl and certain other teratogenic agents. The anti-
tubulin action of
benomyl is known to impair microtubule formation and it may produce brain and ocular malformations by disruption of neuronal proliferation and migration.