Teratogenic effects of benomyl in the Wistar rat and CD-1 mouse, with emphasis on the route of administration

Abstract

Benomyl, a systemic fungicide whose molecular basis of action is inhibition of tubulin polymerization, was administered during organogenesis via the dietary and gavage routes to pregnant Wistar rats, and via the gavage route to pregnant CD-1 mice. Benomyl was fetotoxic and teratogenic in both species via the po route of administration, producing a broad spectrum of malformations at a dose of 62.5 mg/kg/day in the rat and 100 mg/kg/day in the mouse. Via the dietary route of administration, benomyl produced fetotoxicity, but no teratogenic effects. The fetotoxic potential of benomyl from dietary exposure was approximately an order of magnitude less effective than from gavage exposure. Benomyl did not affect postnatal growth, viability, or locomotor activity at subteratogenic doses. The most sensitive indicator of perinatal exposure to benomyl via the po route of administration was a permanent reduction in testes and accessory sex gland weight noted in male offspring of dams receiving 31.2 mg/kg/day benomyl during gestation and lactation. No effects on any parameters were evident in rats receiving 15.6 mg/kg/day by po gavage. The relevance of the two routes of administration for risk extrapolation is discussed.