Evaluation of the OECD 421 reproductive toxicity screening test protocol using 1-(butylcarbamoyl)-2-benzimidazolecarbamate (benomyl).
The OECD 421 reproductive toxicity screening test protocol was evaluated using the fungicide benomyl as a test compound at 10, 30, or 90 mg/kg per day. Male rats showed dose-dependent testicular degeneration after 28 days exposure, as expected on the basis of literature data. Dams in the high dose group, exposed from 14 days premating to postnatal day 6, had pups with decreased weights at postnatal days 1 and 6. Prenatal deaths were increased, but no malformations were found. In contrast, in a developmental toxicity test with exposure between gestation days 6 and 15, 90 mg/kg induced a high level of postimplantation loss, with ophthalmic malformations in the surviving offspring, in agreement with literature data. It is suggested that premating exposure in the OECD 421 protocol may have induced tolerance to the compound, e.g., by modulation of biotransformation in the dam. These findings indicate that the teratogenic potential of a compound need not necessarily be revealed using this screening test. The OECD 421 protocol appeared sufficiently sensitive to reveal the reproductive hazard of benomyl on the basis of prenatal deaths and testicular and pup weight effects. However, the absence of congenital anomalies in the offspring after benomyl treatment according to the OECD 421 protocol underscores the notion that lack of biological activity in the test should not be regarded as evidence of lack of activity of a compound on reproductive parameters.
Unit Teratology, Endocrinology, and Perinatal Screening, National Institute for Public Health and Environmental Protection, Bilthoven, The Netherlands.
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Piersma
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Verhoef
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Dortant
D000818:Animals; D001542:Benomyl / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D005313:Fetal Death; D005659:Fungicides, Industrial / Q000633:toxicity*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017208:Rats, Wistar; D013723:Teratogens / Q000633:toxicity*; D013737:Testis / Q000187:drug effects / Q000473:pathology; D018675:Toxicity Tests / Q000379:methods*; D015430:Weight Gain / Q000187:drug effects
D005659:Fungicides, Industrial; D013723:Teratogens; D001542:Benomyl