Formamide and dimethylformamide: Reproductive assessment by continuous breeding in mice

Reproductive toxicity in Swiss mice, during chronic exposure to formamide (FORM) or dimethylformamide (DMF), was evaluated using the Reproductive Assessment by Continuous Breeding Protocols. FORM administered in drinking water at 0, 100, 350, and 750 ppm (similar to 20 to 200 mg/kg/d) reduced fertility and litter size in F-0 animals without generalized toxicity at 750 ppm FORM. Crossover matings suggested that females were the affected sex. After F-1 mating, FORM reduced F-2 litter size, increased days to litter, reduced relative ovarian weight, and lengthened estrous cycles at 750 ppm, The No-Observed-Adverse-Effect-Level for generalized toxicity was 750 ppm for the F-0 and 350 ppm for the F-1 generation. Reproductive performance was normal at 350 ppm for both F-0 and F-1 mice. Chronic exposure to DMF in drinking water at 0, 1000, 4000, and 7000 ppm (similar to 200 to 1300 mg/kg/d) reduced fertility by the first litter at 4000 ppm, reduced body weight in F-0 females at 7000 ppm, and increased liver weights at all doses in both sexes. A crossover mating at 7000 ppm identified F-0 females as the affected sex. F-1 postnatal survival was reduced at greater than or equal to 4000 ppm DMF, F-1 mating reduced F-2 litter size and live pup weight at greater than or equal to 1000 ppm. At necropsy, body weight of F-1 males and females was reduced at greater than or equal to 4000 ppm. DMF-treated pups (both F-1 and F-2) and F-1 adults had cranial and sternebral skeletal malformations. Only DMF caused overt developmental toxicity. A No-Observed-Adverse-Effect-level for DMF was not established. (C) 1998 Elsevier Science Inc.