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 (approximately 20 to 200 mg/kg/d) reduced fertility and litter size in F0 animals without generalized toxicity at 750 ppm FORM. Crossover matings suggested that females were the affected sex. After F1 mating, FORM reduced F2 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 F0 and 350 ppm for the F1 generation. Reproductive performance was normal at 350 ppm for both F0 and F1 mice. Chronic exposure to DMF in drinking water at 0, 1000, 4000, and 7000 ppm (approximately 200 to 1300 mg/kg/d) reduced fertility by the first litter at 4000 ppm, reduced body weight in F0 females at 7000 ppm, and increased liver weights at all doses in both sexes. A crossover mating at 7000 ppm identified F0 females as the affected sex. F1 postnatal survival was reduced at > or =4000 ppm DMF. F1 mating reduced F2 litter size and live pup weight at > or =1000 ppm. At necropsy, body weight of F1 males and females was reduced at > or =4000 ppm. DMF-treated pups (both F1 and F2) and F1 adults had cranial and sternebral skeletal malformations. Only DMF caused overt developmental toxicity. A No-Observed-Adverse-Effect-Level for DMF was not established.