The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings were not evaluated in accordance with the levels of evidence for reproductive or developmental criteria established by NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of NTP or the U.S. Government.
N,N-Dimethyl Formamide (DMF), a high production industrial solvent with high potential for human exposure, was evaluated for reproductive toxicity in CD-l (Swiss) mice using the Reproductive Assessment by Continuous Breeding (RACB) Protocol. Male and female mice were exposed to DMF in drinking water at doses of 0, 1000, 4000. and 7000 ppm (mean exposure 193 to 1216 mg/kg/day for non-lactating F0 animals and 259 to 1934 mg/kg/day for F1 animals).
At 1000 ppm in F0 mice, there was increased relative liver weight for males and females and increased relative kidney plus adrenal weight For females. Although liver histopathology was only examined in DMF-treated animals exhibiting gross hepatic lesions (2/10 high-dose males and 2/10 mid-dose females), all those examined exhibited centrilobular hepatic hypertrophy that was considered treatment related. Reproductive toxicity was observed in the F0 generation, primarily at the mid- and high-dose levels. At 4000 and 7000 ppm, fertility and fecundity were reduced; pups were observed to have various craniofacial malformations. The crossover mating trial was not able to determine the gender responsible for the decrease in fertility observed in the continuous breeding phase of the study. However, females treated with 7000 ppm DMF produced somewhat smaller litters compared to the control pairs or the treated males. In addition, 7000 ppm DMF females, mated to control males, produced pups with malformations similar to those observed in Task 2, confirming the developmental toxicity of this compound. Further examination of pups from 7000 ppm Task 3 females revealed abnormal ossification of the cranial plates and sternebrae. At F0 necropsy, all male and female organ weights, sperm parameters, and estrous cycle length were not adversely affected, with the exception of a slight decrease in sperm concentration at the high dose and spermatid concentration at the low and high doses.
F1 postnatal survival at 4000 and 7000 ppm was reduced during the pre- and post-weaning periods, and F1 body weight was reduced at the mid and high doses. Surviving F1 pups in the mid- and high-dose groups exhibited cranial malformations, including small and foreshortened skulls. In the F1 mating trial. the mating index was reduced at 7000 ppm, while the pregnancy index, litter size, and proportion of pups born alive were reduced at 4000 and 7000 ppm. Litter weight was reduced at all doses of DMF. Malformation incidence appeared to be increased at greater than or equal to 4000 ppm in the F2 pups. The F1 animals in the 1000 ppm group had an increase in relative liver weight in both males and females, associated with treatment- related hepatic hypertrophy. Reproductive toxicity, including decreased indices of fertility or pregnancy, litter size, and malformation incidence in F2 offspring, was observed at doses of 4000 ppm and above, whereas 7000 ppm DMF lengthened the estrous cycle of exposed females. At necropsy, F1 animals exposed to greater than or equal to 4000 ppm DMF and selected For skeletal evaluation exhibited malformations persistent from birth. In summary, the MTD for generalized toxicity was 1000 ppm for both the F0 and F1 generations. The No-Observed-Adverse-Effect-Level (NOAEL) for generalized toxicity could not be determined For either the F0 or F1 generation. Reproductive and developmental toxicity, observed at greater than or equal to 4000 ppm DMF For the F0 and at greater than or equal to 1000 ppm DMF For the F1 generations, occurred in the presence of mild general toxicity.
NTIS # PB92-123842