ASSESSMENT OF THE DEVELOPMENTAL TOXICITY, METABOLISM, AND PLACENTAL-TRANSFER OF N,N-DIMETHYLFORMAMIDE ADMINISTERED TO PREGNANT RATS

This study evaluates the developmental toxicity and placental and milk transfer of N,N-dimethylformamide (DMF) in rats. Sprague-Dawley rats were given 0, 50, 100, 200, and 300 mg DMF/kg/day, by gavage, on Gesta tional Days (GD) 6 through 20. Maternal toxicity was indicated by depr essions in weight gain and food consumption at doses greater than or e qual to 100 mg/kg. Fetal toxicity was indicated by decreased fetal bod y weight at doses greater than or equal to 100 mg/kg, and by increased incidences of two skeletal variations (absent or poorly ossified supr a-occipital and sternebrae) at 200 and 300 mg/kg. Thus, the maternal a nd developmental no-observed-adverse-effect level was 50 mg/kg/day. Th e time course disposition of [C-14]DMF was examined over a 48-hr perio d in GD12- and GD18-pregnant rats after a single oral dose of 100 mg [ C-14]DMF/kg. Peak concentrations of radiocarbon occurred within 1 hr a fter dosing. Embryonic (GD12) and fetal (GD18) tissues accounted for 0 .15 and 6% of the administered dose, respectively. Levels of radiocarb on in embryonic and fetal tissues were equal or slightly less than in maternal plasma up to 8 and 24 hr, respectively, and higher thereafter . HPLC analysis performed at intervals from 1 to 8 hr on GD12 and 1-24 hr on GD18 indicated that unchanged DMF and metabolites were readily transferred to the embryonic and fetal tissues, where their levels wer e generally equal to those in maternal plasma. The parent compound acc ounted for most of the radioactivity until 4-8 hr and then decreased. N-Hydroxymethyl-N-methylformamide (HMMF) and N-methylformamide (NMF) w ere the predominent metabolites and increased with time. Much lower co ncentrations were found for formamide and N-acetyl-S-(N-methylcarbamoy l)cysteine. Transfer of radioactivity into milk was studied in dams gi ven a single oral administration of 100 mg [C-14]DMF on Lactation Day 14. DMF, HMMF, and NMF were found in the milk at concentrations equal to those in plasma. (C) 1997 Society of Toxicology.