Assessment of the Developmental Toxicity, Metabolism, and Placental Transfer of N,N-Dimethylformamide Administered to Pregnant Rats

This study evaluates the developmental toxicity and placentaland milk transfer of N,N-dimethylformamide (DMF) in rats. Sprague-Dawleyrats were given 0, 50, 100, 200, and 300 mg DMF/kg/day, by gavage,on Gestational Days (GD) 6 through 20. Maternal toxicity wasindicated by depressions in weight gain and food consumptionat doses 100 mg/kg. Fetal toxicity was indicated by decreasedfetal body weight at doses 100 mg/kg, and by increased incidencesof two skeletal variations (absent or poorly ossified supraoccipitaland sternebrae) at 200 and 300 mg/kg. Thus, the maternal anddevelopmental no-observed-adverse-effect level was 50 mg/kg/day.The time course disposition of [¹⁴C]DMF was examined over a48-hr period in GD12- and GD18-pregnant rats after a singleoral dose of 100 mg [¹⁴C]DMF/kg Peak concentrations of radiocarbonoccurred within 1 hr after dosing. Embryonic (GD 12) and fetal(GD18) tissues accounted for 0.15 and 6% of the administereddose, respectively. Levels of radiocarbon in embryonic and fetaltissues were equal or slightly less than in maternal plasmaup to 8 and 24 hr, respectively, and higher thereafter. HPLCanalysis performed at intervals from 1 to 8 hr on GD12 and 1–24hr on GD18 indicated that unchanged DMF and metabolites werereadily transferred to the embryonic and fetal tissues, wheretheir levels were generally equal to those in maternal plasma.The parent compound accounted for most of the radioactivityuntil 4–8 hr and then decreased. N-Hydroxymethyl-N-methylformamide(HMMF) and N-methylformamide (NMF) were the predominent metabolitesand increased with time. Much lower concentrations were foundfor formamide and N-acetyl-S-(N-methylcarbamoyl)cysteine. Transferof radioactivity into milk was studied in dams given a singleoral administration of 100 mg [¹⁴C]DMF on Lactation Day 14.DMF, HMMF, and NMF were found in the milk at concentrationsequal to those in plasma.