Distribution and metabolism of the teratogen nitrofen (2,4-dichloro-4'-nitro diphenyl ether) in pregnant rats

Oral exposure of pregnant Long-Evans rats on day 11 of gestation to the teratogen, nitrofen (2,4-dichloro-4'-nitro diphenyl ether), which was uniformly labeled with 14C in the nitrophenyl ring, resulted in the accumulation of radioactivity in maternal fat with lesser amounts found in liver, kidney, other tissues, and in the embryonic compartment. The peak concentration of radioactivity occurred 7-9 h after dosing and the half-life of the label in maternal blood was approximately 8 days. In the embryonic compartment, radioactivity was first detected at 2 h after dosing, peaked at 4-6 h, and declined to half of that initially seen by 24 h. High performance liquid chromatography of embryo-placental extracts revealed 4 metabolites in addition to the parent compound: 4'-amino and 4'-acetylamino derivatives plus 2 hydroxylated derivatives. A similar metabolic profile was observed in maternal blood and liver. In another experiment, purified 4'-amino metabolite was found to have no adverse effect on neonatal survival when administered orally on day 11 of gestation at doses up to 215 mg/kg. These results suggest that the teratogenicity of nitrofen cannot be readily explained by preferential distribution of the compound in the embryo or by a unique profile of stable, extractable metabolites in the embryonic compartment.