Further characterization of the distribution and metabolism of nitrofen in the pregnant rat.

Nitrofen (2,4-dichloro-4'-nitrodiphenyl ether) is an herbicide with potent teratogenic activity in rodent species. The present study was an extension of previous efforts to characterize the distribution and metabolism of nitrofen in pregnant rats. Following a single p.o. exposure to radiolabeled compound on day 10 of pregnancy, maternal and embryonic tissues were collected at intervals from 1.5 to 72 hours. Radioactivity was accumulated and retained in maternal fat for over 72 hours. Peak levels were reached in other maternal organs at 3-12 hours. The half-life in maternal plasma was estimated to be 42 hours. Radioactivity was first detected in the embryonic compartment at 3 hours and continued to increase through the 72-hour time point. HPLC analysis indicated that the parent compound is initially deposited in maternal fat and after 48 hours redistributes to other maternal organs and to the embryo. The 5-hydroxy derivative was the major nitrofen metabolite found in maternal tissues, while the 4'-amino and 4'-acetylamine derivatives were found at lower levels and all exhibited single-phase kinetics. The parent compound alone was found in the embryo, and levels increased gradually as nitrofen redistributed from the fat at 48 hours after exposure. The results of this and other studies of nitrofen metabolism in pregnant rats suggest that its teratogenicity is not mediated via generation of mutagenic intermediates through nitroreduction of the parent compound. Rather, the embryo is exposed to the parent compound alone and appears to be a deep compartment for accumulation of nitrofen.