Embryotoxicity in rats and rabbits from cutaneous application of amide-type solvents and substituted ureas

Abstract

Six amide-type solvents [formamide (F); N-methylformamide (MMF); N,N-dimethylformamide (DMF); N,N-di( n-butyl)formamide (DBF); N-methylacetamide (MMAC); N,N-dimethylacetamide (DMAC)] and four substituted ureas [1,1,3,3-tetramethylurea (TMU); 1,1,3,3-tetramethylthiourea (TMTU); ethylenethiourea (ETU); and tetrahydro-3,5-dimethyl-4 H-1,3,5-oxadiazine-4-thione (TDOT)] were applied to the skin of pregnant rats during the period of fetal organogenesis. In addition, TMU, MMF, DMF, and DMAC were applied to the skin of pregnant rabbits during the period of fetal organogenesis. All test chemicals were applied as liquids except ETU, TMTU, and TDOT, which were solids dissolved in dimethylsulfoxide (DMSO). The following parameters of toxicity were determined: (1) maternal approximate lethal dose by skin application, (2) maternal body weight during the exposure period, (3) embryomortality, (4) fetal weight, and (5) teratogenicity. Marked teratogenic effects were demonstrated with ETU; moderate with MMF; and slight with TMU, F, DMAC, and MMAC. Marked embryomortality was found with MMF and TMU; moderate with DMAC, TMTU, and TDOT; and slight with F, DBF, MMAC, and DMF. In rats, six skin applications of MMF, each amounting to 1 6 of the single daily dose, applied during an 8-hr period were more toxic to the mother and embryo than a single daily dose. Mixing TMU with mineral oil increased maternal TMU toxicity when applied to the skin of rats. The skin approximate lethal dose for TMU, MMF, DMF, and DMAC was lower for pregnant rabbits than for pregnant rats.