Developmental toxicity induced by inhalation exposure of pregnant rats to N,N-dimethylacetamide

Developmental toxicity of N,N-dimethylacetamide (DMAC) was examined by exposing pregnant rats by inhalation to DMAC vapor at 0 (control), 100, 300, 450 or 600 ppm (v/v) for 6 h/d during Gestation Days 6 through 19. Fetal body weight and the number of male live fetuses were significantly decreased, along with a tendency of the number of intrauterine deaths to increase. The number of fetuses with visceral and skeletal malformations was significantly increased in the 450 and 600 ppm groups, while the number of fetuses with anasarca as an external malformation was increased at 600 ppm. Observed cardiovascular malformations included ventricular septum defect, persistent truncus arteriosus, malpositioned subclavian branch and retroesophageal subclavian artery. Persistent truncus arteriosus was accompanied by ventricular septal defect (VSD). Incidences of the persistent truncus arteriosus, which was classified as a serious congenital heart disease affecting postnatal survival, were increased at 450 and 600 ppm. Increased liver weights and hepatocellular swelling occurred in the dams exposed to 300 ppm and above, whereas neither hepatocellular necrosis nor increased serum activity of liver transaminases was observed in any of the exposed groups. Maternal body weights were decreased at 450 and 600 ppm. The most sensitive signs of developmental toxicity appeared at the exposure level of 300 ppm which was also the level of slight maternal toxicity. The No-Observed-Adverse-Effect-Level (NOAEL) was determined as 100 ppm for the endpoints of fetal and maternal toxicities. The NOAEL of 100 ppm and the induction of serious cardiovascular malformations occurring at 450 ppm and above were discussed with reference to the existing occupational exposure limit for DMAC.