Developmental Toxicity of Inhaled N-Methylformamide in the Rat

The developmental toxicity of N-methylformamide (MMF), an industrial chemical intermediate used in the production of agrichemicals, was examined in pregnant rats. MMF was administered by nose-only inhalation, 6 hr daily on Days 7–16 of gestation (the day copulation was confirmed was termed Day 1 of gestation, Day 1G) at exposure concentrations of 0, 15, 50, or 150 ppm. Dams were regularly monitored throughout gestation for body weight gain, feed consumption, and clinical signs. Cesarean sections were performed on Day 22G and the offspring were examined. Maternal toxicity was evident in dams exposed to 50 or 150 ppm; one dam exposed to 150 ppm died on Day 14G (considered to be treatment-related) and dams in the 50 and 150 ppm groups exhibited concentration-related clinical findings. Clinical signs of wheezing and rattling were observed both during and after the exposure period. The 150 ppm group also showed significant decreases in weight gain and feed consumption. A significant increase in the mean number of resorptions per litter at the 150 ppm level indicated an embryolethal effect. Developmental toxicity was apparent by a significant decrease in mean fetal body weight and increases in fetal malformations (subcutaneous cysts on the head, microphthalmia, anophthalmia, fused ribs and/or vertebra, and distended brain ventricles) and variations (misaligned and fused sternebrae) due to retarded development at 150 ppm. Significant fetal body weight decreases were also present at 50 ppm. Thus, in this study, the no-observable-adverse-effect level for both dam and fetus was 15 ppm MMF, indicating that for the parameters included in this study, the conceptus is not uniquely sensitive to MMF.