Teratogenic effects of trichloroacetonitrile in the Long-Evans rat

Trichloroacetonitrile (TCAN) is among a number of contaminants found in drinking water produced by reactions of chlorine with background organic material. Long-Evans rats were intubated with TCAN (0, 1, 7.5, 15, 35, 55 mg/kg) in a tricaprylin vehicle on gestation days 6-18. The highest dose tested (55 mg/kg) was lethal in 21% of the dams and produced 100% resorptions in two-thirds of the survivors. Only one maternal death was seen at the next-lower dose; however, fetal weight and viability were decreased in a dose-related manner. The percentage of embryolethality was 13.9% at the lowest dose and 78.4% at the high dose, with resorption of entire litters seen at 7.5 mg/kg and above. At all doses, cardiovascular (interventricular septal defect, levocardia, common carotid, and right-sided aortic arch and ductus arteriosus) and urogenital (hypoplastic, missing, misplaced and fused kidneys, and hypoplastic uterine horns) malformations were seen in the offspring. Frequency of these malformations was dose related, ranging from 8% to 35% at the 1.0- and 35-mg/kg doses, respectively. The incidence of total soft tissue malformations was statistically significant at 15 and 35 mg/kg. There were no significant treatment-related changes in the incidence of skeletal malformations. The no-effect dose was established by statistical analysis to be 1.0 mg/kg/day.