© 1992 Oxford University Press
research-article |
The Developmental Toxicity of Diethylene and Triethylene Glycol Dimethyl Ethers in Rabbits1
National Toxicology Program, P.O. Box 12233, Research Triangle Park, North Carolina 27709 *Chemistry and Life Sciences, Center for Life Sciences and Toxicology, Research Triangle institute P O Box 12194, Research Triangle Park, North Carolina 27709
Received August 12, 1991; accepted January 24, 1992
Diethylene glycol dimethyl ether (diEGdiME) and triethylene glycol dimethyl ether (triEGdiME), widely used organic solvents, are structurally related to several compounds that produce reproductive and developmental toxicity, including teratogenicity in laboratory animals. In the present studies, diEGdiME (0, 25, 50, 100, or 175 mg/kg/day) or triEGdiME (0, 75, 125, 175, or 250 mg/kg/day) were administered by gavage in distilled water to timed-pregnant New Zealand white rabbits (15–25 dams/ group) during major organogenesis [Gestational Days (gd) 6–19]. Treated females were euthanized on gd 30, uterine contents were examined, and live fetuses were examined for morphological alterations. In the diEGdiME study, evidence of maternal toxicity, per Se, was observed only at 175 mg/kg/day with 15% mortality among treated females compared to 4% among controls. No significant maternal toxicity was observed in the 25 mg/kg/day group, and only minimal maternal toxicity (decreased maternal weight gain during treatment) was observed at 50 and 100 mg/kg/day compared to the vehicle control group. The no-observed-adverse-effect level for developmental toxicity in rabbits for diEGdiME was 50 mg/kg/day. The incidences of prenatal mortality and malformed live fetuses were significantly above controls at 100 and 175 mg/kg/day. Malformations observed most frequently included fusion of ribs to each other and hydronephrosis; clubbing of the limbs without underlying bone deformities, a variation, was also observed. In the triEGdiME study, clinical signs of toxicity were minimal and there was no increased maternal mortality. Maternal body weight and gravid uterine weight were significantly reduced at 250 mg/kg/day, whereas maternal weight gain during treatment was significantly depressed at doses of 175 mg/kg/day and above. Prenatal mortality was significantly increased at 250 mg triEGdiME/kg/day. TriEGdiME at doses of 175 and 250 mg/kg/day caused a significant increase in the incidence of malformed fetuses per litter. Malformations noted most frequently in fetuses of normal size included anonychia (missing toenails with no digital abnormalities), abnormally small spleen, and hydronephrosis. In conclusion, exposure of rabbits to diEGdiME at 25 mg/kg/day during major organogenesis produced no adverse maternal or developmental effects. Doses of 50 and 100 mg/kg/day produced minimal maternal toxicity. Significant developmental toxicity was observed at 100 mg/kg/day. The incidence of adverse de velopmental effects was further increased at 175 mg/kg/day and there was also maternal mortality at that dose. Exposure of rabbits to 75 or 125 mg triEGdiME/kg/day produced no evidence of maternal or developmental toxicity. Significant developmental toxicity and mild maternal toxicity were observed at 175 and 250 mg/kg/day.