The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings may not have been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. For more information, see the Explanation of Levels of Evidence for Developmental Toxicity. The findings and conclusions for this study should not be construed to represent the views of NTP or the U.S. Government.
Diethylene glycol dimethyl ether, a widely used organic solvent, is structurally related to several compounds which produce reproductive and developmental toxicity, including teratogenicity in laboratory animals. In the present study, DYME (0, 25, 50, 100 or 175 mg/kg/day ) was administered by gavage in distilled water to timed-pregnant New Zealand White rabbits (15-22 dams/group) during major organogenesis [gestational days 6-19] based on preliminary rangefinding studies. Treated females were sacrificed on gd 30, uterine contents were examined, and live fetuses examined for malformations.
Evidence of maternal toxicity, per se, was observed only at 175 mg/kg/day . At this high dose, the mortality among treated females was 15.4% as compared to 4% among controls. No significant maternal toxicity was observed in the 25 mg/kg/day group, and only minimal maternal toxicity (maternal weight gain during treatment) was observed at 50 mg/kg/day as compared to the vehicle control group. However, even these lower doses appeared to contribute to significant dose-related trends for indices of maternal body weight, weight gain, and gravid uterine weight maternal.
The lowest dose of DYME (25 mg/kg/day ) appeared to be a no-observed-effect level for developmental toxicity in NZW rabbits. At 50 mg/kg/day , apparent adverse effects on prenatal growth, viability and morphological development were in accord with significant dose-response relationships observed across all groups. At 100 and 175 mg/kg/day , adverse effects upon fetal weight were in accord with significant dose-response relationships, but individual treatment groups did not differ significantly from controls. The incidence of resorptions and malformed live fetuses, as well as other cumulative indices which included these endpoints, were significantly above controls at 100 and 175 mg/kg/day . Major malformations affected the development of the digits, craniofacial structures, abdominal wall, cardiovascular system, urogenital organs and axial skeleton. The most frequently observed individual defects were fusion of ribs to each other (19%), hydronephrosis (23%), and clubbing of the limbs (19%) without underlying bone deformities (i.e., of presumed neuromuscular origin).
In conclusion, exposure of NZW rabbits to diethylene glycol dimethyl ether at 25 mg/kg/day during major organogenesis produced no adverse maternal or developmental effects. Doses of 50 and 100 mg/kg/day were associated with adverse developmental effects, but did not produce distinctive evidence of maternal toxicity. The incidence of adverse developmental effects was further increased at a dose associated with increased maternal mortality (e.g., 175 mg/kg/day). The principal manifestations of developmental toxicity were increased resorptions and a higher incidence of major malformations among surviving fetuses.