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.
Triethylene glycol dimethyl ether, a widely distributed industrial chemical, was evaluated for toxic and teratogenic effects in timed-pregnant CD-1 mice. TGDM (0, 250, 500, or 1000 mg/kg/day) was administered by gavage on gestational days 6 through 15. Females were weighed and observed daily during treatment and at 1 hour postdosing for clinical signs of toxicity. At sacrifice a total of 26-28 dams (i.e., confirmed-pregnant females) per treatment group were evaluated. The gravid uterus of each dam was weighed, and the number and status of each uterine implantation site (i.e., resorption, dead fetus or live fetus) was recorded. All live fetuses were weighed and examined for external, visceral, and skeletal malformations.
During TGDM treatment, dams exhibited clinical signs of toxicity consisting primarily of piloerection and weight loss. No dose-related maternal deaths occurred during this investigation. Maternal body weight or measures of maternal weight gain did not differ significantly among treatment groups at any time during the investigation. Gravid uterine weight exhibited a significant decreasing trend but no significant difference among dose groups. Absolute maternal liver weight was unaffected by treatment, although relative maternal liver weight (i.e. , percent maternal body weight) was significantly greater than controls in the 500 and 1000 mg/kg/day dose groups.
There were no differences among treatment groups in the number of corpora lutea or implantation sites per dam or in the percent preimplantation loss. TGDM treatment had no effect on the percent of resorbed implants, dead fetuses, or nonlive implants per litter, or on the number of litters with one or more resorptions, dead fetuses, or nonlive implants.
TGDM resulted in a significant trend toward a dose-related increase in the percent adversely affected implants per litter in the proportion of litters with adversely affected implants. With regard to live litters only, TGDM had no effect on the number of live fetuses per litter or on the percent live male fetuses per litter. Average fetal body weight exhibited a significant dose-related decrease and main effect for dose with the 500 and 1000 mg/kg/day dose groups significantly below controls. Female fetuses were affected by TGDM treatment with significantly depressed body weight in both the 500 and 1000 mg/kg/day dose groups, while male fetuses exhibited a significant decrease in body weight only in the 1000 mg/kg/day dose group.
TGDM caused a significant increase in the percent fetuses malformed per litter and in the proportion of litters with one or more malformed fetuses, with the high dose group significantly increased over controls for both measures. Malformed fetuses occurred with an incidence of 0.27%, 0.00%, 0.76%, and 11.09% per litter in the 0, 250, 500 and 1000 mg/kg/day group respectively. When the proportion of malformed fetuses per litter was analyzed separately by sex, male and female fetuses were equally affected. The incidence of external and skeletal, but not visceral malformations per litter was significantly increased by TGDM at the 1000 mg/kg/day dose level. External malformations in the high dose group included (in order of decreasing incidence) exencephaly, cleft palate, meningocele, and meningoencephalocele. All of the observed skeletal malformations in the 1000 mg/kg/day dose group were fused ribs.
In conclusion, TGDM (0, 250, 500, or 1000 mg/kg/day, po) administered on gd 6 through 15, produced at the high dose level an increase in the percent malformed fetuses per litter and the incidence of external and skeletal malformations, but did not affect the incidence of visceral malformations. Malformations observed in the 1000 mg/kg/day dose group were primarily fused ribs and craniofacial anomalies including exencephaly and cleft palate, and occurred at an exposure level which caused minimal maternal toxicity. TGDM also caused a significant reduction of fetal body weight at the 500 and 1000 mg/kg/day dose level. Under the conditions of the present study, 250 mg/kg/day represented a no-effect level. The results of this study indicated that TGDM presents a selective risk to the unborn offspring, and causes a significant decrease in fetal body weight and a significant increase in the incidence of fetal malformations at doses which cause little or no maternal toxicity.