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© 1991 Oxford University Press

research-article

Bis(2-Methoxyethyl) Ether: Metabolism and Embryonic Disposition of a Developmental Toxicant in the Pregnant CD-1 Mouse1

F. B. DANIEL2, K. L. CHEEVER3, K. B. BEGLEY, D. E. RICHARDS, W. W. WEIGEL and C. J. EISENMANN

Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health, Division of Biomedical and Behavioral Science 4676 Columbia Parkway, Cincinnati, Ohio 45226

Received August 6, 1990; accepted December 18, 1990

Bis(2-Methoxyethyl) Ether: Metabolism and Embryonic Disposition of a Developmental Toxicant in the Pregnant CD-I Mouse. DANIEL, F. B., CHEEVER, K. L., BEGLEY, K. B., RICHARDS, D. E., WEIGEL, W. W., AND EISENMANN C. J. (1991). Fundam. Appl. Toxicol. 16, 567–575. An embryotoxic oral dose of bis(2-methoxyethyl) ether (DGDME), 3.73 mmol/kg body wt (500 mg/kg), administered on the 11th day of gestation to pregnant CD-I mice was metabolized predominantly by O-demethylation to 2-(2-methoxyethoxy)ethanol with subsequent oxidation to (2-methoxyethoxy)acetic acid. Urinary excretion of this metabolite over 48 hr amounted to 63 ± 2% of the dose. A smaller percentage of the administered dose was metabolized at the central ether linkage to produce 2-methoxyethanol, which was further metabolized by alcohol dehydrogenase to methoxyacetic acid. Urinary excretion of methoxyacetic acid, a potent developmental toxicant, amounted to 28 ± 1% of the administered dose by 48 hr and was the second most prominent urinary metabolite. Unchanged DGDME and methoxyacetic acid were detected in the embryonic tissues from these animals, and embryos harvested after the initial 6-hr period showed detectable amounts of only methoxyacetic acid. The average amount of methoxyacetic acid per embryo was calculated to be 1.5 ± 1.0 µmol (5.9 mmol/kg body wt) at the 6-hr termination time. This finding suggests that the reported teratogenic effects of DGDME are due to methoxyacetic acid formed, either in the fetus or by hepatic metabolism in the dam with subsequent distribution to the embryonic tissue. These results suggest that such developmental toxicity may occur with structurally similar aprotic ethylene glycol ethers in which metabolic O-dearylation would yield 2-methoxyethanol.


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