Dimethoxyethylphthalate metabolism: Teratogenicity of the diester and its metabolites in the pregnant rat

Abstract

The rat foetus, in contrast with the maternal liver and placenta, has little or no ability to hydrolyse di‐(2‐methoxyethyl)‐phthalate (DMEP) to mono‐2‐methoxyethylphthalate (MMEP). At short times after the administration of DMEP to the dam on the 14th day of gestation, however, both the di‐ and mono‐ester are present in the foetus. Clearance of total phthalate from the foetus and placenta, is rapid and the foetal burden is reduced by 96% between 45 min and 4h. Although MMEP, when injected into the dam at the same molar dose level, crosses the placenta, its concentration in the foetus is lower than that after the injection of DMEP. MMEP (2.49 mmol kg⁻¹), is no teratogenic when administered as an aqueous solution of the sodium salt on day 8, 10, 12 or 14 of gestation, in contrast with the same molar dose of the liquid DMEP. The alcohol, 2‐methoxyethanol (ME), when administered as a single injection at this dose level (2.49 mmol kg⁻¹), however, is highly teratogenic and its effects cannot be differentiated clearly from those of DMEP. These results, which indicate the possibility that ME, derived by metabolism of DMEP, may be the teratogenic agent, suggest that both the rate of hydrolysis to the monoester and the chemical properties of the liberated alcohol, could be important determinant factors in the teratogenic activities of different phthalate diesters.