Metabolism and excretion of 2-ethoxyethanol in the adult male rat.

Abstract

The routes of 14C excretion following the administration of a single oral 230 mg/kg body weight dose of 2-ethoxyethanol [ethanol-1,2-14C] or 2-ethoxyethanol [ethoxy-1-14C] to male Sprague-Dawley rats were investigated. Elimination of the 14C by the urinary route accounted for 76 to 80% of the dose within 96 hr. The main pathway of biotransformation is oxidation to the corresponding acid, with some subsequent conjugation of the acid metabolite with glycine. The major metabolites, ethoxyacetic acid and N-ethoxy-acetyl glycine, representing 73 to 76% of the administered dose, were eliminated in the urine. The major difference in the metabolic profiles of the two radiochemicals was in the rate and amount of 14CO2 expired via the lung. Of the administered 14C, 11.7% of the ethoxy-labeled and 4.6% of the ethanol-labeled compounds were eliminated as CO2. The biological half-time was 9.9 +/- 1.5 hr for the ethoxy-labeled compound and 12.5 +/- 1.9 hr for the ethanol label. After administration of the ethanol-labeled compound, the only radiolabeled component found in the rat testes was identified as ethoxyacetic acid. Results of this study suggest that the reported testicular effects in the rat may be a result of tissue levels of ethoxyacetic acid.

A Toxicokinetic Study of Inhaled Ethylene Glycol Ethyl Ether Acetate and Validation of a Physiologically Based Pharmacokinetic Model for Rat and Human

“…Since the half-life of 2-EAA in urine is on the order of 9 -24 h in rats (Cheever et al, 1984;Medinsky et al, 1990), exposures to EGEEA were conducted over a 5-day period to allow near steady-state conditions to be achieved. Preliminary modeling indicated that five exposures of 6 h/day should be sufficient.…”

“…However, the model predictions would be expected to include all 2-EAA- derived urinary metabolites, and the analytical method measures only 2-EAA. Experimental work (Cheever et al, 1984;Groeseneken et al, 1988;Sabourin et al, 1992;Kennedy et al, 1993) indicates that 2-EAA-derived urinary metabolites such as glycine conjugates may contribute 14 to 74% more 2-EAAderived urinary metabolites. The average in studies with male SD rats, the strain used in the study reported here, was 68% (Cheever et al, 1984).…”

“…Experimental work (Cheever et al, 1984;Groeseneken et al, 1988;Sabourin et al, 1992;Kennedy et al, 1993) indicates that 2-EAA-derived urinary metabolites such as glycine conjugates may contribute 14 to 74% more 2-EAAderived urinary metabolites. The average in studies with male SD rats, the strain used in the study reported here, was 68% (Cheever et al, 1984). It was therefore estimated that measured amounts of urinary 2-EAA should be multiplied by a factor of 1.7 to approximate the total flux through the 2-EAA pathway (amount of unchanged 2-EAA plus glycine conjugates and other metabolites).…”

“…EGEE and EGEEA are known to be developmentally toxic in rodents (Hardin et al, 1982;Andrew and Hardin, 1984;Doe, 1984;Nelson et al, 1984;Kalf et al, 1987;Union Carbide, 1984;Paustenbach, 1988), produce testicular toxicity in male rodents (Cheever et al, 1984;Foster et al, 1984;Kalf et al, 1987;Nagano et al, 1979), and also produce hematological effects (Barbee et al, 1984;Nagano et al, 1979;Union Carbide, 1984). The acid metabolite, 2-ethoxyacetic acid (2-EAA), resulting from metabolism of both EGEE and EGEEA, has been identified as the putative toxicant (Cheever et al, 1984;Foster et al, 1984;Groeseneken et al, 1988). Therefore, assessment of potential risks posed by exposure to EGEE or EGEEA should include evaluation of an internal dose of 2-EAA, using measures such as maximum concentration in the blood (C max ) and the integrated area under the blood concentration vs time curve (AUC).…”

Clinical Toxicology of Ethylene Glycol Monoal Ethers

“…4.11 As with haemotoxicity, in vitro studies indicate that the acetic acid metabolite, not the parent glycol ether, is responsible for the testicular toxicity.4$ Following the administration of radiolabelled EE by gavage, EAA was the only radioactive compound found in rat testicular tissue. 49 Miller et 01.40 have demonstrated that the testicular toxicity of methoxyacetic acid (MAA) is qualitatively similar to that of its parent compound, ME. These results are consistent with in vitro findings that suggest the alkoxyacetic acid metabolite is the primary testicular toxin.…”