Subchronic dermal toxicity and oral neurotoxicity of triethylene glycol monomethyl ether in CD rats

Abstract

These studies were conducted to evaluate the potential for repeated subchronic administration of triethylene glycol monomethyl ether (TGME) to produce systemic toxicity in the rat following dermal application, and neurotoxicity in the rat following peroral administration. The route of administration and maximum dose levels for these studies were specified by the U.S. Environmental Protection Agency (EPA) in a testing consent order for TGME. In the subchronic dermal toxicity study, TGME (undiluted) was applied to the clipped backs of CD rats (10 rats/sex/group) for 6 h/day (occluded), 5 days/wk for 13 wk at dose levels of 0, 0.4, 1.2, and 4.0 g/kg/day. Four groups of satellite animals (5 rats/sex/group) employed for interim hematology and clinical chemistry measurements were dosed in the same manner for 31 days. Experimental evaluations included clinical examinations, food consumption, body weight, ophthalmology, estrous cyclicity, hematology, clinical chemistry, urinalysis, and necropsy for all animals and microscopic examination of a complete set of tissues (including bone marrow smears) for animals in the control and high-dose treatment groups. In addition, the testes and epididymides were processed for examination of spermatocyte development. None of the experimental endpoints included in this study to evaluate the potential for systemic toxicity were affected by treatment with TGME. For the neurotoxicity study, TGME was mixed in the drinking water and administered ad libitum to rats (15 rats/sex/group) for 13 wk at concentrations that resulted in the consumption of approximately 0, 0.4, 1.3, and 4.2 g TGME/kg/day. Experimental evaluations included clinical examinations, food consumption, body weight, functional observational battery (FOB), automated motor activity analysis, necropsy, and histopathology. The central and peripheral nervous system, liver, and testes were examined microscopically. Dose-related decreases in body weight and food consumption were observed for males and females following peroral administration of 1.3 and 4.2 g TGME/kg/day. TGME treatment did not result in clinical signs of toxicity, alterations in the FOB, or gross or microscopic changes in the nervous system. Minor decreases in motor activity were observed for animals in the high-dose group after 8 and 13 wk of treatment. Changes in motor activity were considered to be secondary to the systemic toxicity observed for these animals. Hepatocellular hypertrophy and vacuolization were observed for most animals in the high-dose group and for a few animals in the low- and intermediate-dose groups. These latter changes were considered to reflect reversible adaptation of the liver to metabolize large daily doses of the test substance. Finally, testicular degeneration and atrophy of spermatocytes and developing spermatids were observed for males in the high-dose group. Similar testicular effects were not observed at dose levels of 0.4 or 1.3 g/kg/day in the drinking water study or at 4.0 g/kg/day in the subchronic dermal toxicity study. The results of these studies indicate that treatment of CD rats with excessively high doses of TGME for 13 wk does not produce systemic toxicity following repeated dermal application, or neurotoxicity following administration in the drinking water. The testicular toxicity observed in rats in the drinking water study is not expected to pose a potential risk associated with exposure to TGME in humans because of the very large oral doses required and the fact that exposure to TGME by the oral route does not occur in humans under normal conditions for use. Moreover, similar effects could not be produced in rats following dermal exposure, the relevant route of exposure in humans.