The methoxy polyethylene glycols (MPEGs), also referred to as polyethylene glycol methyl ethers, are high molecular weight polymers similar in structure and nomenclature to the polyethylene glycols. Because of the potential for repeated cutaneous exposure of humans to MPEG-350 and the known toxicity of lower alkylene glycol ethers such as ethylene glycol monomethyl ether (EGME), studies were conducted to evaluate the potential toxicity and irritation of MPEG-350 following repeated, cutaneous treatment. New Zealand White rabbits were cutaneously treated with 1.0 ml of either undiluted MPEG-350 or a 50% solution of MPEG-350 in 0.1% methyl cellulose in distilled water for 9 or 90 days. CD(SD)BR rats were cutaneously treated with up to 5 g/kg/day of undiluted MPEG-350 for 14 or 28 days. The treatment area was not occluded but animals were fitted with Elizabethan collars during treatment. Rabbits were treated 6 hr/day 5 days/wk. Rats were treated for at least 19 hr/day (at weekends, the exposure time was approximately 70 hr). None of the animals died. Slight decreases in mean absolute body weight of all dose groups of male rats as compared with the concurrent control group may have been related to minimal toxicity of the test substance but was probably secondary to the dosing procedures. Signs of slight cutaneous irritation were observed in many treated animals of both species but only a few rabbits had confirmatory microscopic diagnoses while none of the rats had microscopic changes in the skin. Slight decreases in the mean absolute weight of the testes, spleen and thymus were observed in rats treated with 5 g undiluted MPEG-350/kg/day for 14 days. Similar changes were not observed in rats following 28 days of treatment. There were no microscopic changes in any of these organs except for one rat that had moderate to high aspermatogenesis and multinucleated spermatids. There were no microscopic changes observed in the testes of any other animals (including rats treated for 28 days with 5 g undiluted MPEG-350/kg/day). Therefore, a relationship of the testicular changes observed in this one animal to treatment with MPEG-350 was considered to be improbable. While a mechanism for the production of toxic metabolites from systemically absorbed MPEG-350 was considered to be possible, there was no indication from these and other cutaneous studies of significant cutaneous absorption of the compound. Therefore, repeated cutaneous exposure to MPEG-350 was not expected to result in significant toxicological effects.