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' UO/lo/too VX1 1b 56 PAA. 91b dbb lUtd ALh1r41'h1.UhK + bluuAIUA �1 Uuu Chemical Summary Methyl-Tert-Butyl Ether - Microsoft Internet Explorer Page 8 of 13 adenomas was significantly increased over control values (10/50 vs 2/50) in animals exposed to 7973 ppm MTBE (6 h/day, 5 days/week, for 18 months) Male mice exposed to the same MTBE concentration exhibited a slight increase in the combined incidence of liver adenomas and carcinomas (16/49 vs 12/49 in controls) , but this increase was not statistically signifi- cant and was within the range of historical control values (316/891) _ In male rats, the incidence of renal tubular cell tumors (adenomas and carcinomas) was 8/50 for animals exposed to 3023 ppm (6 h/day, 5 days/week, for up to 97 weeks) , 3/50 for animals exposed to 7977 ppm (for up to 82 weeks) , but only 1/50 in the control group (statistical significance not reported) . In female rats, the only reported kidney tumor was a renal cell adenoma in an animal exposed to 3023 ppm MTBE. The ' incidence of testicular tumors (interstitial cell adenomas) was increased above control values (41/50 in the 3023 ppm group and 47/50 in the 7977 ppm group vs. 32/50 for the controls) It was noted by the investigators that the frequency of testicular tumors in the MTBE-exposed animals was within the range (64-98%) reported for aged Fischer 344 rats, and that the frequency of these tumors in the control group was lower than historical controls from the same laboratory. E. Genotoxicity The genotoxicity of MTBE has been evaluated in microbial mutation ' assays, a sister chromatid exchange (SCE) assay, a mouse lymphoma assay, and in a Drosophila sex-linked recessive lethal test (U S EPA 1993a) The only study in which MTBE gave a positive response was the mouse lymphoma forward mutation assay, and this response occurred only in the presence of a metabolic activation system F Developmental/Reproductive Toxicity Information on the developmental or reproductive toxicity of MTBE in humans was not found in the available secondary sources In animal studies, high concentrations of MTBE produced develop- mental and reproductive toxicity in mice and rats (U.S EPA 1993x) ' 1 Humans - No data were found in the secondary sources searched to i nrli rafiP char MTRF i g a eiP►rPl npment a I J reproductive toxicant in humans �. sul-"U'dAw - In uaELS on UU-1, mice, erpocuro to in, 9uu mg/ms and 28, 800 mg/m3 on gebLdLion days 6-15 resulted an reduced pup viability_ lin increase in the incidence of cleft palate was seen at the higher concentration Exposure to 3, 600 mg/m3 ' resulted in no adverse effects (EPA, 1993c) In a one- generation study on Sprague-Dawley rats, no adverse develop- mental effects occurred at 1, 062 mg/m3, but reduced pup viability was seen at 4,470 mg/m3 In a two-generation study ' conducted on the same strain of rats, an exposure level of 1, 453 mg/m3 caused no adverse effects, however, 10,899 mg/m3 (3019 ppm) resulted in maternal toxicity, a significant .increase in dead pups on day 4, a significant reduction in litter size on days 21 and 28, and a significant reduction in mean jauy wc4.94 . L1&.Lvuy1ivuL lay Lal.lvti QuidcA zuii, 1391, LrrL, 1533j_j EPA (1993c) applied an uncertainty factors of 3 (to extrapolate from rats to humans) and 10 (for sensitive subpopulations) to the rat NOAEL of 1, 453 mg/m3, to derive a human NOAEL for developmental effects of 48 mg/m3 (with uncertainty spanning at least an order of magnitude) G. Neurotoxicity Fnday, August 16, 1996 4 25 PM