Government specifications on the oxygen content of motor gasoline sold in certain areas of the USA have resulted in commercialization of the oxygenate fuel additives tertiary amyl methyl ether (TAME) and ethyl tertiary butyl ether (ETBE). TAME and ETBE were evaluated in 4-week rat inhalation studies sponsored by Amoco Corporation. Target vapor concentrations were 0, 500, 2000, or 4000 ppm for 6 h per day, 5 days per week, for 4 weeks. TAME exposure at 4000 ppm resulted in 25% mortality, apparently as a consequence of severe CNS depression. Body weight gain was decreased in the TAME high dose male rats. In contrast, no ETBE exposed animals died during the study and no changes in body weight gain were observed. Significant effects on functional observational battery (FOB) parameters were only found in the TAME high and mid-dose groups immediately after exposure. All affected FOB parameters were normal by the next day. Both TAME and ETBE exposures significantly increased relative liver weights in the high and mid-dose groups. However, no treatment-related histopathologic findings were noted for either compound. Clinical chemistry and hematology findings were absent with ETBE exposure and minimal with TAME exposure. The results indicate that 500 ppm was a NOAEL for both compounds in these studies.