Neurotoxicological evaluation of ethyl tertiary-butyl ether following subchronic (90-day) inhalation in the Fischer 344 rat.

The purpose of this study was to evaluate whether repeated 6-h exposure (65 exposures over a 14- week period) of male and female Fischer-344 rats (n = 12 rats/sex/concentration) to ethyl tertiary-butyl ether (ETBE) atmospheres at 500, 1750, or 5000 ppm would result in neurotoxicity. Neurotoxicity was assessed by a blinded functional observational battery (FOB), motor activity, and terminal neuropathology. Motor activity was assessed 4 days prior to ETBE exposure and following 20, 42, and 65 days of exposure. The FOB was assessed 4 days prior to ETBE exposure and following 1, 6, 10, 20, 42, and 65 days of exposure. Transient ataxia, a sign of narcosis, was noted in male rats immediately following the 6-h exposure to 5000 ppm ETBE. Statistically significant treatment effects on motor activity were not observed. Minor changes in grip strength and hindlimb splay were observed; however, none demonstrated a dose-response relationship or a consistent pattern of neurological dysfunction. No gross or microscopic abnormalities were observed in the central, peripheral, or autonomic nervous systems of rats exposed to 5000 ppm ETBE. No statistically significant differences in brain weight or size were observed in ETBE-exposed rats. A statistically significant increase in body weight was observed in female rats exposed to 5000 ppm following 42 and 65 exposure days. Although ataxia was a common feature of acute ETBE neurotoxicity in rats following high-level exposure, adverse neurological effects are not expected in the general public at the anticipated exposure levels associated with automotive refueling.