Inhalation exposure to the fuel additive ETBE at 5000 ppm has been reported to cause liver tumors in male rats; this response has not been observed at lower inhalation exposures or in rats chronically exposed to ETBE via drinking-water.  However, male rats developed kidney tumors in chronic drinking water studies with TBA, a metabolite of ETBE.  A PBPK model for ETBE and TBA was developed to provide insights into the role that exposure- and gender-specific differences in the toxicokinetics of ETBE and TBA may play in the different tumor responses.  The model was developed based on a previously published model for methyl tertiary butyl ether, a structurally similar chemical that also is metabolized to TBA, and included a description of ETBE and TBA binding to the male rat-specific protein a2u-globulin, which may play a role in the kidney toxicity (ETBE and TBA) and kidney tumors (TBA) observed in male rats following exposure to ETBE or TBA.  Metabolism of ETBE and TBA was included in the liver via a single, saturable pathway for each chemical, and the low-affinity pathway for TBA was assumed inducible following repeated exposures.  This ETBE/TBA model was verified with data sets available in the literature and chemical study reports.  The model predicted similar kidney AUC_0-∞ for TBA for various exposure scenarios from ETBE and TBA cancer bioassays, which support a male-rat-specific mode of action for TBA-induced kidney tumors. However, the blood AUC_0-∞ for ETBE and TBA, under cancer bioassay exposure scenarios, showed that ETBE and TBA kinetics shift from linear to nonlinear at a concentration associated with liver tumors in rats, suggesting the possibility of a mode of action that occurs only at a high exposure concentration that is not relevant for assessing human risk.