IRIS Toxicological Review of ETBE: kidney toxicity, MOA analyses, and derived toxicity values
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In August 2021, US EPA’s IRIS program finalized a health assessment for the fuel additive ethyl tertiary -butyl ether (ETBE). ETBE is a man-made ether oxygenate used primarily as a gasoline additive. ETBE is released into the environment through gasoline leaks with potential exposure through contaminated groundwater or soil. Animal studies demonstrate that exposure to ETBE is associated with noncancer kidney effects following oral and inhalation exposure. Dose-related changes in several indicators of kidney toxicity were observed in male and female rats, including increased absolute kidney weight, histopathological changes, increased serum biomarkers of kidney dysfunction, and increased severity of chronic progressive nephropathy (CPN). An evaluation of whether ETBE causes alpha 2u-globulin-associated nephropathy was done using the EPA and IARC frameworks. ETBE induced an increase in hyaline droplet accumulation and increased alpha 2u-globulin deposition in male rats; however, most of the subsequent steps in the pathological sequence were not observed, and animals did not develop kidney tumors. The U.S. EPA’s framework states that “[i]f a compound induces α2u-globulin accumulation in hyaline droplets, the associated nephropathy in male rats is not an appropriate endpoint to determine noncancer (systemic) effects potentially occurring in humans.” However, because alpha 2u-globulin nephropathy is strictly a male rat phenomenon, the dose-related kidney effects in female rats are not confounded by alpha 2u-globulin nephropathy. CPN also plays a role in exacerbating nephropathy in rats of both sexes, though its etiology is unknown. Given that there is no definitive pathogenesis for CPN, it cannot be fully ruled out that chemicals that exacerbate CPN in rats may have the potential to exacerbate other disease processes in the human kidney. Thus, kidney effects were identified as the strongest hazard for ETBE and an RfD of 1 mg/kg-day, based on increased kidney weight in female rats, was derived.
Disclaimer: The views expressed in this abstract are those of the author(s) and do not necessarily represent the views or the policies of the U.S. Environmental Protection Agency.