Hepatotoxic and nephrotoxic effects of etoxazole in rats: dose-response relationships, oxidative stress mechanisms, and provisional NOAEL/LOAEL estimates

Etoxazole (ETX) is a widely used organofluorine acaricide/insecticide applied to many food crops, and its residues have been detected in food matrices at levels of concern for human dietary exposure. However, its hepatotoxic and nephrotoxic potential following subchronic oral exposure remains insufficiently characterized. This study investigated the dose-dependent effects of repeated oral ETX administration on serum biochemical parameters, hepatic and renal antioxidant enzyme activities, lipid peroxidation, and histopathological features in Wistar albino rats. Six groups of seven female rats each received normal control (NC) or ETX at 25, 100, 250, 500, or 750 mg/kg/day by gavage for 28 consecutive days. At the end of the exposure period, serum parameters (AST, ALT, ALP, GGT, creatinine, uric acid, glucose, total cholesterol, triglycerides, HDL, LDL), catalase (CAT), glutathione S-transferase (GST), reduced glutathione (GSH), and malondialdehyde (MDA) levels in liver and kidney tissues, and histopathological changes were evaluated. ETX caused significant, dose-dependent increases in AST and ALT from ETX100, in ALP and GGT from ETX500, and in creatinine and uric acid at higher doses, indicating progressive hepatic and renal injury. Hepatic and renal CAT, GST, and GSH activities significantly decreased, whereas MDA levels significantly increased in the higher-dose groups, demonstrating oxidative stress-mediated disruption of antioxidant defenses. Histopathological evaluation revealed dose-dependent liver injury and significant tubular damage in kidneys. The tentative NOAEL and LOAEL were estimated at 25 and 100 mg/kg/day, respectively. These findings demonstrate that ETX induces dose-dependent hepatorenal toxicity in rats through an oxidative stress-mediated mechanism and provide relevant data for dietary risk assessment.