Dose-response studies have shown a sharp threshold for the renal papillary toxic effect in male rats between 0.25% and 0.5% ethoxyquin (Eto) in the diet over 6 months. Although similar elevated urinary protein (albumin) levels resulted from dietary Eto (0.5%) in both males and females, papillary necrosis was male specific. Following [14C]Eto administration, radiolabel was associated with urinary albumin but not alpha 2 globulin (alpha(2mu)-g). Autoradiographic studies indicated that the sex differences in nephrotoxicity do not involve differences in distribution or retention of Eto. Faecal and urinary metabolic profiles were also similar in the two sexes. The sharp threshold of toxicity in the male rat could indicate a fine balance between toxifying/detoxifying metabolism of Eto.