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According to EU Risk Assessment, the mechanism underlying the nephrotoxicity of 1,4-dichlorobenzene in the male F344 rat has been elucidated. It turns out that the 1,4-dichlorobenzene reversibly binds itself to a low molecular weight protein, alpha-2µ-globulin, that is synthesized in the liver of the SD and F344 male rats. The 1,4-diclorobenzene-alpha-2µ-globulin complex can resist the catabolic action of the lysozymes, which then causes a renal lysosomal protein overload and the formation of tubular protein droplets (where the low molecular weight proteins are normally reabsorbed). This lysosomal overload leads to cell death, and then stimulates a secondary cellular proliferation. This alpha-2µ-globulin is specific to male rats. An increase in kidney type alpha-2µ-globulin was detected in urine of male adult SD rats treated with 1,4-dichlorobenzene by gavage and in F344 male rats after single oral administration, with a positive correlation between the male rat nephropathy and 1,4-dichlorobenzene accumulation. The NBR male rats , species not synthesizing alpha-2µ-globulin, did not develop renal lesions or hyaline droplets after oral administration of 1,4-dichlorobenzene (500 mg/kg/day for 4 days). Moreover, a different elimination kinetic was found in male rat kidney from other tissues and could be related to the presence of the protein alpha-2µ-globulin. Compared to the control, an accelerated development of chronic nephrosis appears in treated F344 male rats during the recovery period after cessation of 1,4-dichlorobenzene treatment (9 months inhalation exposure to 75, 300, 600 ppm), in spite of the lack of any persisting alpha-2µ-globulin mediated nephropathy (EU RAR 2004).

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