1,4-dichlorobenzene

Endpoint summary

Additional information

EU RAR 2004 indicated the following Summary of toxicokinetics, metabolism and distribution: "In animals, absorption takes place through the digestive and respiratory tracts rapidly (peak blood levels at one hour after dosing) but not completely, and subcutaneously; absorption after inhalation exposure (59% in mice versus 25-33% in rats); was poor compared to oral exposure (after single dose: 72% in rats and 71% in mice; after repeated exposure: 62% in rats). From acute dermal and repeated-dose toxicity studies via dermal route, the likelihood that dermal absorption is negligible can be made. No quantitative data on human absorption are available. The major differences in toxicokinetics, biotransformation and distribution of 1,4-dichlorobenzene via oral and inhalation exposure in F344 rats and B6C3F1 mice were the absorption percentage. 1,4-dichlorobenzene is distributed primarily in the fatty tissues, the kidneys, the liver, the lungs, the gonads and muscle tissues, similarly for oral, inhalation and subcutaneous routes of exposure. [¿] Regardless the penetration, 1,4-dichlorobenzene is principally metabolized in vivo to the sulphate and glucuronide conjugates of 2,5-dichlorophenol but also to free 2,5-dichlorophenol in rats, mice and human; In vivo, there are some species differences in metabolism between rats and mice, with 2,5-dichlorohydroquinone found in F344 and SD rats (and human possibly), but not in Wistar rats nor mice; to be noted that 2,5-dichlorohydroquinone was found in B6C3F1 mice and Wistar rat liver microsomes in vitro (Hissink 1997b; Den Besten 1992). In vivo, 1,4-dichlorobenzene induces dose-dependently liver cytochrome P450 dependent monooxygenases: in vivo CYP2B in F344 rats and B6C3F1 mice (Lake 1997, James 1998) but also CYP2A in F344 rats (Lake 1997), CYP4A in F344 rats and B6C3F1 mice (James 1998) and CYP2E1 in Wistar rats and B6C3F1 mice (Hissink 1997a). In vitro 1,4-dichlorobenzene induces CYP2E1 in human (for more than 90% of all CYP activity) but also CYP2A (Bogaards 1995). The hydroxylation of the aromatic ring seems to result in the formation of intermediate epoxides: 2,3-epoxide through liver cytochrome P450 CYP2E1 (subsequent metabolism to 2,5-or 2,4-dichlorophenol) and 1,2-epoxide through CYP2B (subsequent metabolism to 2,4-dichlorophenol). The metabolic fate of epoxide appears species dependent: the epoxide may form a conjugate with glutathione [in vivo: Wistar, F344 and SD (CFY) rats, in vivo: human, Wistar, F344 and SD rats, B6C3F1 mice] or be catalysed by epoxide hydrolase to form a dichlorophenol [in vivo: rat, mouse, human, in vitro: rat, mouse, human] or be secondary metabolized to form an hydroquinone metabolite[ in vitro: rat, mouse, human, in vivo: F344 and SD rat and human probably, no data in mouse] In vitro, the major metabolites are in rat, mouse and human liver microsomes dichlorophenols (50%), hydroquinone metabolites (10 to 27%) and to a less extent glutathione-epoxide and glutathione-quinone conjugates. Differences in the hepatic microsomal metabolism between rats and mice (and human) were shown (but not by Fischer 1995) were chemical species and quantities formed in SD and F344 rats and human were comparable): conversion of 1,4-dichlorobenzene was much higher in B6C3F1 mouse microsomes than in F344, Wistar or SD rat or human microsomes; mouse, F344 rat and human liver microsomes produce more hydroquinones metabolites than Wistar rat liver microsomes and addition of ascorbic acid increases the recovery of hydroquinones metabolites while decreasing protein binding; rat liver microsomes form glutathione-epoxide conjugates in the absence of exogenous glutathione (significantly increased with exogenous GSH) compared with very low detectable level from mouse and human liver microsomes in the presence of exogenous glutathione and no detectable level from human and mouse liver microsomes in the absence of exogenous glutathione. Elimination is principally via the urine (>80%) and most likely via the feces and lung; there appears to be considerable enterohepatic circulation of 1,4-dichlorobenzene and metabolites in the rat. The biological residence time is short, with a majority of 1,4-dichlorobenzene eliminated in the urine and feces by 48 hours. Routes of elimination and percentage of an administered dose of 1,4-dichlorobenzene eliminated are similar among rats and mice and comparable after oral and inhalation exposure. In human absorption occurs via the digestive and respiratory tracts and 1,4-dichlorobenzene is essentially distributed to the fatty tissue. Elimination occurs essentially through the urine and via the respiratory tract with a maximum level at approximatively the 8th hour, and continues for several days. Excreted metabolites are 2,5-dichlorophenol and its sulfate and glucuronide conjugates; 2,5-dichloroquinol was also found. [¿] 1,4-dichlorobenzene induces a dose-dependent hepatocellular proliferation in F344 rats and B6C3F1 mice, sometimes in spite of the lack of hepatotoxicity. It does not induce peroxisomal proliferation in CF1 mouse liver" (European Union Risk Assessment Report 2004).