1,3-dichlorobenzene

Endpoint summary

Description of key information

The toxicokinetik behaviour and biotransformation of 1,3-dichlorobenzene was thoroughly investigated and described in the literature. 
1,3-dichlorobenzene is readily absorbed and mainly eliminated as a glutathione conjugate, glucuronide or sulfate.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

1,3-Dichlorobenzene is readily absorbed after ingestion (MAK 2013)

Following oral administration of a dose of 200 mg/bw, 1,3-dichlorobenzene in rats the maximum blood levels was achieved within 30 minutes. Within the following 12 hours, there was a biphasic decline in concentration in the blood (half-life =4.4 hour) (Kimura et al. 1984).

1,3-dichlorobenzene is hydroxylated in the liver by cytochrome P450-dependent monooxygenases via a reactive epoxide to form a phenolic compound which is eliminated as a glutathione conjugate, glucuronide or sulfate. At least twelve metabolites, for the most part glutathione conjugates and their degradation products, were isolated in the gallbladder of rats after intraperitoneal injection of 1,3-dichlorobenzene. The main metabolites were trans-2,4-dichloro-6-(glutathione-S-yl) cyclohexa-2,4-dien-1-ol and trans-3,5-dichloro- 6-(glutathione-S-yl) cyclohexa-2,4-dien-1-ol as well as their resultant cysteine conjugates. Eliminated as further metabolites were 3,5-dichlorophenyl conjugates with glutathione or cysteine and 3,5-dichlorophenyl mercapturic acids and their 2,4-dichlorophenyl isomers, including S-(2,4-dichlorophenyl) cysteine and S-(3,5-dichlorophenyl) cysteine (Kimura et al. 1992).

Cultivation of liver slices from Sprague-Dawley rats showed that about 70% of the 1,3-dichlorobenzene is metabolized to glutathione and cysteine conjugates and only small quantities, about 3% to 5%, to glucuronides or sulfates. In cultivated human liver slices, on the other hand, about 40% of the substance is found as glucuronide or glutathione conjugates and about 20% as sulfates (Fisher et al. 1990). A further study with human liver slices and liver slices from Fischer-344 and Sprague-Dawley rats confirmed that mainly glutathione and cysteine conjugates and in human liver slices noticeably more glucuronides occur than in liver slices from rats (MAK 2013).

After oral administration of 1,3-dichlorobenzene the presence of glucuronides (31%), sulphates (11%), mercapturic acid (9%) and catechol (4%) (Azouz et al 1954. Biochem J 12, 57) was observed in rabbits and the presence of 2,4-dichlorophenylmethylsulfone, 3,4-dichlorophenylmethylsulfone and their respective sulfoxide in rats urine and blood (Kimura et al 1984.).

Parke and Williams (Parke and Williams 1955. Biochem. J. 59:415-422) found after administration of 1,3-dichlorobenzene 54% of metabolites as conjugate in rabbits´ urine: primarily glucuronides (36%), derived mercapturic acid (11%) and ether sulphate (7%). The hydrolysis of the urine showed 2,4-dichlorophenol (21%), 3,5-dichlorophenol (3.6%) and dichlorocatechol (2.6%).

1,3-Dichlorobenzene and its metabolites are inducers of xenobiotic metabolizing enzymes of the phenobarbital type in the liver. Increased activities of aniline hydroxylase, aminopyrine N-demethylase, ethoxyresorufin-O-deethylase, delta-aminolevulinic acid synthetase and NADPH cytochrome c-reductase as well as of glucuronosyl transferases I and II were found (Hoechst AG 1989; Kato et al. 1986, 1988 a, b; Kimura et al. 1983, 1985).

In rabbits after administration of 500 mg/kg bw 1,3-dichlorobenzene the excretion of metabolites ended after 5 days (Parke & Willians, 1955).