For definition of Groups, see Preamble Evaluation.
VOL.: 73 (1999) (p. 223)
Chem. Abstract No.:
Chem. Abstr. Name: 1,2-Dichlorobenzene
Chem. Abstr. No.:
Chem. Abstr. Name: 1,3-Dichlorobenzene
Chem. Abstr. No.:
Chem. Abstr. Name: 1,4-Dichlorobenzene
5.1 Exposure data
Dichlorobenzenes are chemical intermediates used widely in the manufacture of dyes, pesticides and various industrial products. ortho-Dichlorobenzene is further used as a solvent and an insecticide. para-Dichlorobenzene is used widely as a moth repellent and an air deodorizer and also as a pesticide.
Occupational exposure to dichlorobenzenes may occur during their manufacture and use, at levels reaching up to a few hundred milligrams per cubic meter in the case of para-dichlorobenzene. ortho-Dichlorobenzene and para-dichlorobenzene are found in ambient air at levels usually below 1 m g/m3; in indoor air, para-dichlorobenzene is typically found at a level an order of magnitude higher. These two isomers have been detected in some drinking-water supplies at levels usually below 1 m g/L and in some foods at levels up to 10 m g/kg. Concentrations of 5–30 m g/kg ortho- and para-dichlorobenzene have been reported in human milk.
meta-Dichlorobenzene is produced in smaller quantities than the ortho and para isomers and is used primarily as a chemical intermediate. The data on exposure to this chemical are limited.
5.2 Human carcinogenicity data
In a cohort study from the United States, no association was observed between occupational exposure to ortho-dichlorobenzene and mortality from multiple myeloma or non-Hodgkin lymphoma; however, the risk estimates were based on exceedingly few observations.
5.3 Animal carcinogenicity data
ortho-Dichlorobenzene was tested by oral administration in one well-conducted study in mice and one well-conducted study in rats. No increased incidence of tumours was observed.
meta-Dichlorobenzene has not been adequately tested for potential carcinogenicity in laboratory animals.
para-Dichlorobenzene was tested by oral administration and inhalation in mice and rats. After oral administration, it increased the incidence of adenomas and carcinomas of the liver in male and female mice and of renal tubular carcinomas in male rats. Studies in mice and rats exposed by inhalation were judged to be inadequate. para-Dichlorobenzene did not promote hepatic foci in a two-stage model of carcinogenesis in rats.
5.4 Other relevant data
No data were available on the absorption, distribution, metabolism or excretion of ortho-, meta- or para-dichlorobenzene in humans.
The major route of biotransformation of ortho-dichlorobenzene in male rats was via the glutathione pathway; most of the urinary metabolites were mercapturic acids. Other metabolites were conjugates of 2,3- and 3,4-dichlorophenol. A high dose of ortho-dichlorobenzene results in depletion of glutathione. The major metabolite of para-dichlorobenzene is 2,5-dichlorophenol. After administration of a high oral dose of para-dichlorobenzene to male rats, dichlorohydroquinone was identified in the urine only after acid hydrolysis.
No data were available to evaluate the toxicity of meta-dichlorobenzene in humans. Occupational exposure to ortho- and para-dichlorobenzene caused ocular irritation; ortho-dichlorobenzene also caused irritation in the upper respiratory tract.
para-Dichlorobenzene was reported to be hepatotoxic at doses of 600 mg/kg bw and higher in rats. ortho-Dichlorobenzene was found to be a more potent hepatotoxicant in rats than para-dichlorobenzene. para-Dichlorobenzene was reported to cause a mitogenic response in both mouse and rat liver under the dosing conditions used in the cancer bioassay.
para-Dichlorobenzene causes male rat-specific nephrotoxicity resulting from accumulation of the male rat-specific protein a 2u-globulin. Both para-dichlorobenzene and its major metabolite, 2,5-dichlorophenol, bind reversibly to a 2u-globulin. para-Dichlorobenzene causes sustained cell proliferation in proximal renal tubular cells, and the dose–response relationships for tumour outcome, enhanced cell proliferation and other histopathological end-points typical of a 2u-globulin nephropathy are similar. Female rats, male rats of strains that do not express this protein and mice are not susceptible to the nephrotoxic action of para-dichlorobenzene.
ortho-Dichlorobenzene did not cause developmental toxicity in rats or rabbits exposed by inhalation during gestation. After administration by gavage to rats during gestation, decreased fetal growth and an increased incidence of extra ribs were observed. para-Dichlorobenzene did not cause developmental toxicity in rabbits exposed during gestation.
A statistically significant, fourfold increase in the frequency of persistent chromosomal aberrations was observed in peripheral blood lymphocytes of individuals accidentally exposed to ortho-dichlorobenzene. No data were available on the genetic and related effects of meta-dichlorobenzene or para-dichlorobenzene in humans.
ortho-Dichlorobenzene induced micronuclei in the bone marrow of mice treated in vivo. Radiolabelled ortho-dichlorobenzene was found to bind covalently to DNA, RNA and proteins of the liver, kidney, lung and stomach of treated rats and mice. It bound to DNA in vitro in the presence but not in the absence of metabolic activation. It was mutagenic to yeast and fungi but not to bacteria.
meta-Dichlorobenzene increased the frequency of micronuclei in the bone marrow of mice treated in vivo. It caused gene conversion in yeast. It was not mutagenic to bacteria but gave contradictory results with respect to DNA damage.
para-Dichlorobenzene bound to DNA in liver, lung and kidney of mice but not of male rats. It induced DNA damage in liver and spleen but not in kidney, lung or bone marrow of mice. No conclusion can be drawn from the few data on genotoxicity in vivo. There is weak evidence for the genotoxicity of para-dichlorobenzene in mammalian cells in vitro. It was not mutagenic to bacteria. Overall, the results of tests for genotoxicity do not support a mechanism for renal-cell tumour induction in male rats that involves a direct interaction between para-dichlorobenzene or its metabolites and DNA.
There is inadequate evidence in humans for the carcinogenicity of dichlorobenzenes.
There is evidence suggesting lack of carcinogenicity in experimental animals of ortho-dichlorobenzene.
There is inadequate evidence in experimental animals for the carcinogenicity of meta-dichlorobenzene.
There is sufficient evidence in experimental animals for the carcinogenicity of para-dichlorobenzene.Overall evaluation
In making its overall evaluation of the carcinogenicity of para-dichlorobenzene to humans, the Working Group concluded that para-dichlorobenzene produces renal tubular tumours in male rats by a non-DNA-reactive mechanism, through an a 2u-globulin-associated response. Therefore, the mechanism by which para-dichlorobenzene increases the incidence of renal tubular tumours in male rats is not relevant to humans.
para-Dichlorobenzene caused a high incidence of liver tumours in male and female mice. Supporting evidence that its mechanism of carcinogenesis may be relevant for humans includes evidence that it causes DNA damage in liver and spleen of mice and weakly binds to DNA in mouse liver.
ortho-Dichlorobenzene is not classifiable as to its carcinogenicity to humans (Group 3).
meta-Dichlorobenzene is not classifiable as to its carcinogenicity to humans (Group 3).
para-Dichlorobenzene is possibly carcinogenic to humans (Group 2B).For definition of the italicized terms, see Preamble Evaluation.
Previous evaluations of ortho-dichlorobenzene and para-dichlorobenzene: Vol. 29 (1982); Suppl. 7 (1987)
See Also: Toxicological Abbreviations