1,4-dichlorobenzene

Endpoint summary

Additional information

Several in vitro and in vivo genetic toxicity tests with 1,4-dichlorobenzene were performed.

In vitro:

In an Ames test performed according to OECD guideline 471 and GLP, 1,4-dichlorobenzene did not prove to be mutagenic in the strains of Salmonella typhimurium tested (TA 98, TA 100, TA 1535, TA1537,TA 1538) (Winker 1993).

This result is supported by another Ames test (with and without metabolic activation) in which it is concluded that no evidence of mutagenic potential of 1,4-dichlorobenzene was obtained in the strains of Salmonella typhimurium tested (TA 98, TA 100, TA 1535, TA 1537, TA 1538) (Jones 1987).

In two gene mutation assays (Paolini 1998, Prasad 1970) 1,4-dichlorobenzene showed weak positive results for the induction of gene mutations in fungi. Tests in fungi play only a minor role for human risk assessment if testing in higher, more adequate organisms has been performed as in case of 1,4-dichlorobenzene (Position paper of the "Beraterkreis Toxikologie" 2003), therefore these results are not regarded to be relevant.

In a HGPRT study performed under GLP conditions the genotoxicity of 1,4-dichlorobenzene was tested negative for a dose range of 70-350 µg/ml (Litton, Bayer AG 1986).

A Chromosomal Aberration test revealed negative results at the test concentrations of 25-150µl/ml. No toxicity or cell cycle delay was found up to the limits of solubility (Galloway 1987).

This result is supported by an other study in which it was shown that the test article

1,4-dichlorobenzene up to the concentration of 100 µg/ml in the absence and in the presence of metabolic activation respectively, did not induce a statistically significant increase of chromosomal aberrations in cultured human lymphocytes (Pirovano , RBM 1987).

In vivo:

In a Micronucleus test no indications of a clastogenic effect of 1,4-dichlorobenzene were found after treatment with 2x 177.5 mg/kg and 355 mg/kg per os (Herbold, Bayer AG 1988).

This finding is supported by another Micronucleus test in which no indications of a clastogenic effect of 1,4-dichlorobenzene were found after a single treatment with 2500 mg/kg per os (Herbold, Bayer AG 1986).

In contrast, 1,4-dichlorobenzene was found to be clastogenic (P<0,01) in a single publication in which positive results were reported for 1,4-dichlorobenzene (and another eight benzenes) in the mouse MNT (Mohtashamipur 1987), but due to the following aspects the result of this single study can be considered as disproved (Position paper of the "Beraterkreis Toxikologie" 2003): the absence of sufficient numbers of vehicle control animals (5 control mice in total versus 180 chemically treated mice) suggests that no concurrent controls have been included in this study. Using comparable treatment conditions and doses as Mohtashamipur et al., no enhanced micronucleus frequencies could be detected in mouse bone marrow by Herbold (1986, 1988; published in Tegethoff 2000, Morita 1997). Up to MTD doses were used which led to toxic effects in the bone marrow (significant decrease in % PCE, Tegethoff 2000). Likewise, subchronic treatment of mice with 1,4-dichlorobenzene did not induce micronucleus formation in peripheral blood (NTP 1987).

Conclusion

Overall 1,4-dichlorobenzene was shown to be negative in various validated in vitro and in vivo test systems, like gene mutation tests in bacteria, gene and chromosomal aberration tests in permanently dividing mammalian cells, in vivo mouse bone marrow micronucleus tests and mammalian germ cell tests. Furthermore, negative results were obtained in in vivo UDS tests on mouse liver and rat kidney after 16 hour treatment with 1,4-dichlorobenzene.

The predominantly negative results obtained for 1,4-dichlorobenzene in several mutagenicity test systems give no indication of a relevant potential to induce heritable genetic damage

Justification for selection of genetic toxicity endpoint
no study was chosen because all three key studies yielded negative results. All three studies were performed according to or equal to guideline and evaluated a with Klimisch score 1 or 2

Short description of key information:
Based on the relevant studies (key studies) there is no evidence for mutagenicity ( Ames test, HPRT-test, and Chromomes Aberration test in vitro)

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Based on the discussed data p-dichlorobenzene is evaluated ton non-mutagenic and no classification or labelling is required