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IN-VITRO DATA In several Ames tests according to the respective guideline, in the absence and in the presence of a metabolic activation system, tested up to cytotoxicity, m-cresol revealed no genotoxic activity (MHLW 2001, JETOC 1998, Pool and Lin 1982, Haworth 1993) This is confirmed by the negative result in the Mouse-Lymphoma Assay performed according to the respective guideline with and without a metabolic activation system (CMA 1988). In a test for chromosome aberration in mammalian cell systems in-vitro according to guideline in the presence and in the absence of a metabolic activation system, m-cresol revealed clastogenic activity (MLHW 2001). In another test in which CHO cells were treated for 2 hours (instead of 3-6 hours as requested by the respective guideline) in the presence of S9-mix m-cresol induced a significant increase of chromosomal aberrations only at cytotoxic doses whereas without S9-mix and a sufficient treatment time m-cresol yielded a negative result (CMA1988b). Hibika et al., 2005, observed clastogenicactivity with and without S9-mix, however the evaluation criteria is not defined as requested by the respective OECD guideline. There are limited data available which indicate no induction of sister chromatid exchange in mammalian cells. Cheng and Kligerman (1984) did not observe increases in SCEs in cultured human fibroblasts but tested only in the absence of a metabolic activation system and only 20 metaphases were scored (the guideline requested 25 metaphases per plate and with and without metabolic activation system). No increase in the frequencies of SCEs in human lymphocytes were reported by Jansson et al (1986) who examined m-cresol up to 1 mM only in the absence of metabolic activation systems. There are ambiguous data in limited unscheduled DNA synthesis studies reported. Freshly isolated hepatocytes, treated for up to 18 hours with m-cresol in concentrations up to cytotoxicity, did not show unscheduled DNA synthesis (UDS) in an assay in compliance with the respective guideline, but the result was not confirmed by an independent second trial (CMA 1988f). Hamaguchi and Tsutsui (2000) observed no UDS after treatment of cultured Syrian Hamster Embryo (SHE) cells following an incubation period of up to 3 hours without metabolic activation system but noted dose-related increase in UDS induced in SHE cells (treatment time: 6 hours) in the presence of exogenous metabolic activation. However, in both trials cytotoxicity was not reached and neither negative nor positive controls were reported. IN-VIVO DATA There is a reliable but limited in-vivo chromosomal aberration assay in mice bone marrow and in vivo micronucleus test which can be taken into account. The chromosomal aberration test, following oral dosing of 96 -960 mg/kg bw to mice, yielded a negative result. The doses were chosen from dose-range finding study with 400-2000 mg/kg bw resulting in mortality (0/6-6/6) and difficulty in breathing and lethargy (CMA 1989). However, because of experimental deficiencies (only 50 instead of 100 metaphases were scored) and the information that the mitotic index in the target tissue is comparable to those of the controls, the reliability of the test result is questionable. Thus, this assay cannot fully compensate the result from the in-vitro assay. There is another reliable in vivo micronucleus test available (US Health and Human Services 1991, 2007, Witt 2000) using m/p-cresol mixture evaluating erythrocytes for micronuclei after a treatment period of 13 weeks, yielded a negative result, too. This, in vivo study can be considered, because - as already discussed in the section Repeated Dose Toxicity - m/p-cresol mixture in repeated dose toxicity studies caused histopathological changes which are consistent with the observed effects on cresols in general. Therefore using m/p-cresol mixture for in vivo investigations on clastogenicity, such a study can provide reliable information on in vivo clastogenicity and thus help to clear the suspicion from the in vitro study that m-cresol might be clastogenic In the respective study, male and female B6C3F1 mice were fed with diet containing 0, 625, 1250, 2500, 5000, and 10000 ppm m/p-cresol mixture for 13 weeks. At termination of the 13 week study peripheral blood samples were obtained by cardiac punctuire to prepare smears. Slides were stained with Hoechst 33258/pyronin Y. At least 10000 normochromatic erythrocytes from each animal were scored for micronuclei. In addition, the percentage of polychromatic erythrocytes (PCEs) among the total erythrocyte population was scored as measure of bone marrow toxicity. No increases in the frequencies of micronucleated erythrocytes were seen in male or female mice in either study (US Department of Health and Human Services 1991, 2007; Witt 2000). There is an additional limited in vivo SCE study available supporting that m-cresol has no in vivo genotoxicity potential. Cheng and Kligerman (1984) injected intraperitoneal 200 mg/kg bw. m-cresol to healthy and partly hepatectomized mice 21.5 hours prior to sacrifice inducing symptoms including lethargy piloerection an lacrimation. There is no information on the target tissue (bone marrow, alveolar macrophages, liver) reaction. 20 metaphases were scored for evaluation. Compared to negative control (solvent sunflower oil) bone marrow did not show an increase in SCE frequencies in intact or partly hepatectomized mice and alveolar macrophages developed only a slight not significant increase in partly hepatectomized mice. However, results from regenerating liver cannot be taken into account due to the choice of application route: intraperitoneal injection, which might implicate the damage of the liver. Overall, m-cresol is not mutagenic in bacterial systems and mammalian cell systems. With respect to clastogenicity, m-cresol induced chromosomal aberrations in vitro and the respective in vivo studies yielded negative results. Taking into account the in vitro and in vivo data m-cresol is not mutagenic in vitro and not clastogenic in vivo and, consequently, should be considered as not genotoxic.

Short description of key information:
Overall, m-cresol is not mutagenic in bacterial systems and mammalian cell systems. With respect to clastogenicity, m-cresol induced chromosomal aberrations in vitro and the respective in vivo studies yielded negative results. Taking into account the in vitro and in vivo data m-cresol is not mutagenic in vitro and not clastogenic in vivo and, consequently, should be considered as not genotoxic.

Endpoint Conclusion: No adverse effect observed (negative)

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No classification is required.