Registration Dossier

Administrative data

Key value for chemical safety assessment

Additional information

In vitro studies:

p-Cresol yielded a negative result in several Ames tests performed according to OECD TG 471 in the presence and in the absence of a metabolic activation system and tested up to cytotoxicity (Pool and Lin 1982, Haworth 1993). p-Cresol was not mutagenic in the mouse lymphoma forward mutation assay according to OECD TG 476 with and without metabolic activation (CMA 1988). In 2 SCE (sister chromatid exchange) assays p-cresol was negative under the conditions of these assays.

p-Cresol induced chromosome aberrations in a test according to OECD TG 473 with Chinese Hamster Ovary cells in the presence and in the absence of a metabolic activation system and tested up to cytotoxicity (CMA 1988).

In vivo studies:

Several in-vivo genetic toxicity assays are available:

When p-cresol was tested according to OECD TG 478 /Rodent Dominant Lethal Assay the substance did not induce dominant lethal mutations in male germ cells of mice (CMA 1989).

In an additional assay p-cresol was evaluated for mutagenic activity using the Drosophila melanogaster Sex-Linked recessive Lethal Test. The test was negative; the treatment did not increase the frequency of sex-linked recessive lethal mutations, indicating that the test substance was not mutagenic in Drosophila under the conditions of this assay (CMA 1989).

Furthermore, there is a Micronucleus Test in vivo using m/p-cresol mixture evaluating erythrocytes for micronuclei after a treatment period of 13 weeks. This 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 of cresols in general.

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 puncture 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 indication of clastogenicity is reported in this study because 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).

Additional, p-cresol was evaluated in an in vivo SCE assay. p-Cresol did not induce significant increases in SCE frequencies in any of the cell types examined: bone marrow cells, alveolar macrophages, liver cells. p-Cresol was negative under the condition of this assay (Cheng, 1984).

Overall, considering the available data on clastogenicity there is reliable and sufficient information to conclude that clastogenic activity of p-cresol is unlikely in vivo.

Additional comment: On 2011-11-24 ECHA has sent to the registrant a draft decision for p-cresol, CAS 106-44-5 (EC No 203-398-6), communication number: CCH-C-0000002106-84-02/F.

ECHA stated: lf there is a positive result in any of the in vitro genotoxicity studies conducted to fulfil the Information requirements specified in Annex VII or VIII, a second in vivo test may be necessary depending on the quality and relevance of all available data. The absence of an appropriate second in vivo study has not been justified. ECHA proposed pursuant to Article 12 (1) e and Annex X, 8.4 of REACH, you should provide a justification to show whether or not a second in vivo test is necessary.

In the updated IUCLID dataset, four in-vivo genetic toxicity tests are included. All tests were negative. From our opinion further in vivo tests are not necessary and not justified.

Furthermore ECHA stated: We have noted that you have not provided in your dossier information that is available in the public domain on the frequency of micronuclei in peripheral blood erythrocytes of mice exposed to m- and p-cresols (NTP report on the toxicity studies of cresol, NTP, 1992).

The requested information was added in the IUCLID dataset: 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 puncture to score micronuclei. 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 1992, 2007; Witt 2000).

Overall conclusion: In four in-vivo genetic toxicity tests p-cresol was negative. No increases of micronuclated erythrocytes were seen in male of female mice in an MNT.

Therefore further in-vivo genetic toxicity tests are not justified.


Justification for selection of genetic toxicity endpoint
Several valid genotoxicity tests are available

Short description of key information:
p-Cresol was tested in-vitro in several Ames tests, a mouse lymphoma test, several chromosome aberration, sister chromatid exchange and UDS tests.
Additional p-cresol or m/p-cresol was tested in vivo in an MNT test, a Rodent Dominant Lethal Test, a Drosophila melanogaster Sex-Linked recessive Lethal Test and an in vivo SCE test. All in vivo tests were negative.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

No classification and labelling is necessary.