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Key value for chemical safety assessment

Additional information

In several tests performed according to OECD 471 in the presence and in the absence of a metabolic activation system and tested up to cytotoxicityo-,m- andp-cresol revealed no genotoxic activity when tested from concentrations of 5 to 5000 µg/plate (Pepper, Hamilton & Scheetz 1981, Pool & Lin 1982, Pool 1992, Haworth 1993, JETOC 1998 and MHLW 2001). All cresols had been tested with theSalmonella typhimuriumstrains recommended in the guideline TA98, TA100, TA1535, TA1537 and TA1538. Additionally m-cresol was tested with the recommendedEscherichia coliWP2uvrA and WP2uvrA/pKM101strains to cover the detection of certain oxidising mutagens, cross-linking agents and hydrazines as well (JETOC 1998).

The results from the tests are confirmed by the negative results in the mouse lymphoma assays performed according to the respective guideline with and without a metabolic activation system on all three components (Pepper, Hamilton & Scheetz 1981, CMA 1988a,b).

In contrast to that the tests for chromosome aberration in mammalian cell systems in the presence and in the absence of a metabolic activation system revealed clastogenic activity for cresols when tested up to cytotoxicity (CMA 1988c,d, MLHW 2001).

Anin-vivochromosomal aberration assay withm-cresol in mice bone marrow following oral dosing of 96-960 mg/kg bw 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 1989b). However, the reliability of the test result is questionable because of experimental deficiencies (only 50 instead of 100 metaphases were scored). Thus, this assay cannot fully compensate the result from thein-vitroassays.

Additionally performed reliablein-vivostudies generally showed negative results for cresols. The Dominant Lethal Assay (DLA) witho-cresol in the mouse was negative (CMA 1989f). When tested according to OECD TG 478 /Rodent Dominant Lethal Assay)p-cresol did also not induce dominant lethal mutations in male germ cells of mice (CMA 1989g).

Following repeated dosing of mice with 0 and 1250-20000 ppm for 13 weeks peripheral blood smapling was undertaken for micronucleus assessment in erythrocytes in mice that were dosed with 0, 5000, 10000 and 20000 ppm was carried out (US Department of Health and Human Services (1991). No evidence of an imcrease in erythrocyte micronuclei were observed. In a further repeat dose study (13 weeks) conducted with male and female B6C3F1mice fed diet containing 0, 625, 1250, 2500, 5000, and 10000 ppmm/p-cresol peripheral blood samples were obtained by cardiac puncture to score micronuclei. No increase in micronuclei frequency was observed (US Department of Health and Human Services 1992, 2007; Witt 2000).

The NOAEL for general toxicity is 1250 ppm based on increased relative kidney and liver weights at higher doses. In the erythrocytes of the chosen miceo-cresol did not induce a significant elevation in the frequency of micronucleated erythrocytes (US Department of Health and Human Services 1991).

Thus, cresols reveal no gene mutation activity and the clastogenic activityin vitrowas not confirmed by respectivein vivostudies.

Short description of key information:
In vitro:
Bacterial reverse mutation assay (Ames): negative (o-, m-, p-cresol)
Mammalian cell gene mutation: negative (o-, m-, p-cresol)
Chromosome aberration test: positive (o-, m-, p-cresol)
In vivo:
Dominant Lethal Assay (DLA) in mice: negative (o-cresol)
Chromosome aberration in mice bone marrow: negative (m-cresol)
Rodent Dominant Lethal Assay in male mice germ cells: negative (p-cresol)

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

The in vivo tests disproved the positive result from the in vitro chromosome aberration assays. Therefore cresols have not to be classified for mutagenic potential.