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Genetic toxicity in vitro

Genetic toxicity of pentan-1-ol in vitro was examined in an Ames test performed by the National Toxicology Program according to the NTP standard procedure (NTP 1986). The bacterial strains S. typhimurium TA 1535, TA 1537, TA 98, TA97 and TA 100 were treated with concentrations of 33, 100, 333, 1000, 3333, 6666 and 10000 µg/plate pentan-1-ol with and without metabolic activation by S9 mix from Aroclor 1254-induced male Sprague-Dawley rat or Syrian hamster liver. Although cytotoxicity was observed at 6666 and 10000 µg/plate, no mutagenicity was detected.

 

The read across substance branched and linear pentanols was also not mutagenic in Salmonella typhimurium strain TA98, TA100, TA1535, TA1537 and TA1538 with or without metabolic (S9) activation in a study conducted to a method similar to OECD TG 471 (Union Carbide Corp. 1983). The substance was tested at doses of 0.01, 0.03, 0.1, 0.3 and 1 µg /plate. Cytotoxicity was observed at 1 µg/plate with and without S9 mix (Aroclor 1254 induced rat liver homogenate).

Kreja & Seidel (2002) performed a mammalian cell gene mutation assay (HPRT) according to the method described by Bradley et al. (1981) with the structural analogues 3-methylbutan-1-ol (CAS No. 123-51-3) and 2-methylbutan-1-ol (CAS No. 137-32-6). Chinese hamster lung fibroblasts were exposed to 3-methylbutan-1-ol and 2-methylbutan-1-ol with and without metabolic activation by Aroclor 1254-induced rat liver S9-mix. Even at the highest concentrations of 51.5 mM and 46 mM tested, no genetic toxicity was found.

In addition, the mutagenic potential of primary amyl alcohol (= pentanol, branched and linear) was examined in the Chinese Hamster Ovary (CHO) gene mutation assay (HPRT) according to a method similar to OECD TG 476 (Union Carbide Corp. 1983). The substance did not produce any dose-related or repeatable statistically significant increases in the frequency of mutations of CHO cells at concentrations which spanned a cytotoxic to non-cytotoxic range (0.075, 0.10, 0.15, 0.20 and 0.25 % v/v) tested with and without an S9 metabolic activation system.

 

The publication by Kreja & Seidel (2002) also includes the results of an in vitro mammalian cell micronucleus test with Chinese hamster lung fibroblasts (V79) for pentan-1 -ol, 3 -methylbutan-1 -ol, and 2 -methylbutan-1 -ol. The test was conducted according to the method described by Miller et al. (1995). Pentan-1-ol was tested for 4 hours at concentrations of 23 and 46 mM in DMSO with and without metabolic activation by S9-mix. Since no significant increase of micronuclei was found after the treatment with pentan-1-ol as opposed to the positive controls methylmethanesulfonate and cyclophosphamide, pentan-1-ol was regarded as non clastogenic (Kreja & Seidel 2002). The same test was conducted with the category members 3-methylbutan-1-ol and 2-methylbutan-1-ol. 3-methylbutan-1-ol and 2-methylbutan-1-ol were tested for 4 hours at concentrations of 5, 9 and 23 mM (3-methylbutan-1-ol) and 23 and 45 mM (2-methylbutan-1-ol) in DMSO with and without metabolic activation by a S9-mix. Again, no significant increase of micronuclei was found in both assays.

 

A chromosome aberration assay was conducted with pentanol, branched and linear according to OECD TG 473 and in compliance with GLP regulations in primary cultures of lymphocytes obtained from Sprague-Dawley derived CD ISG (outbred Crl:CD(SD)) rats (Dow Chemical Company 2006). Approximately 48 hours after the initiation of whole blood cultures, cells were treated either in the absence or presence of S9 activation with concentrations of pentanol, branched and linear ranging from 0 (solvent control) to 881.5 µg/mL of culture medium. The highest concentration was based on the limit dose of 10 mM in this assay system. The duration of treatment was 4 or 24 hours without S9 and 4 hours with S9. Based upon the mitotic indices, cultures treated for 4 hours with targeted concentrations of 0 (solvent control), 220.4, 440.8, and 881.5 µg/mL in the absence and presence of S9 activation and cultures treated for 24 hours with 0 (solvent control), 110.2, 220.4, and 440.8 µg/mL were selected for determining the incidence of chromosomal aberrations. There were no significant increases in the frequencies of cells with aberrations in either the presence or absence of S9 activation. Cultures treated with the positive control chemicals had significantly higher incidences of abnormal cells in all assays. Based upon these results, primary amyl alcohol-mixed isomer was considered to be non-genotoxic in this in vitro chromosomal aberration assay utilizing rat lymphocytes.

These negative results are confirmed by several additional assays: Pentan-1 -ol was not mutagenic in e.coli in a paper disc assay (Szybalski, 1958). In another HPRT assay, 3 -methylbutan-1 -ol did not show a mutagenic potential (Seidel & Plappert, 1999). Neither pentan-1 -ol nor 3 -methylbutan-1 -ol or 2 -methylbutan-1 -ol led to a difference in tail moment compared to the negative control in a comet assay (Kreja & Seidel, 2002) (Seidel & Plappert, 1999). No changes were observed with pentanol, branched and linear in a sister chromosome exchange assay (UCC, 1983).

Genetic toxicity in vivo

No in vivo study results are available for pentan-1-ol, but data are available for another member of the category of pentanols. The genetic toxicity of 3 -methylbutan-1-ol in vivo was analyzed in a micronucleus assay performed according to OECD guideline 474. Five male and five female NMRI mice received a single dose of 1500 mg/kg bw of this read across substance in 0.25 % aqueous Methocel K4M premium by gavage. Although the dose of 1500 mg/kg bw was severely toxic in a preceding range finding test, no mortality occurred. 24 or 48 hours after administration, the animals were sacrificed and bone marrow was prepared for analysis. As result, 3-methylbutan-1-ol did not produce a significant, exposure-related increase in the incidence of micronucleated polychromatic erythrocytes in male or female animals.


Justification for selection of genetic toxicity endpoint
Several reliable study results and publications, including read across data, were used in a weight of evidence approach to assess the endpoint "genetic toxicty".

Short description of key information:
Genetic toxicity:
- in vitro: negative (Ames, MNT); (Ames, CA, HPRT, Read across to CAS 94624-12-1); (HPRT, MNT, Read across to CAS No. 123-51-3 and 137-32-6)
-in vivo: negative (MNT, NMRI mice, OECD TG 474, Read across to CAS No. 123-51-3)

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

The available data are considered reliable and suitable for classification purposes under Regulation (EC) No 1272/2008 (CLP). No positive result has been observed in any of the assays. Gene mutation tests in bacteria were performed with pentan-1 -ol or pentanol, branched and linear. No gene mutation potential in mammalian cells was confirmed for 2 -methylbutan-1 -ol, 3 -methylbutan-1 -ol, and pentanol, branched and linear. Assays for chromosomal abberration exist for all four category members in vitro and for 3 -methylbutan-1 -ol also in vivo. It was thus concluded that pentan-1-ol is not genotoxic to bacteria or mammalian cells in vitro and also not clastogenic in mammalian cells in vitro or in vivo.

As a result, the substance is not classified for genetic toxicity under Regulation (EC) No 1272/2008, as amended for the seventh time in Regulation No (EC) 1297/2014.