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Key value for chemical safety assessment

Additional information

Genetic toxicity in vitro

Bacterial mutation

The mutagenicity of the substance has been investigated in three separate screening studies reporting results for a large number of substances. Individually, the studies are of limited reliability as the level of reporting for individual substance is inevitably of limited detail; the individual studies also have some methodological deficiencies. Nevertheless, it is concluded based on a weight of evidence approach that consistent negative results in a large number of strains of S. typhimurium and E. coli at concentrations of up to 100 mg/plate show that the substance is not mutagenic in this test system.

Simmon (1975) reports neagtive results in S. typhimurium strains TA 1535, TA 1536, TA 1537, TA 1538, TA 98 and TA 100 in the presence and absence of a metabolic activation system at concentrations of 250 µg/plate. McCann et al (1975) report negative results in S. typhimurium strains TA98, TA100, TA1537 and TA1535 with and without metabolic acitvation as concentrations of up to 10 mg/plate. Rosenkranz & Poirier (1979) report negative results in S. typhimurium strains TA 1535 and TA 1538, and a DNA polymerase deficient E. coli in the presence and absence of metabolic activation.

Mutagenicity in mammalian cells

E-Caprolactone was tested for mutagenicity in the CHO cell mutation assay at HGPRT locus, with and without rat liver S9 activation (San & Clarke; 1997). In the initial mutagenesis assay, no positive responses were observed, i.e. there were no treated cultures with >40 mutants per 106clonable cells (laboratory criteria). Toxicity was not observed in the non-activated cultures, but was observed at concentrations of ≥3000µg/ml with S9 activation. In the independent repeat assay, no positive responses were observed, i.e. there were no treated cultures with >40 mutants per 106clonable cells. Toxicity was not observed in the non-activated cultures, and was observed at concentrations of ≥2100 µg/ml with S9 activation.

Clastogenicity

E-Caprolactone also was tested in an in vitro chromosome aberration assay using Chinese hamster fibroblasts, without metabolic activation (Ishidate and Odashima, 1977). e-Caprolactone was negative in the test at a maximum concentration of 43.8mg/ml; an incidence of 4% aberration was observed. The read-across substance adipic acid was tested in a chromosome aberration assay, in a study commissioned by the FDA (Litton Bionetics, 1974).

Human lung fibroblasts were cultured with the test material at concentrations of 0 (saline), 2, 20 and 200 µg/ml. Chromosome aberrations were evaluated when the cells were in anaphase. Only one cell (in the 200 µg/ml group) was found to contain a bridge, no other aberrations were seen. Therefore, it was concluded that adipic acid was negative for mutagenic activity in the mammalian cell chromosome aberration assay (Litton Bionetics, 1971).

Addtional data

The OECD SIDS document (2005) summarises an addtional study conducted by Slesinski et al (1981). The authors conducted a gene mutation assay and a sister chromatid exchange assay with CHO cells, and an unscheduled DNA synthesis study with rat hepatocytes. e-Caprolactone produced three statistically significant increases in the frequency of genetic mutations without metabolic activation, but there was no dose-related effect nor was there a significant effect on mutant frequency with S9 activation. No statistically significant increase in the frequency of sister chromatid exchange was obtained at any concentration tested with or without metabolic activation. Three e-Caprolactone concentrations tested produced statistically significant increases in the amount of unscheduled DNA synthesis, and all six concentrations produced numerical increases compared to the solvent control. However, there was no dose-related effect in the amount of UDS. The results reported here are from the OECD SIDS document, the original study is not available and has therefore not been summarised in the endpoint study records.

Genetic toxicity in vivo

Two in vivo studies, commissioned by the FDA, were conducted by Litton Bionetics (1971) to investigate the genetic toxicity of the read-across substance adipic acid.

Adipic acid was administered to male rats by gavage at single doses of 0, 3.75, 37.5, 375 and 5000 mg/kg bw, or at five consecutive daily doses of 0, 3.75, 37.5, 375 and 2500 mg/kg (Litton Bionetics, 1971). Rats were sacrificed at varying intervals after dosing, and bone marrow cells were evaluated for chromosome aberrations. There were no increases, relative to negative controls, in the incidence of chromosome aberrations, and all values were within normal limits. No evidence of clastogencitiy was seen under the conditions of this study. A rodent dominant lethal study was conducted with Sprague-Dawley rats, in two separate experiments. The test substance was administered to male rats by gavage at single doses of 0, 3.75, 37.5, 375 and 5000 mg/kg bw, or at five consecutive daily doses of 0, 3.75, 37.5, 375 and 2500 mg/kg bw. Negative controls (saline) and positive controls (triethylene melamine) were included. The male rats were mated to virgin untreated females for a period of 7 -8 weeks. The females were sacrificed 2 weeks after mating and the uterine contents examined for the number of corpora lutea, implantations and losses. The data revealed no dose-response or time-trend patterns, therefore it was concluded that adipic acid does not induce dominant lethal mutations (Litton Bionetics, 1971).

Additional data

An in vivo mouse micronucleus study conducted by Gudi & Ritter (1997) is summarised in the OECD SIDS (2005) document. e-Caprolactone did not cause a significant increase in micronucleated polychromatic erythrocytes in the bone marrow of exposed groups compared to controls, and was therefore concluded to be negative in the micronucleus assay. The results reported here are from the OECD SIDS document, the original study is not available and has therefore not been summarised in the endpoint study records.


Short description of key information:
Negative results are reported in vitro in three Ames tests and in two studies of clastogenicity. An additional study of clastogenicity with the read-across substance adipic acid also gives a negative results. In vivo, negative results are reported in a rat bone marrow cytogenicity assay and in a rat dominant lethal assay, both performed with the read-across substance adipic acid.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

All studies in vitro and in vivo report negative results and therefore do not indicate that e-caprolactone requires classification according to Directive 67/548/EEC and Regulation (EC) No 1272/2008 (the CLP Regulation).