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Key value for chemical safety assessment

Additional information

In vitro mutagenic activity of potassium isoamyl xanthate has been evaluated in one study with bacterial cells and in two studies with mammalian cells. These studies are performed according to the current guidelines in accordance with GLP, and evaluated to be reliable without restrictions. Thus, it is justified to select all three studies as key studies.

Mutagenicity in bacterial test systems

A bacterial mutagenicity study by Bedranikova, M. (2013) is considered reliable without restrictions as the study was performed in compliance with GLP according to OECD guideline 471. This study was conducted by using five strains of Salmonella typhimurium bacteria (TA97, TA98, TA100, TA102 and TA1535) with and without metabolic activation. Potassium isoamyl xanthate was tested for its ability to induce mutations in the main assay at the concentration range of 0.0001-0.5 mg/plate. The test substance in concentration range 0.000001-0.5 mg/plate was evaluated for mutagenic potential in test with preincubation in the absence and presence of metabolic activation. The test substance did not induce mutations under conditions of this study.

Cytogenicity in mammalian cells

The potential of potassium isoamyl xanthate to induce chromosome aberration was assessed in cultured peripheral human lymphocytes by Verbaan I. A. J (2013). This study is considered reliable without restrictions as the study was performed in compliance with GLP according to OECD guideline 473. Potassium isoamyl xanthate was tested up to 666 and 1000 µg/ml for a 3 h exposure time with a 24 h fixation time in the absence and presence of 1.8 % (v/v) S9-fraction, respectively. The compound was not clastogenic in human lymphocyte assay either in the presence or absence of metabolic activation, i. e., it did not increase the number of polyploid cells and cells with endoreduplicated chromosomes in the cells.

Mutagenicity in mammalian cells

The potential gene mutagenic activity of potassium isoamyl xanthate has been evaluated in L5178Y mouse lymphoma cells by Verspeek-Rip, C.M. (2013b). The test method was performed according to OECD guideline 476 and in compliance with GLP.

In the absence of S9-mix, potassium isoamyl xanthate induced 3.9- and 2.8-fold increases in the mutation frequency in the two independent repeat experiments. The mutation frequencies of 219 and 202 x 10-6 were above the global evaluation factor plus mutation frequency of the negative controls (GEF + MF(controls): 182 x 10-6 and 197 x 10-6) and outside the historical control data range. This response fulfilled the criteria for a positive response. The increase in the first mutation experiment was only observed at the highest dose level of 900 µg/ml with severe toxicity, a total growth of 8 %.

In the presence of S9-mix, potassium isoamyl xanthate induced a 2.7-fold increase in the mutation frequency. The mutation frequency of 196 x 10-6 was just below the global evaluation factor plus mutation frequency of the negative controls (GEF + MF(controls): 199 x 10-6), but outside the historical control data range.

Potassium isoamyl xanthate is mutagenic in the absence of S9-mix in the TK mutation test system under the experimental conditions described in this report. Since the meaningful increase in the mutation frequency at the TK locus in the presence of S9-mix is only observed at one cytotoxic concentration and the mutation frequency was just below the MF(mean solvent control) + GEF and above the historical control data range, it is concluded that the mutagenic response observed in the mouse lymphoma L5178Y test system in the presence of S9-mix is equivocal under the experimental conditions described in the report.

This study shows evidence on the mutagenicity potential for the potassium isoamyl xanthate. However, in vitro tests generally present crucial limitations which affect the usefulness of the assays to predict mutagenicity/genotoxicity potential of a substance in vivo in mammals and especially in humans.

These limitations are:

- lack of a “human like” metabolic capacity of the cell lines used

- absence of toxicokinetics

- oversensitivity compared toin vivosituations – low specificity

- sometimes the use of cell lines that are not relevant to predict genotoxic endpoints at target organs

 

Due to these limitations, no single in vitro test can be used for the evaluation of the mutagenicity/genotoxicity potential of a substance.

 

Furthemore, potassium isoamyl xanthate hydrolyses when in contact with water or moisture releasing alcohol, carbon disulphide, potassium carbonate and potassium trithiocarbonate. These decomposition products are not classified for mutagenicity. Neither of other xanthates have classification for mutagenicity.

Based on the above facts, potassium isoamyl xanthate is not considered to be mutagenic in humans.

Justification for selection of genetic toxicity endpoint
No study was selected, since the conclusion is based on the following assays: Bacterial reverse mutation assay (Ames test), In vitro mammalian cell gene mutation assay, In vitro mammalian chromosome aberration test.

Short description of key information:
Gene mutation (reverse mutation assay/Ames test): negative in all tested bacterial strains with and without metabolic activation (equivalent to OECD TG 471).
Chromosome aberration study in mammalian cells: negative, with and without metabolic activation (OECD 473).
Gene mutation study in mammalian cells: positive, without metabolic activation; equivocal, with metabolic activation (OECD 476). However, based on the classification of the decomposition products and other xanthates, the target substance is not considered to be mutagenic in humans.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Based on the results of in vitro bacterial gene mutation study, in vitro mammalian chromosomal aberration and gene mutation studies and the current classification of decomposition products no classification is proposed for genotoxicity according to the criteria of CLP regulation 1272/2008 and the EU directive 67/548/EEC.