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Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

in vitro:

- gene mutation (bacterial reversion assay/Ames test): Negative

- gene mutation (mammalian cell TK+/- assay in L5178Y mouse lymphoma cells): Negative

- cytogenicity (chromosomal aberration assay in human lymphocytes): Negative

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

The substances in the category are considered to be similar on the basis that they have common structures of a lithium ion varying only by the length of the fatty acid chain and the presence of unsaturated and/or hydroxyl functional groups. As a result, it is expected that the substances will have similar, predictable properties. Due to the close structural similarity and the narrow range of carbon chain numbers covered in this category, the genotoxicity properties are expected to be similar across the category. Although fatty acids C18 (unsaturated) lithium salts is not in the list of substances being registered, this substance falls within the definition of the lithium salts of fatty acids C14-C22 category by virtue of its chemical structure and therefore read across from data on fatty acids C18 (unsaturated) lithium salts to other members of the category is considered to be justified (see category and read across justification). On the basis of the category justification, it is appropriate therefore to read across the genotoxicity data on lithium fatty acid salts to all C14 – C22 category members.

In order to provide evidence across the C14 to C22 category, key bacterial reversion assays (Ames test) have been conducted on lithium myristate (C14), lithium 12-hydroxystearate (C18) and lithium behenate (C22), together with fatty acids C18 (unsaturated) lithium salts. In addition, a chromosomal aberration assay and a mouse lymphoma assay have been performed on the latter lithium salt. Finally, a mouse lymphoma assay was conducted on lithium myristate. In all cases, the results were negative.

Tests are currently ongoing for bacterial reversion assays (Ames test) on fatty acids C16 -18 (even numbered) saturated and C16 -20 (even numbered) unsaturated lithium salts, fatty acids C16 -18 lithium salts, fatty acids C16 -22 lithium salts, lithium tallowate, and lithium stearate. Chromosome aberration tests are currently ongoing for fatty acids C16 -18 (even numbered) saturated and C16 -20 (even numbered) unsaturated lithium salts, lithium myristate and lithium 12 -hydroxystearate, and gene mutation in mammalian cell tests are currently ongoing for fatty acids C16 -18 (even numbered) saturated and C16 -20 (even numbered) unsaturated lithium salts, and lithium 12 -hydroxystearate.

A further chromosomal aberration assay has been conducted on lithium 12 hydroxystearate. Significant cytotoxicity was observed at the highest concentrations used. In all treatments in this study, there was a slight increase in the frequency of aberrant cells, which included gaps and chromosomal breaks, which were also present in negative controls. The frequency without chromosomal gaps did not exceed 5% (the lower limit used for the positive control response). There was no clear dose-dependency and the aberrant cell increase was not always reproducible in duplicate cultures. There was also induced formation of polyploid cells as a numerical aberration. In addition, rare aberration types consisting of one exchange and some dicentric chromosomes were observed in treated cultures, both with and without S9, and were not observed in either the negative controls or in historical control values in the laboratory.

Since the minor aberrations were only slightly above the concurrent and historic negative controls, were not reproducible between duplicate cultures, nor observed in a concentration-dependent manner, it can be concluded that there is little or no biological significance attached to these findings and therefore the substance did not demonstrate clastogenicity. The low level of rare findings (exchange and dicentric chromosomes) could indicate potential clastogenicity of the substance or any impurities present. However, the chromosomal aberration assay on fatty acids C18 (unsaturated) lithium salts showed no evidence of adverse chromosomal effects, and this substance also falls within the lithium salts of fatty acids C14-C22 category as indicated above. A mouse lymphoma assay on this substance also did not show the presence of small colonies which are indicative of potential clastogenicity.

On a weight of evidence basis, the published and publicly available data indicate that the results from the chromosomal aberration study on lithium 12 hydroxystearate are considered to be anomalous and isolated and not therefore relevant for the classification of the C14 – C22 category of lithium fatty acid salts. Due to the non-dose dependent response and the lack of reproducibility, with effects only observed in one of the two replicates, the study has been disregarded. As the test follows an in vitro method, the study is being repeated in order to obtain robust, repeatable results.

From the results of the experimental studies on substances which fall in the definition of the lithium salts of fatty acids C14-C22 category, it can be concluded that there is a significant volume of data to indicate that the substances are not genotoxic.


Justification for selection of genetic toxicity endpoint
Studies are representative of the suite of genotoxicity studies conducted.

Justification for classification or non-classification

Not classified for genetic toxicity. From the results of the experimental studies on substances which fall in the definition of the lithium salts of fatty acids C14-C22 category, it can be concluded that there is a significant volume of data to indicate that the substances are not genotoxic.