Lithium neodecanoate

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

No genetic toxicity study with lithium neodecanoate is available, thus the genetic toxicity will be addressed with existing data on the individual moieties lithium and neodecanoate. Lithium neodecanoate is not expected to be genotoxic, since the two moieties lithium and neodecanoic acid have not shown gene mutation potential in bacteria and mammalian cells as well as in vitro clastogenicity.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

No genetic toxicity study with lithium neodecanoate is available, thus the genetic toxicity will be addressed with existing data on the individual moieties lithium and neodecanoate.

Lithium

In vitro assays with bacteria

Bacteria reverse mutation test with lithium carbonate is not available. Read-across was applied using study results obtained from lithium hydroxide. Lithium hydroxide was tested in the Salmonella typhimurium reverse mutation assay according to OECD Guideline 471. The test was performed with four histidine-requiring strains of Salmonella typhimurium (TA 1535, TA 1537, TA 100 and TA 98) and in the Escherichia coli reverse mutation assay with a tryptophane-requiring strain of Escherichia coli WP2uvrA in two independent experiments. Lithium hydroxide was tested up to concentrations of 5000 µg/plate in the absence and presence of S9-mix. Lithium hydroxide did not precipitate on the plates at this dose level. The bacterial background lawn was not reduced at all concentrations tested. Reduction in the number of revertants was observed in the tester strain TA 1535, TA 98, TA 100 and WP2uvrA at the limit concentration of 5000 ug/plate, indicating some bacteriotoxicity. Lithium hydroxide did not induce a dose-related, two-fold, increase in the number of revertant (His+) colonies in each of the four tester strains (TA 1535, TA 1537, TA 98 and TA 100) and in the number of revertant (Trp+) colonies in the tester strain WP2uvrA both in the absence and presence of S9-metabolic activation. These results were confirmed in an independently repeated experiment. Based on the results of this study it is concluded that lithium hydroxide is not mutagenic in the Salmonella typhimurium reverse mutation assay and in the Escherichia coli reverse mutation assay.

 

In vitro assays with cultured Peripheral Human Lymphocytes

A chromosome aberration test with lithium carbonate is not available. Read-across was applied using study results obtained from lithium hydroxide.

The effect of lithium hydroxide on the induction of chromosome aberrations in culture peripheral human lymphocytes in the presence and absence of a metabolic activation system (Aroclor-1254 induced rat liver S9-mix) was investigated according to OECD Guideline 473 and EU method B.10.

In the absence of S9-mix lithium hydroxide was tested up to 560 µg/mL for a 3-h treatment time with a 24-h fixation time in experiment 1A and up to 375 µg/mL in experiment 1C. In the presence of 1.8 % (v/v) S9-fraction lithium hydroxide was tested up to 560 µg/mL for a 3-h treatment time with a 24-h fixation time in experiment 1A and up to 400 µg/mL in experiment 1C. In both experiments 1A and 1C, lithium hydroxide did not induce a statistically or biologically significant increase in the number of cells with chromosome aberrations in the absence and presence of S9-mix.

In the second experiment lithium hydroxide was tested up to 350 µg/mL for a 24 hours continuous treatment time and up to 400 µg/mL for a 48 hours continuous treatment time (both without S9-mix). In the second experiment lithium hydroxide was tested up to 450 µg/mL for a 3-h treatment time with a 48-h fixation time with S9-mix. In the absence of S9-mix, at the 24-hours continuous treatment time, lithium hydroxide induced statistically significant increases in the number of cells with chromosome aberrations at the lowest tested concentration of 275 µg/mL (only when gaps were included) and at the highest cytotoxic concentration of 350 µg/mL both when gaps were included and excluded. At the intermediate concentration of 300 µg/mL lithium hydroxide did not induce a statistically significant increase in the number of cells with chromosome aberrations. Since the increase of chromosome aberrations at 275 µg/mL was observed only when gaps were included and furthermore the increase was within the historical control data range and revealed no dose-response relationship, the increase was not considered biologically relevant. At the continuous treatment time of 48 hours exposure of cells to 350, 375 or 400 µg/mL lithium hydroxide did not induce a significant increase in the number of cells with chromosome aberrations. In the presence of S9-mix, lithium hydroxide did not induce a statistically or biologically significant increase in the number of cells with chromosome aberrations.

Finally, it is concluded that this test is considered valid and that lithium hydroxide is not clastogenic under the experimental conditions of this test. Positive control chemicals mitomycin C and cyclophosphamide indicated that the test conditions were adequate and that the metabolic activation system (S9-mix) functioned properly.

 

In vitro assays with mammalian cells

A mammalian cell gene mutation test with lithium carbonate is not available. Read-across was applied using study results obtained from lithium hydroxide monohydrate.

An in vitro mammalian cell assay was performed in mouse lymphoma L5178Y TK +/- cells to test the potential of lithium hydroxide to cause gene mutation and/or chromosome damage according to OECD Guideline 476 and the EU method B.17. Lithium hydroxide monohydrate was assayed in a gene mutation assay in cultured mammalian cells (L5178Y TK +/-) both in the presence and absence of metabolic activation by a liver post-mitochondrial fraction (S9-mix) from Aroclor 1254-induced rats. The test was carried out employing 2 exposure times without S9-mix: 3 and 24 hours, and one exposure time with S9-mix: 3 hours; this experiment with S9-mix was carried out twice. In the preliminary experiment without and with metabolic activation, concentrations tested were 0.25, 1, 2.5, 10, 25, 100 and 200 µg/mL. Cytotoxicity (decreased survival) was noted at the top concentration of 200 μg/mL. Hence, in the experiments without or with metabolic activation the concentrations of 12.5, 25, 50 100 and 200 µg/mL were used. In the main study, cytotoxicity (decreased survival) was noted immediately after treatment (plating efficiency step 1) and in the following plating for 5-trifluoro-thymidine (TFT) resistance (plating efficiency step 2) in the presence and absence of metabolic activation at the top concentration of 200 μg/mL. The mean values of mutation frequencies of the negative controls ranged from 61.61 to 98.34 per 106 clonable cells in the experiments without metabolic activation, and from 68.23 to 82.61 per 106 clonable cells in the experiments with metabolic activation and, hence, were well within the historical data range. The mutation frequencies of the cultures treated with lithium hydroxide monohydrate ranged from 64.74 to 92.63 per 106 clonable cells (3 hours exposure) and 50.42 to 92.34 per 106 clonable cells (24 hours exposure) in the experiments without metabolic activation and 75.88 to 105.59 per 106 clonable cells (3 hours exposure, first assay) and 45.04 to 99.10 per 106 clonable cells (3 hours exposure, second assay) in the experiments with metabolic activation. These results were within the range of the negative control values and, hence, no mutagenicity was observed according to the criteria for assay evaluation.

Methylmethanesulfonate was employed as positive control in the absence of exogenous metabolic activation and 3-Methylcholanthrene in the presence of exogenous metabolic activation and indicated that the test conditions were adequate and that the metabolic activation system functioned properly.

Lithium hydroxide monohydrate, tested up to a pronounced cytotoxic concentration in the absence and presence of metabolic activation in two independent experiments, was negative with respect to the mutant frequency in the L5178Y TK +/- mammalian cell mutagenicity test. Therefore, lithium hydroxide monohydrate also did not exhibit clastogenic potential at the concentration range investigated. According to the evaluation criteria for this assay, these findings indicate that lithium hydroxide monohydrate, tested up to a cytotoxic concentration in the absence and presence of metabolic activation did neither induce mutations nor had any chromosomal aberration potential.

In vivo genotoxicty

The Nordic Expert Group stated, that considering the chemical properties of the lithium compounds it is unlikely that they act as direct mutagens. A possible explanation to the apparent genotoxicity they see in a secondary effect of increased cell survival caused by lithium’s inhibition of GSK3 Consequently, Lithium carbonate has not to be considered as a genotoxic or clastogenic substance.

These negative findings for lithium hydroxide are supported by experience with long-term administration of lithium carbonate in humans. Thus, there is no evidence that the negative findings in in-vitro tests with lithium hydroxide, do not really predict the genotoxicity potential of lithium carbonate.

 

Neodecanoate

Neodecanoic acid is not mutagenic in vitro in bacterial mutation assays (with and without metabolic activation) and was not clastogenic in a cytogenetic assay. Although a test on in vitro gene mutation in mammalian cells is not provided, the bacterial reverse mutation test covering the same endpoint did not show any sign of mutagenic potential with and without metabolic activation. This data suggests that neodecanoic acid is not genotoxic in vitro and likely not genotoxic in vivo.

No classification for genetic toxicity is indicated according to the classification, labelling and packaging (CLP) regulation (EC) No 1272/2008.

 

 

Lithium neodecanoate

Lithium neodecanoate is not expected to be genotoxic, since the two moieties lithium and neodecanoic acid have not shown gene mutation potential in bacteria and mammalian cells as well as in vitro clastogenicity. Further testing is not required. Thus, lithium neodecanoate is not to be classified according to regulation (EC) 1272/2008 as genetic toxicant. For further information on the toxicity of the individual moieties, please refer to the relevant sections in the IUCLID and CSR.

Justification for classification or non-classification

Lithium neodecanoate is not expected to be genotoxic, since the two moieties lithium and neodecanoic acid have not shown gene mutation potential in bacteria and mammalian cells as well as in vitro clastogenicity. Thus, lithium neodecanoate is not to be classified according to regulation (EC) 1272/2008 as genetic toxicant.