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All publicly available information on the genotoxicity of silver substances was identified in a comprehensive literature search and subjected to a reliability and quality screening procedure according to Klimisch et al (1997). To increase readability of this dossier only the relevant and reliable studies are presented in this dossier in detail.

The majority (10) of the retrieved publications represent bacterial assays of varying relevance and quality, most of them in fact originating from a time before internationally adopted test guidelines became available. All of these were either rated “invalid” or “not assignable”. Most of them reported negative results, while one recent assay conducted with silver iodide (Eliopoulos & Mourelatos, 1998) reported a positive finding; however, this study was also rated with RL=3 (not reliable) because of several inconsistencies and lack of plausibility, and is considered outweighed by the numerous other negative assay results. Whereas this may be considered as a formal data gap, based on the recommendations given by the HERAG fact sheet on mutagenicity as also implemented in REACH guidance documents, it was considered fully justified to waive the conduct of this bacterial mutagenicity test on principal considerations: both guidance documents state that the uptake of metal ions by bacteria is considered to be low and thus the sensitivity of bacterial test systems on the detection of the mutagenic potential of dissolved metal ions appears to be low (cf. REACH Guidance on information requirements and chemical safety assessment, Chapter R.7a (Version May 2008), Page 390; HERAG fact sheet No 5 Mutagenicity, Chapter 2.1).

Beyond the above information, guideline-conform gene mutation and clastogenicity tests in vitro are available (Lloyd, 2010a/b), as well as one in vivo clastogenicity test (Kim et al., 2008). The overall result from all these tests is negative, with the exception of an equivocal result in the in vitro mammalian cell gene mutation assay. In this GLP assay on disilver sulfate, small increases in mutation frequency (MF) were seen only at the highest concentrations following treatments in the presence of S9, and in the 24 hr treatment in the absence of S9, but did not achieve biological or statistical significance. However, at the top 1 or 2 concentrations in the 3 hr treatments in the absence of S9, increases in MF were seen that did achieve statistical and biological significance. This finding is not considered to be biologically plausible for the following reasons: the fact that the increases in MF in the mouse lymphoma study were only seen at >80% toxicity is significant. It has been reported (Scott et al, 1991; Kirkland and Müller, 2000; Müller and Kasper, 2000) that a number of indirect mechanisms may lead to genotoxicity, usually seen in vitro because higher concentrations of chemical can be used. Some of these mechanisms involve non-DNA targets such as protein synthesis, lysosomes, receptors, signalling pathways, ionic balance etc. Inhibition of DNA synthesis or DNA repair may also indirectly lead to DNA damage, and such indirect mechanisms would be expected to have a threshold (Scott et al, 1991). In most cases, disruption of these types of non-DNA targets usually leads to marked cytotoxicity at the same concentrations where genotoxic effects are seen. Genotoxicity only seen at low levels of cell survival may therefore be seen as arising indirectly to these cytotoxic effects.

Given the negative response in this assay without metabolic activation and considering that “metabolism” as such is not relevant for inorganic cations such as silver, the outcome of this assay may be considered as equivocal.

Overall, after considering the predominantly negative test results in highly reliable genotoxicity assays, by applying a weight-of-evidence approach the conclusion is reached that no genotoxicity is associated with exposure to silver ions, and hence to silver substances.


Eliopoulos, P.; Mourelatos, D. (1998): Lack of genotoxicity of silver lodide in the SCE assay in vitro, in vivo, and in the Ames/Microsome test. Teratogenesis, carcinogenesis, and mutagenesis 18, 303-308.

Kirkland,D.J. and Müller,L. (2000) Interpretation of the biological relevance of genotoxicity test results: the importance of thresholds. Mutat. Res. 464: 137-147.

Klimisch, HJ, Andreae E, and Tillmann, U. 1997. A systematic approach for evaluating the quality of experimental and ecotoxicological data. Regulatory Toxicology and Pharmacology 25:1-5.

Müller,L. and Kasper,P. (2000) Human biological relevance and the use of threshold-arguments in regulatory genotoxicity assessment: experience with pharmaceuticals. Mutat. Res. 464: 19-34.

Scott,D., Galloway,S.M., Marshall,R.R., Ishidate,M., Jr., Brusick,D., Ashby,J., and Myhr,B.C. (1991): International Commission for Protection Against Environmental Mutagens and Carcinogens. Genotoxicity under extreme culture conditions. A report from ICPEMC Task Group 9. Mutat. Res.257: 147-205.

Justification for selection of genetic toxicity endpoint
Two key studies are available addressing gene mutation and chromosome aberration in mammalian cells, using a readily bioavailable silver substance as the test item. In addition, published data was collected an assessed, and the conclusion is reached in a weight-of-evidence approach.

Short description of key information:
By applying a weight-of-evidence approach, after consideration of the predominantly negative test results in highly reliable genotoxicity assays, the overall conclusion is reached that no genotoxicity needs to be expected from exposure to the silver ion, and hence silver substances.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

In consideration of the predominantly negative test results in highly reliable genotoxicity assays, no genotoxicity needs to be expected from exposure to silver substances, and therefore no classification for this endpoint needs to be proposed.