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Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

An Ames test performed with lead di(acetate) is available resulting in a negative study outcome.

Furthermore, different in vitro and in vivo data were generated and made public available using diverse lead substances (i.e., lead dinitrate, acetic acid, lead salt, basic and lead dichloride) as test material. Results suggesting that lead may induce genotoxicity in vitro appear to be induced by indirect mechanisms and at very high concentrations and lacking any physiological relevance.

Regarding the acetate, there is no evidence that acetate (i.e., acetic acid, sodium acetate) induces genetic toxicity in vivo or in vitro.

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

Genetic toxicity in vivo

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

Mode of Action Analysis / Human Relevance Framework

Based on the read across approach (details given in the RAAF document attached on IUCLID section 13.2) lead di(acetate) dissolved into lead cations and acetate anions. As discussed for acetate and based on the long history of use it appears highly unlikely that acetate (i.e., sodium acetate, acetic acid, etc.) produces any genotoxicity. Hence, the lead ion is considered as being the toxicologigally relevant ion and risk assessment and C&L is based on soluble lead compounds.

Additional information

Read across to diverse lead substances are fully justified. Hence, please refer to the endpoint summary in IUCLID section 7.6 "Pb_Genetic toxicity". Further, details on read-across are attachment on IUCLID section 13.2 "PbAc_Read Across Assessment Framework Report" as RAAF document.

Justification for classification or non-classification

While it is not possible to ascribe genotoxic activity to lead in vivo, soluble lead compounds appear to have weak genotoxic activity in vitro. Effects observed usually, but not always, require treatment with highly soluble compounds at cytotoxic concentrations several orders of magnitude higher than that which could reasonably be expected to occur in vivo. There is further general agreement that if lead produces genotoxicity it likely occurs via indirect mechanisms. The ability to directly damage DNA appears to be lacking. Rather, a diverse range of indirect mechanisms have been proposed such as increased production of oxygen radicals, depletion of glutathione, impaired DNA repair and interference with components of the mitotic apparatus during cell division. Which, if any, of these hypothesised mechanisms explains lead’s effects in vitro cannot be determined at this time. However, indirect mechanisms imply potential non-linear dose response and the presence of apparent thresholds below which effects will not be observed. There is as yet little evidence suggesting that the indirect effects suspected of mediating lead genotoxicity occur at lead concentrations that can be reasonably maintained in experimental animals or humans without rapid lethality. On both a mechanistic and a dosimetric basis, the results of most in vitro studies cannot be readily extrapolated to in vivo exposure scenarios.

Based upon this weight of evidence evaluation, genotoxicity is not an endpoint appropriate for use in Risk Characterization nor are the data sufficient as the basis for Classification on the basis of Mutagenicity.