Cadmium

Endpoint summary

Additional information

Data from in vitro and in vivo experimental systems are not consistent but suggests that cadmium, in certain forms, has mutagenic properties. With regard to human exposure, data are also conflicting but again a mutagenic potential both via oral and inhalation exposure routes cannot be excluded.

Different possible non-mutually exclusive direct and indirect mechanisms of mutagenicity have been identified in vitro, although their relevance toin vivosituations is not clearly established. A recent review by Parry and Parry (2009) (available in IUCLID 5 under ‘7.12 Additional toxicological information’) concluded that there is considerable evidence to suggest that the primary mechanism of genotoxicity is the production of oxidative lesions. In this case, there could be a threshold at low doses where the DNA repair enzymes remove the lesions, thus reducing the potential for genetic changes in cells. The EU Risk Assessment Report (RAR) (ECB, 2007) states that most of the mechanisms proposed to explain the mutagenicity of cadmium ions are dose-dependent and support the possibility of a threshold for mutagenic effects (Madle et al., 2000; Kirsch-Volders et al., 2000). Further research may be able to determine No Adverse Effect Levels (NOAEL) and generate dose-response curves.

It should however be noted that cadmium has also been suggested to act as a co-mutagen rather than as a mutagen, e.g. by decreasing fidelity in DNA synthesis or interfering with DNA repair mechanisms (Schwerdtle et al., 2010). In this case, repair activity within a potential thresholded region of the dose-response-curve would be limited (Parry and Parry, 2009).

If cadmium inhibits the repair of DNA damage induced by other agents, this could explain some of the differences in the results of cytogenetic studies in human populations. Indeed, chromosome aberrations might be increased in the different populations/subjects with different additional occupational/environmental exposures as a result of unrepaired damage (Forni, 1992).

The study of Forni et al.(1990; 1992), is cited in SCOEL (2010), for referring to the 10 µg/g creatinin in Cd/urine as a threshold for genotoxicity. SCOEL also published (draft note on the 76^thmeeting, March 2010) that ‘having defined a threshold for genotoxicity, it was shown that renal and respiratory effects are more sensitive than genotoxicity, in turn thought to be a pre-requisite for carcinogenicity’.

Based upon the available evidence at present it is concluded that cadmium has a threshold for genotoxicity. A second important conclusion is that the renal respiratory effects are more sensitive than the genotoxic effects. The risk management for cadmium consequently is based on the protection for renal and inhalatory effects.

Short description of key information:
Data from in vitro and in vivo experimental systems are not consistent but suggests that cadmium, in certain forms, has mutagenic properties. With regard to human exposure, data are also conflicting but again a mutagenic potential both via oral and inhalation exposure routes cannot be excluded. Threshold for mutagenic effects.

Endpoint Conclusion: Adverse effect observed (positive)

Justification for classification or non-classification

Based on available data and read-across, cadmium chloride and sulphate are currently classified as Muta. Cat. 2; R46 (may cause heritable genetic damage)in Annex I of Directive 67/548/EC(the corresponding GHS-CLP classification would be Mutagenic category 1B; H340). By analogy, the other highly soluble forms of cadmium (i.e. cadmium nitrate) warrant comparable classifications.

At present, the slightly soluble cadmium metal and oxide are classified as Muta. Cat. 3; R68 (possible risk of irreversible effects) in Annex I of Directive 67/548/EC (the corresponding GHS-CLP classification would be Mutagenic category 2; H341). A similar classification for cadmium hydroxide and carbonate may therefore be considered.

Apart from cadmium sulphide, none of the insoluble cadmium compounds(e.g. cadmium sulfoselenide, cadmium zinc sulphide or cadmium telluride), not expected to penetrate easily into the organisms, are classified for mutagenicity. Cadmium sulphide (Muta. Cat. 3; R68 or Mutagenic category 2; H341 underGHS-CLP) is an exception for which a revision of the classification could be considered based on solubility properties.