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Carbonyl iron and electrolytic iron were tested adequately for gene mutations in bacteria (Salmonella/microsome test) and in mammalian tissue culture cells in the TK +/- L5178Y mouse lymphoma test. Both of these particulate forms of metallic iron afforded negative results in the bacterial test. In the mammalian assay electrolytic iron again gave a negative response, while a positive result was obtained for carbonyl iron. The difference in mutagenicity between the two particulate forms of metallic iron in the mammalian test can be attributed to the fact that smaller carbonyl iron particles are phagocytosed by the cells, while the larger and more irregularly-shaped electrolytic iron particles are not.

The third in vitro test was waived on the grounds that the effects of carbonyl iron in the TK +/- L5178Y mouse lymphoma test were most probably the result of the general genotoxicity of poorly soluble particles (see Schins and Knaapen, 2007; summarized in IUCLID Section 7.12). A positive effect based on this particle-dependent effect is also expected in a cytogenetic assay with mammalian tissue culture cells when the iron particles are phagocytosed.

If no phagocytosis occurs, no effect is expected because metallic iron does not dissolve (ionize) at the pH of 7.4 of the tissue culture media, which means that no exposure to iron ions occurs. A third in vitro test can thus be deemed redundant.

Notwithstanding the positive TK +/- L5178Y mouse lymphoma test, in vivo genotoxicity testing with metallic iron powders is also waived, based on the following scientific arguments.

1) Systemic exposure to metallic iron is impossible because the particles are too large to translocate (the present dossier does not consider nanoparticles made of metallic iron; see IUCLID Section 7.1), no absorption of dissolved metallic iron is possible and the absorption in the duodenum of ionized iron formed at the low pH levels in the gastric juice is strictly regulated in healthy humans. So no genotoxic effects in organs/tissues/cells away from the port of entry are to be expected do to a lack of exposure.

2) In vivo studies aimed at the detection of local genotoxic effects, i.e., effects at the port of entry are also deemed redundant, because of the insolubility of metallic iron under physiological conditions and the expected particle-dependent genotoxicity of phagocytosed metallic-iron particles


Short description of key information:
Carbonyl iron and electrolytic iron were tested adequately for gene mutations in bacteria (Salmonella/microsome test) and in mammalian tissue culture cells (mouse lymphoma test). Both these particulate forms of metallic iron gave negative results in the bacterial test. In the mammalian assay electrolytic iron again gave a negative result, while a positive result was obtained for carbonyl iron. The difference in mutagenicity between the two particulate forms of metallic iron in the mammalian test is most probably the result of the fact that smaller carbonyl iron particles are phagocytosed by the cells, while the larger and more irregular electrolytic iron particles are not.
The third in vitro test and in vivo genotoxicity testing were waived based on the lack of solubility of metallic iron under physiological conditions, the limited systemic exposure and the known genotoxicity of phagocytosed particles as such, independent of the dissolution of their components.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

As the genotoxicity of metallic iron is only related to the specific particle effects of phagocytosed metallic-iron particles, it is not justified to classify and label metallic iron for genotoxicity.