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EC number: 231-793-3 | CAS number: 7733-02-0
Some data were available on the genotoxicity of zinc sulphate. Data on other zinc compounds have been also used, as the basic assumption is made that after intake all zinc compounds (including metallic zinc) are changed (at least in part) to the ionic species and that it is this zinc cation that is the determining factor for the biological activities of the zinc compounds.
The genotoxicity of soluble and slightly soluble zinc compounds have been extensively investigated in a wide range of in vitro and in vivo studies. The in vitro investigations included non-mammalian and mammalian test systems covering the endpoints of gene mutation, chromosomal aberrations, sister chromatide exchange, unscheduled DNA synthesis (UDS), as well as cell transformation. Available in vivo genotoxicity assays included the micronucleus test, sister chromatide exchange (SCE) and chromosomal aberration test and the dominant lethal mutation assay in mouse or rat as well as investigations for sex-linked recessive lethal mutation in drosophila melanogaster.
The investigated zinc compounds did not increase the mutation frequencies in the majority of bacterial or mammalian cell culture systems. For example, zinc chloride, zinc sulphate, zinc bis(dihydrogen phosphate), zinc oxide or zinc monoglycerolate were consistently negative in the Ames test. While zinc chloride was also negative for gene mutations in the mouse lymphoma assays, there was some evidence that zinc oxide, zinc acetate or zinc monoglycerolate induced in the absence of metabolic activation the formation of mutation colonies. Several reviewers noted, however, that these mutations were observed at cytotoxic concentrations and that the analysis did not distinguish between big and small colonies which could be caused by gene mutation or chromosomal aberrations (Thompson et al.,1989, WHO, 2001; EU RAR, 2004; MAK, 2009).
Conflicting information was further found when zinc compounds were examined for their potential to induce chromosomal aberrations or sister chromatide exchange in mammalian cell systems or when evaluated in the cell transformation assay. Positive as well as negative results were obtained in these cell systems with either soluble or slightly soluble zinc compounds. In those studies where chromosomal aberrations or sister chromatide exchange has been observed, these were generally considered to be weak and occurred only at high, often cytotoxic concentrations. Moreover, these positivein vitro findings have also to be seen in context of the impact that changes in zinc levels can have on cell system processes that are controlled by a strict metal homeostasis. A change of this metal homeostasis due to increased zinc levels, may lead to a binding of zinc to amino acids like cystein and therefore to an inhibition of certain enzymes. This can lead to interactions with the energy metabolism, signal transmission and apoptotic processes which can lead to the observed clastogenic or aneugenic effects inin vitro systems (EU RAR, 2004; MAK, 2009).
In addition to above mentioned in vitro investigations, various soluble and slightly soluble zinc compounds have also been studied in a range of in vivo studies including the micronucleus test, SCE and chromosomal aberration test or dominant lethal mutation assay in mice or rats as well as in the Drosophila Melanogaster SLRL test. The zinc compounds were consistently negative in the micronucleus and in the assay with Drosophila Melanogaster. Zinc sulphate was further negative in a dominant lethal assay in rats.
Equivocal and sometimes contradicting results were found for the induction of chromosomal aberrations which have been studied in bone marrow cells harvest from animals exposed to zinc compounds zinc chloride, and zinc oxide. Negative findings for chromosome aberrations have been produced after intraperitoneal injection of zinc chloride into mice (Vilkina et al., 1978) or when rats were given zinc sulphate by gavage once or daily for 5 consecutive days (Litton Bionetics, 1974). In contrast, increased aberrations have been reported in rats after inhalation exposure to zinc oxide (Voroshilin et al., 1978), in rats after oral exposure to zinc chloride and in mice after multiple intraperitoneal injections of zinc chloride (Gupta et al., 1991). Moreover, increased chromosomal aberrations were found in calcium-deficient mice when fed zinc (in form of zinc chloride) via the diet (Deknudt, 1982).These equivocal finding likely a reflection of inter-study differences in routes, levels, and duration of zinc exposure, the nature of lesions scored (gaps compared to more accepted structural alterations) and great variability in the technical rigour of individual studies (WHO, 2001). The German MAK committee reviewed the existingin vivoevidence and concluded that particularly those studies indicating clastogenic effects involved a lot of methodological uncertainties which do not allow overruling those in vivo studies which did not provide any evidence for chromosomal aberrations in vivo. Moreover, the Dutch rapporteur of EU risk assessment of zinc compounds under the EU existing substance legislation considered the positive in vitro findings for chromosomal aberration and SCE assays to be overruled by the overall weight of evidence of negative in vivo tests for this endpoint (EU RAR, 2004).
The only identified publicly available genotoxicity study in humans related to the identification of chromosomal aberrations in lymphocytes of 24 workers in a zinc smelting plant (Bauchinger et al.,1976). This study was, however, not suitable to draw any conclusions to the association of these effects with zinc exposure, as the workers displayed also increased blood levels of lead and cadmium, and the clastogenic effects were predominantly attributed to cadmium exposure. There were no further reports in the accessible literature on genotoxic effects of zinc compounds in human populations.
The overall weight of the evidence from the existing in vitro and in vivo genotoxicity assays suggests that zinc compounds do not have biologically relevant genotoxic activity. This conclusion is in line with those achieved by other regulatory reviews of the genotoxicity of zinc compounds (WHO, 2001; SCF, 2003; EU RAR, 2004, MAK, 2009). Hence, no classification and labelling for mutagenicity is required.
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