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FATTY ACIDS, C14 -18 AND C16 -18 -UNSATD., ZINC SALTS:

No data are available on genetic toxicity of Fatty acids, C14 -18 and C16 -18 -unsatd., zinc salts. However, few data on genetic toxicity of Fatty acids, C16-18, zinc salts (a bacterial (gene mutation inS. typhimurium) and an eukaryotic assay (gene mutation inS. cerevisiae), both tests negative) have been cited in EU RAR Zinc stearate (see below). Data on other zinc compounds have been used, as it is assumed that after intake Fatty acids, C14 -18 and C16 -18 unsatd., zinc salts are changed (at least in part) to ionic zinc and that only ionic zinc is determining biological activities. A full read-across of data based on the solubility and a molecular weight correction is considered for Fatty acids, C14 -18 and C16 -18 -unsatd., zinc salts, see the hazard assessment of soluble zinc within the framework of Regulation (EC) No 1907/2006 below.

The read-across approach and the conclusions are in accordance to the conclusion on mutagenicity as derived in the EU RAR for the structural analogue Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN:

“Some data were provided on the genotoxicity of zinc distearate. Data on other zinc compounds have also been used, based on the assumption that after intake the biological activities of the zinc compounds are determined by the zinc cation.

The available data indicate that the genotoxicity results vary widely. Conflicting results have been found, even in the same test systems. Overall, the results of thein vitrotests indicate that zinc has genotoxic potential in vitro based on positive results in mammalian test systems for gene mutations and chromosomal aberrations and on the positive in vitro UDS test.

Invivo,increases in chromosomal aberrations were found in calcium-deficient mice exposed via the diet as well as in mice with normal calcium status when dosed intraperitoneally. In mice also negative results were obtained and even at higher intraperitoneal dose levels. Rats tested negative for chromosomal aberrations after oral dosing, either via gavage or via the diet. The positive result for chromosomal aberrationsin vitrois considered overruled by negativein vivotests for this endpoint.

The positive sperm head abnormality test is considered sufficiently counter-balanced by two negative SLRL tests as well as two negative dominant lethal tests. Moreover, this sperm test is not adequately reported and without details on scoring criteria, interpretation of the observations is rather subjective. In addition, sperm head abnormalities are indicative rather than proof for genotoxicity.

Based on the available data there is insufficient ground to classify zinc as genotoxic. It should be noted that the potential to induce gene mutations was not adequately testedin vivo. However, there is no clear evidence from the available data that zinc is genotoxicin vivoand without a clear indication for carcinogenicity (see below) guidance for further testing with respect to target tissue is not available.”

ZINC:

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 (Thompsonet al.,1989, WHO, 2001; EU RAR, 2008; 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 positive in 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 in in vitro systems (EU RAR, 2008; 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.

As discussed in section 5.7.1.2, equivocal and sometimes contradictory results were obtained in the in vivo chromosomal aberration assays. 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 existing in vivo evidence 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, 2008).


Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

There is no evidence for a clastogenic or mutagenic potential ofFatty acids, C14-18 and C16-18-unsatd., zinc salts. 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, 2008, MAK, 2009). Hence, no classification and labelling for mutagenicity is required.