Zinc bis(2-ethylhexanoate)

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

No genetic toxicity study with zinc bis(2-ethylhexanoate) is available. In the assessment of toxicity of zinc bis(2-ethylhexanoate), read-across to the assessment entities zinc and 2-ethylhexanoic acid is applied since the ions of zinc bis(2-ethylhexanoate) determine its toxicity in biological compartments.

Zinc bis(2-ethylhexanoate) is not expected to be genotoxic, since its two moieties zinc and 2-ethylhexanoic acid have not shown gene mutation potential in bacteria and mammalian cells as well as in vitro clastogenicity.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Additional information

Genetic toxicity

Existing data on the genetic toxicity of the two moieties of zinc bis(2-ethylhexanoate) are detailed below.

 

Zinc

Several in vitro studies and two in vivo studies are available on the genotoxicity of zinc oxide. Data on other zinc compounds have also to be taken into account, 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 and chromosomal aberration test.

The investigated zinc compounds did not increase the mutation frequencies in bacterial systems. Zinc oxide was consistently negative in the Ames test. There was some evidence that zinc oxide 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 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, 2004; MAK, 2009).

In addition to above mentioned in vitro investigations, zinc compounds have also been studied in in vivo studies including the micronucleus test and chromosomal aberration test. The zinc compounds were negative in both assays.

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, 2004).

2-ethylhexanoic acid

In vitro data

2-ethylhexanoic acid was negative in the bacterial Ames test with S. typhimurium strains TA 98, TA 100, TA 1535 and TA 1537 and E. coli WP2 uvr A (Jung et al., 1982; Zeiger et al., 1988; Warren et al., 1982), as well as in a HPRT locus assay with mammalian CHO cells (Schulz et al., 2007). In cultured human lymphocytes, 2-ethylhexanoic acid induced a minimal increase in frequency of sister-chromatid exchanges (below 1.5 fold increase at concentrations of the test substance of 0.63 to 2.5 mM; Sipi et al., 1992), which is not considered significant.

In vivo data

In an in vivo micronucleus assay with mice, 2-ethylhexanoic acid was administered by gavage up to the maximum tolerated oral dose of 1600 mg/kg/day. No bone marrow toxicity was observed, nor did the test substance induce any bone marrow micronuclei (Holstrom et al., 1994).

Table: Summary of genetic toxicity data of the zinc bis(2-ethylhexanoate) and the assessment entities.

	(slightly soluble) zinc substances	2-ethylhexanoic acid (CAS# 149-57-5)	Zinc bis(2-ethylhexanoate) (CAS# 136-53-8)
In vitro gene mutation in bacteria	negative (weight of evidence)	negative	negative (read-across)
In vitro cytogenicity in mammalian cells or in vitro micronucleus test		negative	negative (read-across)
In vitro gene mutation study in mammalian cells		negative	negative (read-across)

 

Zinc bis(2-ethylhexanoate) is not expected to be genotoxic, since t its two moieties zinc and 2-ethylhexanoic acid have not shown gene mutation potential in bacteria and mammalian cells as well as in vitro clastogenicity in vitro. Thus, zinc bis(2-ethylhexanoate) is not to be classified according to regulation (EC) 1272/2008 as genetic toxicant. Further testing is not required. For further information on the toxicity of the assessment entities, please refer to the relevant assessment entity sections in the IUCLID and CSR.

Justification for classification or non-classification

Zinc bis(2-ethylhexanoate) is not expected to be genotoxic, since its two moieties zinc and 2-ethylhexanoic acid have not shown gene mutation potential in bacteria and mammalian cells as well as in vitro clastogenicity. Thus, zinc bis(2-ethylhexanoate) is not to be classified according to regulation (EC) 1272/2008 as genetic toxicant.