Octanoic acid, zinc salt, basic

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

No genetic toxicity study with Octanoic acid, zinc salt, basic is available, thus the genetic toxicity will be addressed with existing data on the moieties liberated upon dissolution, zinc and octanoic acid.

Octanoic acid, zinc salt, basic is not expected to be genotoxic, since the moiety zinc has not shown gene mutation potential in bacteria and mammalian cells and clastogenicity was also not observed in vitro. In peer-reviewed publicly available assessment reports for the moiety octanoic acid, there were no genotoxic findings reported, as well.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Octanoic acid, zinc salt, basic

Octanoic acid, zinc salt, basic is not expected to be genotoxic, since the moiety zinc has not shown gene mutation potential in bacteria and mammalian cells and clastogenicity was also not observed in vitro. In peer-reviewed publicly available assessment reports for the moiety octanoic acid, there were no genotoxic findings reported, as well.

Thus, octanoic acid, zinc salt, basic is not to be classified according to regulation (EC) 1272/2008 as genetic toxicant.

Read-across approach and conclusion are also in line with the EU risk assessment carried out on the structural analogue substance Fatty acids, C16-18, zinc salts (i.e. zinc stearate) within the framework of EU Existing Chemicals Regulation 793/93 (EU RAR Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II–Human Health. EUR 21168 EN (http://echa.europa.eu/documents/10162/08799aec-42c5-44e0-9969-baa022c66db1):“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 the in vitro tests 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.

In vivo, 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 aberrations in vitro is considered overruled by negative in vivo tests 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 tested in vivo. However, there is no clear evidence from the available data that zinc is genotoxic in vivo and without a clear indication for carcinogenicity (see below) guidance for further testing with respect to target tissue is not available.”

The overall weight of the evidence from the existing in vitro and in vivo genotoxicity assays on soluble zinc substances 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; EU RAR, 2004, MAK, 2009).

Further testing is not required.

Please refer to the respective assessment entity section for data on the moieties zinc and octanoic acid. In brief:

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).

Octanoic acid

Octanoic acid is a naturally occurring saturated C8- fatty acid, which is present in milk of various mammals and also in coconut oil and palm kernel oil. Based on this, the following endpoint is covered by publicly available data on fatty acids with the same or similar structure.

“In a study conducted similar to OECD TG 471, Salmonella (S.) typhimurium TA 98, TA 100, TA 1535, and TA 1537 were exposed to octanoic acid at concentrations up to 1250 ug/plate in the presence and absence of metabolic activation (Aroclor 1254 induced rat liver S-9 mix). There was no information regarding positive, negative and solvent controls. The test substance was not mutagenic” (OECD SIDS, 2014).

 

“In the study by Zeiger et al. (1988), octanoic acid (purity 99%) was assessed for its mutagenicity in the reverse mutation assay using S. Typhimurium strains TA1535, TA1537, TA97, TA98 and TA100 up to a maximum concentration of 3,333 µg/plate in dimethylsulfoxide (DMSO), both in the absence and presence of rat and Chinese hamster S9 metabolic activation at 10% and 30%, and no mutagenicity was observed” (EFSA ANS Panel, 2017).

 

“In the study by Heck et al. (1989), octanoic acid (unknown purity) was tested for induction of gene mutation in the bacterial reverse mutation assay S. Typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 with and without S9 metabolic activation at single concentration of 5,000 µg/plate and for the induction of unscheduled DNA synthesis (UDS) in hepatocytes freshly obtained from male Fisher rats at final concentration of 300 µg/ml. Negative results were obtained in both assays” (EFSA ANS Panel, 2017).

 

Overall, it was considered by the EFSA Panel that the available data did not raise a concern for genotoxicity of fatty acids and their salts.

 

Justification for classification or non-classification

Octanoic acid, zinc salt, basic is not expected to be genotoxic, since the moiety zinc has not shown gene mutation potential in bacteria and mammalian cells and clastogenicity was also not observed in vitro. In peer-reviewed publicly available assessment reports for the moiety octanoic acid, there were no genotoxic findings reported, as well.

Thus, Octanoic acid, zinc salt, basic is not to be classified according to regulation (EC) 1272/2008 as genetic toxicant.