2-ethylhexanoic acid, molybdenum salt

Endpoint summary

Additional information

Read-across approach

Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the metal cation and the organic acid anion. This way forward is acceptable, since metal carboxylates are shown to dissociate to the organic anion and the metal cation upon dissolution in aqueous media. No indications of complexation or masking of the metal ion through the organic acid were apparent during the water solubility and dissociation tests (please refer to the water solubility and dissociation in sections 4.8 and 4.21 of IUCLID). Once the individual transformation products of the metal carboxylate become bioavailable (i.e. in the acidic environment in the gastric passage or after phagocytosis by pulmonary macrophages), the “overall” toxicity of the dissociated metal carboxylate can be described by a combination of the toxicity of these transformation products, i.e. the metal cation and carboxylate anion according to an additivity approach.

 

2-ethylhexanoic, molybdenum salt is the molybdenum metal salt of 2-ethylhexanoic acid, which readily dissociates to the corresponding molybdenum and 2-ethylhexanoate ions. These ions are considered to represent the overall toxicity of 2-ethylhexanoic, molybdenum salt in a manner proportionate to the free acid and the metal (represented by one of its readily soluble salts). 

 

A detailed justification for the read-across approach is added as a separate document in section 13 of IUCLID.

 

Genetic toxicity

No genetic toxicity study with 2-ethylhexanoic acid, molybdenum salt is available, thus the genetic toxicity will be addressed with existing data on the dissociation products as detailed in the table below.

 

Table: Summary of genetic toxicity data of 2-ethylhexanoic acid, molybdenum salt and the individual constituents.

	Disodium molybdate (CAS# 7631-95-0)	2-ethylhexanoic acid (CAS# 149-57-5)	2-ethylhexanoic acid, molybdenum salt (CAS# 34041-09-3)
In vitro gene mutation in bacteria	Negative	Negative	Negative (read-across)
In vitro cytogenicity in mammalian cells or in vitro micronucleus test	Negative	Negative	Negative (read-across)
In vitro gene mutation study in mammalian cells	Negative	Negative	Negative (read-across)

 

Disodium molybdate

The following recently conducted guideline-conform, highly reliable state-of-the-art genotoxicity tests with a soluble molybdenum substance (sodium molybdate) are available:

- an AMES bacterial reverse mutation assay (Beevers, 2009),

- an in vitro micronucleus assay in human lymphocytes (Taylor, 2009), and

- an in vitro gene mutation assay (tk) in mouse lymphoma cells (Lloyd, 2009).

All three tests produced unequivocally negative results, and thus provide strong evidence for an absence of concern for genotoxic effects of molybdenum substances. Since the substance tested represents a highly soluble molybdate, and all molybdenum substances regardless of their solubility, speciation and valence have been shown to transform rapidly to molybdate anions upon dissolution in aqueous media, these results can be read across to all other molybdenum substances without restriction. Because of their ubiquitous physiological presence in biota and/or their essential role in human physiology, the sodium/ammonium/calcium/iron moieties in some of the molybdenum substances are not considered to be of concern for genotoxicity.

In conclusion, no classification of any molybdenum substance for genotoxicity is required.

 

Apart from these high quality, reliable GLP test results, a large number of published studies exist of varying quality and extent of documentation, which is why these were subjected to a detailed quality and reliability screening, the outcome of which can be summarised as follows:

(i) unequivocally negative results were obtained in guideline-conform, valid bacterial reverse mutation assays for high purity (moderately soluble) molybdenum trioxide (studies by Jones, 2004 and Zeiger et al., 1992). Negative results were also obtained in the same test system with (highly soluble) sodium and ammonium molybdates, which however from a perspective of formal regulatory compliance are considered incomplete because of the selected tester strains (studies by Armitage, 1997 and Kubo et al. 2002).

 

(ii) all in vitro clastogenicity test considered as assignable and reliable with or without restrictions are negative.

(iii) in view of the unequivocally negative results in all three in-vitro key studies, the conduct of any further in vivo testing would not be required. Already available in vivo studies were subjected to a thorough evaluation and were found to be seriously flawed and of poor quality, and were thus assigned reliability grades of either 3 or 4. In this context it is explicitly noted that set of studies published by Titenko-Holland (1998) have already previously been criticised and disregarded by the Classification and Labelling Committee of the ECB as deficient during discussions on molybdenum trioxide in 2004.

 

2-ethylhexanoic acid

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 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).

 

2-ethylhexanoic acid, molybdenum salt

2-ethylhexanoic acid, molybdenum salt is not expected to be genotoxic, since the two constituents molybdate and2-ethylhexanoicacid have not shown gene mutation potential in a range of in vitro test systems. Thus, 2-ethylhexanoic acid, molybdenum salt is not classified according to regulation (EC) 1272/2008 as genetic toxicant. Further testing is not required. For further information on the toxicity of the individual constituents, please refer to the relevant sections in the IUCLID and CSR.

Justification for selection of genetic toxicity endpoint
Read-across information.

Short description of key information:
2-ethylhexanoic acid, molybdenum salt is not expected to be genotoxic.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

2-ethylhexanoic acid, molybdenum salt is not expected to be genotoxic, since the two constituents molybdate and 2-ethylhexanoic acid have not shown gene mutation potential in a range of in vitro test systems. Thus, 2-ethylhexanoic acid, molybdenum salt is not classified according to regulation (EC) 1272/2008 as genetic toxicant.