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Introduction to read-across matrix

A comprehensive data gap analysis was conducted for the entire substance portfolio of the REACH Metal Carboxylates Consortium (RMC), covering 10 metal carboxylates in total back in 2013. This literature screening effort included:

 

  • all available proprietary studies from the REACH Metal Carboxylates Consortium (RMC)
  • detailed literature searches in online databases
  • screening of human health review articles
  • rigorous quality and reliability screening according to Klimisch criteria, where those criteria apply

 

During the literature search and data gap analysis it became obvious that the overall database on substance-specific human health hazard data for the metal carboxylates is too scant to cover all REACH endpoints. Therefore, the remaining data gaps had to be covered by either experimental testing or read-across from similar substances.

 

Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the organic acid counterion and the metal (or one of its readily soluble salts). This way forward is acceptable, since metal carboxylates 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 tests (please refer to the water solubility data in section of the IUCLID and chapter of the CSR). Once the individual constituents 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 the toxicity of the “individual” constituents. Since synergistic effects are not expected for this group of metal carboxylates, the human health hazard assessment consists of an individual assessment of the metal cation and the organic anion.

 

The hazard information of the individual constituents was obtained from existing REACH registration dossiers via a license-to-use obtained by the lead registrant. These registration dossiers were submitted to ECHA in 2010 as full registration dossiers, and are thus considered to contain relevant and reliable information for all human health endpoints. All lead-registrant dossiers were checked for completeness and accepted by ECHA, i.e. a registration number was assigned.

 

 

In order to check whether read-across from 2-ethylhexanoic acid, molybdenum salt to sodium molybdate is justified, a combined water solubility and UV spectral analysis was conducted.

 

The water solubility study with 2-ethylhexanoic acid, molybdenum salt was conducted in accordance with OECD 105 and under GLP. The test was conducted in triplicate vessels over 16 days and the solubility of the substance was determined by measuring dissolved Mo by ICP-OES after 1, 2, 3, 14,15 and 16 days. A constant concentration of dissolved Mo was achieved, at ca. 13 mg Mo/L. Throughout the experiment, the pH of the solutions was in the range 3.8 - 4. In order to assess the species of the dissolved molybdenum, UV spectra were taken during each day of sampling.

 

A read-across approach for inorganic molybdenum substances and molybdenum metal was developed by the Molybdenum Consortium, which reports as follows:“The species in solutions of sodium molybdate at concentrations 1–10 mg/L and pH ca 7 is the the molybdate ion, [MoO4]2−with a UV absorption maximum (peak) at 207–208 nm (48000 cm-1). As the pH is lowered the [MoO4]2−ion becomes protonated giving [HMoO4]and [H2MoO4] species, the peaks in the UV spectra shifting to lower energies (longer wavelengths). From our UV spectra we shall see that the predominant (>90%) species from our compounds in solution or in contact with water are the [MoO4]2−and [HMoO4]ions. The UV spectral analysis has enabled us to describe the speciation in water solutions of soluble molybdates (sodium and ammonium molybdates) and in supernatant solutions of suspensions of poorly soluble molybdenum substances (calcium molybdate, molybdenum metal, ferromolybdenum, molybdenum dioxide, molybdenum trioxide, roasted molybdenum concentrate and molybdenum disulfide). The solutions and supernatant liquids contain the molybdate ion and, in addition at lower pHs, protonated molybdate. At biological concentrations and pH the only molybdenum species produced from the molybdenum substances studied is the molybdate, [MoO4]2-, ion. Read across from sodium molybdate is therefore justified.”(International Molybdenum Association (2009) Speciation of molybdenum compounds in water - Ultraviolet spectra and REACH read across - Report for the International Molybdenum Association REACH Molybdenum Consortium, unpublished report).

 

The UV spectral analysis of the samples taken during water solubility testing of 2-ethylhexanoic acid, molybdenum salt show that [MoO4]2−and [HMoO4]ions are formed upon dissolution of 2-ethylhexanoic acid, molybdenum salt in aqueous media. The presence of the molybdate and the protonated molybdate anion represent the dominant species at the pH of 3.8-4 being observed in the water solubility test. Under physiological conditions the molybdate anion will be the relevant molybdenum species liberated form 2-ethylhexanoic acid, molybdenum salt.

 

2-ethylhexanoic acid, molybdenum salt is the molybdenum metal salt of 2-ethylhexanoic acid, which readily dissociates to the corresponding molybdate anion and 2-ethylhexanoic acid anions. The molybdate anion and the 2-ethylhexanoic acid anion are considered to represent the overall toxicity of the 2-ethylhexanoic acid, molybdenum salt in a manner proportionate to the free acid and the metal (represented by the readily soluble disodium molybdate, as detailed above).

 

Although the term „constituent“ within the REACH context is defined as substance (also being part of a mixture), the term constituent within this hazard assessment is meant to describe either part of the metal carboxylate salt, i.e. anion or cation.

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.

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