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Introduction to read-across matrix

A comprehensive data gap analysis was conducted for the entire substance portfolio of the Metal carboxylates REACH Consortium (MCRC), covering 11 metal carboxylates in total. This literature screening effort included:

 

  • all available proprietary studies from the Metal carboxylates REACH Consortium (MCRC)
  • 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.

 

Zinc dibenzoate is the zinc metal salt of benzoic acid, which readily dissociates to the corresponding divalent zinc cation and benzoic acid anions. The zinc cation and the benzoic acid anion are considered to represent the overall toxicity of the zinc dibenzoate in a manner proportionate to the free acid and the metal (represented by one of its readily soluble salts). Based on the above information, unrestricted read-across is considered feasible and justified.

 

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 withzinc dibenzoateis 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 the zinc dibenzoate and the individual constituents.

 

(slightly soluble) zinc substances

benzoic acid
(CAS# 65-85-0)

Zinc dibenzoate
(CAS# 553-72-0)

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

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.

Benzoic acid

All available tests for gene mutations in bacteria did not show any effects of the test substance with or without metabolic activation. A poorly reported test in yeast (no metabolic activation) was positive, but the validity of this result could not be checked (Piper, 1999). No effects were reported after exposure of prophage containing E.coli strains (Rossmann, 1991) or in an SOS/umu test in S. typhimurium (Nakumara 1987). For cytogenetic effects, a chromosome aberration test was ambiguous without metabolic activation (Ishidate, 1983). Several other limited reported tests on sister chromatid exchange (without metabolic activation) were negative. The test substance was positive in a Comet assay (Esref, 2009), but it was clearly negative in an in vitro micronucleus test (with and without metabolic activation) (Nesslany, 1999).

 

Additional studies were identified, but were not available for review. The available results confirm that the test substance does not induce gene mutations and is not likely to induce effects on the chromosomal level.

 

A battery of in vivo tests were conducted with the structurally related sodium benzoate and these all clearly indicated no cytogenetic effects. These studies are considered to fully address and over-ride the ambiguous results found in the in-vitro data set. The toxicokinetic evaluation on sodium benzoate concluded that the substance will not be taken up as the salt, but rather as the test substance entity (NOTOX 2010). Therefore it can be concluded that the results for the test substance will not differ from those found in in vivo tests with sodium benzoate.

 

Based on the clear negative in-vivo results, it is concluded that the test substance does not induce genetic toxicity.

 

A range of in-vitro tests were negative with one ambiguous result. These tests are confirmed as negative by no effects in a battery of in vivo studies with the structural analogue sodium benzoate.

 

Zinc dibenzoate

Zinc dibenzoate is not expected to be genotoxic, since the two constituents zinc and benzoic acid (also by read-across of sodium benzoate) have not shown gene mutation potential in bacteria and mammalian cells as well as in vitro clastogenicity. Thus, zinc dibenzoate 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 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:
Zinc dibenzoate is not expected to be genotoxic.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Zinc dibenzoate is not expected to be genotoxic, since the two constituents zinc andbenzoic acid (also by read-across of sodium benzoate) have not shown gene mutation potential in bacteria and mammalian cells as well as in vitro clastogenicity. Thus, zinc dibenzoate is not to be classified according to regulation (EC) 1272/2008 as genetic toxicant. Further testing is not required.

Furthermore, zinc dibenzoate is not to be classified according to Directive 67/548 EC as genetic toxicant.