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READ ACROSS CONCEPT

Valid genotoxicity studies for barium sulfide are not available. Therefore, because of the lack of appropriate experimental data, read-across from studies with H2S and BaCl2is proposed based on the following reasoning:

 

Read-across to H2S:

The readily water-soluble compound barium sulfide will initially dissociate upon dissolution in water and/or relevant physiological media into barium and sulfide ions.

 

However, sulfide anions will react with water in a pH-dependant reverse dissociation to form hydrogensulfide anions (HS-) or H2S, respectively, according to the following equation:

 

H2S  ↔  H+  +  HS-  ↔  2H+  +  S2-

 

The dissociation behaviour is presented in the Hägg graph reported under IUCLID section 5.1.2 Hydrolysis.

 

The pKa values for the first and second dissociation steps of H2S are 7.0 and 12.9 (for details, refer to the IUCLID section on dissociation constant), respectively. Therefore, at neutral physiological pH values, hydrogen sulfide in the non-dissociated form (H2S) and the hydrogen sulfide anion (HS-) will be present in almost equimolar proportion, whereas only very small amounts of the sulfide anion (S2-) will be present. Conversely, at gastric pH (pH 1-2), non-dissociated H2S will be the predominant species.

 

In conclusion, under physiological conditions, inorganic sulfides or hydrogensulfides as well as H2S will dissociate to the respective species relevant to the pH of the physiological medium, irrespective of the nature of the “sulfide”, which is why read-across between these substances and H2S is considered to be appropriate without any restrictions for the purpose of hazard and risk assessment of barium sulfide.

 

Read-across to Ba(OH)2 and BaCl2, respectively:

 

Upon dissolution in water and/or physiological media, dissociation of barium sulfide to release Ba2+ions may initially be expected.

 

However, based on the established fact that barium ions may form poorly soluble species for example with physiologically present carbonate ions, the bioaccessibility/bioavailability may vary between different physiological conditions. Notwithstanding this limitation, it is considered justified to read-across from available data either on barium hydroxide (similar water solubility) and/or barium chloride (higher water solubility), the latter representing a conservative approach). In this context, the water solubility of a substance is used as a first approximation of bioavailability:

 

- barium chloride is highly water soluble with ca. 375 g/L at 20 °C/pH ca. 6.5 (510.4 g/L at pH 1.5)

- barium hydroxide is also highly water soluble (37.4 g/L at 20 °C/pH > 13).

 

In comparison, the water solubility of barium sulfide is 73.5 g/L at 20 °C (pH 13.7; saturated solution).

 

In conclusion, read across from barium chloride and barium hydroxide to barium sulfide is considered as justified since the toxicity of these substances may reasonably be considered to be determined by the availability of barium cations. It is noted that although BaS is a strong base, substantial neutralisation in the gastrointestinal tract at pH-levels of approx. 1.5 – 2 may nevertheless be anticipated.

Barium

in vitro clastogenicity

(Anonymous (1994))

Based on the outcome of guideline-compliant studies barium dichloride does not induce chromosome aberrations in mammalian cells, when tested up to toxic and/or precipitating concentrations in two independent experiments in the absence and presence of a rat liver metabolic activation system (S9 mix).

Overall it can be concluded that barium dichloride does not induce chromosome aberrations in vitro in somatic mammalian cells. Therefore the conduct of in vivo clastogenicity experiments is not required.

in vitro gene mutation

(Anonymous (1994))

The authors state that barium dichloride induces gene mutations in cultured mouse lymphoma cells (L5178Y) in the presence of S9 in a statistical significant manner. However, the mutation frequency increased from 32 per 106cells in the control culture to a maximum of 59 per 106cells at 1000µg/mL (with a RTG of 10%). Being a statistical significant increase in mutation frequency, the biological significance however is considered questionable, since the highest MF is still well below the value recommended by the IWGT (Moore et al., 2003; Moore et al., 2006; Moore et al., 2007) of 154 per 106cells. Furthermore a comparison with historical data for the performing laboratory is not possible, since the data was not given in the study report.

 

Due to the questionable biological relevance, the statistical significant increase in mutation frequency in both barium dichloride cultures with metabolic activation is not considered as clear positive response. Therefore it was decided to repeat the whole experiment under clearly defined conditions, which a highly pure test item under guideline and GLP compliant conditions.

 

Lloyd (2010)

It is concluded that barium dichloride did not induce gene mutations in the TK locus of L5178Y mouse lymphoma cells when tested up to toxic and/or precipitating concentrations in two independent experiments in the absence and presence of a rat liver metabolic activation system (S9 mix).

 

Overall it can be concluded that barium dichloride does not induce gene mutations in vitro in bacteria and somatic mammalian cells. Therefore the conduct of in vivo gene mutation experiments is not required.

 

Sulfides

in vivo clastogenicity

Gocke (1981)

Based on the outcome of a guideline-compliant study, sodium sulfide does not induce chromosome aberrations in mammalian erythrocytes, when tested in NMRI male and female mice up a concentration of 96.1 mg/kg.

in vitro gene mutation

Engelhardt (1989)

In a reliable in-vitro Ames test (reverse gene mutation assay) it is concluded that sodium sulfide is not mutagenic under the experimental conditions.The test concentrations were chosen up to 5000 µg/plate.

 

Stone (2010)

Sodium sulfide, anhydrous was assayed for mutation at the hypoxanthine-guanine phosphoribosyl transferase (hprt) locus (6 -thioguanine [6TG] resistance) in mouse lymphoma cells.

When tested up to toxic concentrations in the absence and presence of S9 mix in Experiments I and II, there were no significant increases in mutant frequency at any concentration analysed. A weak but statistically significant linear trend was observed in the presence of S9 mix in Experiment II but, in the absence of any marked increases in mutant frequency at any test article concentration analysed in this experiment, this observation was not considered biologically relevant.

 

The REACH requirements according to the endpoints in section 8.4, Annex VII-X in Regulation (EC) 1907/2006 are fulfilled. No further testing is required.


Justification for selection of genetic toxicity endpoint
Data of the genetic toxicity are available for barium compounds and inorganic sulfides (BaCl2 and Na2S)

Short description of key information:
In-vitro studies:
Barium chloride has been tested in bacterial reverse mutation assays, in vitro gene mutation and clastogenicity tests. The tests show a negative response, thus barium chloride is not to be classified as mutagenic.
Sodium sulfide has been tested in bacterial reverse mutation assays and in vitro gene mutation tests. The tests show a negative response.
In-vivo studies:
Chromosome aberration of sodium sulfide has been tested in-vivo in a micronucleus assay performed in mice similar to OECD guideline 474 (Gocke_1981). This study was rated as reliable with restrictions (RL=2) and is used as a key study. The study had a negative result.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

All reliable studies available showed no genetic toxicity for barium and sulfide. Thus, according to Directive EEC 67/548 and to EC Regulation No. 1272/2008, barium sulfide should not be considered to have a mutagenic potential, and hence no classification or labelling is required.