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Key value for chemical safety assessment

Additional information

Read-across concept for sulfites, hydrogensulfites, metabisulfites, dithionites and thiosulfates:

A comprehensive read-across concept has been developed for sulfites, hydrogensulfites and metabisulfites, based on the pH-dependant equilibrium in aqueous solutions which is summarised in the following equations:[1],[2]

           SO2+ H2O <->`H2SO3´         H2SO3<->H++ HSO3-<->2H++SO32-    2HSO3-<->H2O +S2O52-

Since the nature of the cation (i.e., sodium, potassium, ammonium…) is not assumed to contribute substantially to differences in toxicity and solubility (all compounds are very soluble in water), only the chemical and biological properties of the anion are considered as relevant determinants. Based on the described equilibrium correlations, unrestricted read-across between the groups of sulfites, hydrogensulfites and metabisulfites is considered justified.

 

Additionally, it is known that sodium dithionite disproportionates in water to form sodium hydrogen sulfite and sodium thiosulfate (equation II)2,[1], so that this substance can also be considered to be covered by the read-across concept described above. Since it can easily be anticipated that the substance is not stable enough under physiological conditions to fulfil the requirements of study guidelines, instead the products of decomposition have to be considered:

 

       2 S2O42-+ H2O→2HSO3-+ S2O32-

 

Not fully covered by this read-across concept is the substance class of thiosulfates: although the thiosulfates are also well known to disproportionate in aqueous solution to form polythionic acids and SO2(HSO3-), this requires somewhat different, more acidic conditions. Therefore, read-across to sulfites is primarily restricted to appropriate physiological conditions, i.e. oral administration where the gastric passage with the strongly acidic conditions in the stomach will facilitate the chemical disproportionation described above:

 

       HS2O3-+ H2S2O3HS3O3- + SO2+ H2O

 

[1]Hollemann Wiberg, Lehrbuch der Anorganischen Chemie, 101.Auflage

[2]Handbook of Chemistry and Physics, Ed. Lide, DR, 88thedition, CRC Press

In vitro genetic toxicity

Ammonium thiosulfate was tested unequivocally negative at doses up to 5000 µg/plate in a bacterial reverse mutation assay using S. Typhimurium tester strains TA 98, TA 100, TA 1535 and TA 1537 and Escherichia coli strain WP2 uvrA both in the presence and absence of a metabolic activation system (S9) according to OECD 471. Neither precipitation nor any appreciable toxicity were observed. Additionally, another Ames assay according to OECD 471 was conducted with sodium thiosulfate pentahydrate using the strains Salmonella typhimurium strains TA1535, TA1538, TA98, and TA 100 and in Escherichia coli WP2 uvrA. As with the test above, no mutagenicity or toxicity was observed in any of the assays performed.

Further, ammonium thiosulfate was assayed for the ability to induce mutation at the hypoxanthine-guanine phosphoribosyl transferase (hprt) locus (6-thioguanine [6TG] resistance) in mouse lymphoma cells according to OECD 476. The study consisted of a cytotoxicity range-finder experiment followed by two independent experiments, each conducted in the absence and presence of metabolic activation (S9). It was concluded that ammonium thiosulfate did not induce mutations at the HPRT locus of L5178Y mouse lymphoma cells when tested under the conditions employed in this study up to 1482µg/mL. Finally, ammonium thiosulfate also did not induce chromosome aberrations in Chinese hamster ovary cells (CHO) when tested under the conditions employed in this study (OECD 473) up to 1480µg/mL. These conditions included treatments in two independent experiments, in the absence and presence of a rat liver metabolic activation system (S-9).

These above results can be read across between all thiosulfate substances without restriction.


Short description of key information:
Both substance-specific data as well as read across were used to characterise the genotoxicity of thiosulfate substances. Ammonium thiosulfate was tested negative in bacterial reverse mutation assays, in vitro gene mutation and clastogenicity tests. In addition, sodium thiosulfate was also tested negative in a bacterial reverse mutation assay. Overall, the comprehensive set of available assays demonstrates a lack of genotoxicity for thiosulfate substances.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Genetic toxicity, in vitro

None of the in vitro studies for ammonium thiosulfate and sodium thiosulfate, rated as reliable, showed any indications of genotoxicity whatsoever, rendering the group of thiosulfates void of genotoxicity. The classification criteria according to Regulation (EC) 1272/2008 as germ cell mutagen are also not met.

The above described results are considered to apply by way of read-across to all thiosulfate substances without restriction.