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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 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 is concluded that ammonium thiosulfate did not induce mutation at the HPRT locus of L5178Y mouse lymphoma cells when tested under the conditions employed in this study up to 1482µg/mL. Additionally ammonium thiosulfate 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). Based on the findings of this study, Ammonium thiosulfate was concluded to be negative for the induction of structural and numerical chromosome aberrations in CHO cells. Furthermore, ammonium thiosulfate, was tested in the Bacterial Reverse Mutation Assay using S. Typhimurium tester strains TA 98, TA 100, TA 1535 and TA 1537 and Escherichia coli strain WP2 uvrA in the presence and absence of metabolic activation system according to OECD 471. Neither precipitate nor appreciable toxicity was observed. Based on the findings of the toxicity-mutation assay, the maximum dose plated in the mutagenicity assay was 5000 µg/plate. In the confirmatory mutagenicity assay, no positive response was observed.

This result can be read across to potassium thiosulfate without restriction.


Short description of key information:
Read across from ammonium thiosulfate (CAS 7783-18-8) was performed to determine whether potassium thiosulfate has genetic toxicity properties. Ammonium thiosulfate has been tested in bacterial reverse mutation assays, in vitro gene mutation and clastogenicity tests . All tests show a negative response, thus ammonium thiosulfate does not require classification for mutagenic properties. This result can be read across to potassium thiosulfate without restriction.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Genetic toxicity, in vitro

None of the in vitro genotoxicity studies rated as reliable showed any effect in bacterial reverse mutation assays, in mammalian cell gene mutation tests (HPRT assay) or in mammalian cell chromosome aberration tests. The classification criteria according to Regulation (EC) 1272/2008 as germ cell mutagen are also not met.

This result can be read across to potassium thiosulfate without restriction.