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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

Sodium metabisulfite and potassium metabisulfite were tested unequivocally negative at doses up to 5000 µg/plate in three independent bacterial reverse mutation assays using S. Typhimurium tester strains TA 98, TA 100, TA 1535, TA 1537 both in the presence and absence of a metabolic activation system (S9) according to OECD 471. Neither precipitation nor any appreciable toxicity were observed. No indication of any mutagenicity or toxicity whatsoever was observed in any of the assays performed.

Further, sodium metabisulfite 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 sodium metabisulfite did not induce mutations at the HPRT locus of L5178Y mouse lymphoma cells when tested under the conditions employed in this study up to 1902µg/mL.

An in vitro assay for clastogenic effects is not available, but is considered superseded by the in vivo study summarised below.

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

In vivo genetic toxicity tests

Following single intraperitoneal injections of 250 mg/kg, 500 mg/kg and 1000 mg sodium sulfite /kg bw respectively, sodium sulfite did not elicit any chromosome damaging (clastogenic) effects, nor was there any indication of an aneugenic activity in bone marrow cellsin vivo.

This result can be read across between all sulfite substances without restriction.


Short description of key information:
Both substance-specific data as well as read across were used to characterise the genotoxicity of sulfite substances. Sodium metabisulfite and potassium metabisulfite were tested negative in bacterial reverse mutation assays, in vitro gene mutation and sodium sulfite was tested negative in vivo clastogenicity tests. Overall, the available data demonstrates a lack of genotoxicity for sulfite substances.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Genetic toxicity, in vivo

The reference Schulz (2008) is considered as the key study for in vivo genetic toxicity and will be used for classification. The overall results are as follows: under the experimental conditions chosen here, the test substance sodium sulfite did not exert any chromosome-damaging (clastogenic) effect, and there were no indications of any impairment of chromosome distribution in the course of mitosis (aneugenic activity) in bone marrow cells in vivo.

Genetic toxicity, in vitro

None of the in vitro studies for sodium metabisulfite or potassium metabisulfite, rated as reliable, showed any indications of genotoxicity whatsoever, rendering the group of sulfites 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 sulfite substances without restriction.