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Description of key information

A 3-generation chronic toxicity study (Til et al. 1972a) with treatment of rats (20 per sex and group) with dose levels of 0, 0.125, 0.25, 0.5, 1.0 or 2.0% Na2S2O5 administered in a 50 ppm thiamine-containing diet was identified as most reliable study for repeated dose toxicity and was defined as key study (read-across info, see `discussion`). Based on the read across concept for the group of sulfite substances, this result is also applicable to dipotassium disulfite..

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
126 mg/kg bw/day
Study duration:
chronic
Species:
rat

Mode of Action Analysis / Human Relevance Framework

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

Oral toxicity:

Male and female rats received 0, 0.125, 0.25, 0.5, 1.0 or 2.0% Na2S2O5in a thiamine-containing diet (50 ppm) for 104 weeks. Based on the occurrence of occult blood in faeces and changes in gastric morphology at dose levels of 0.5% or more, the NOAEL for local chronic toxicity in this study is represented by the dose of 0.25% metabisulfite (or 0.215% accounting for the loss of metabisulfite). The corrected dose level corresponded to a dose of 108 mg/kg bw/d Na2S2O5or an equivalent dose of 126 mg/kg bw/day potassium metabisulfite. Because there was no evidence of systemic toxicity following chronic treatment, the NOAEL for systemic effects can be expected above the highest dose of 2% sodium metabisulfite corresponding to 955 mg/kg bw/d of Na2S2O5or 1117 mg/kg bw/d potassium sulfite.

Repeated dose toxicity, dermal:

According to regulation (EC) 1907/2006 Annex XI (weight of evidence), testing for sub-chronic dermal toxicity is not considered to be required, for the following reason: repeated dose toxicity study via dermal route does not need to be performed since the physico-chemical and toxicological properties do not suggest potential for a significant rate of absorption through the skin (for more information, refer to the section on toxicokinetics).

Repeated dose toxicity, inhalation:

According to regulation (EC) 1907/2006 Annex XI (weight of evidence), testing for sub-chronic inhalation toxicity is not considered to be required, for the following reasons: iIn accordance with ECHA guidance on information requirements and chemical safety assessment-chapter R.8: characterisation of dose [concentration]-response for human health, May 2008, a DNEL for systemic effects can also be derived by route-to-route extrapolation from a 90-day oral toxicity study in rats. Thus, the calculated NOAEL of 1117 mg/kg bw/d potassium metabisulfite from the chronic oral toxicity study with sodium metabisulfite was used as the starting point for DNEL derivation.

Inconclusion, it is neither scientifically nor justified due to animal welfare reasons to initiate further inhalation toxicity studies.



Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: stomach

Justification for classification or non-classification

Repeated dose toxicity, oral

Local effects in the stomach were the most predominant finding of repeated dose toxicity: The NOAEL for local chronic effects in the study described by Til et al. (1972) is represented by the dose of 0.25% metabisulfite. The corrected dose level corresponded to a dose of 108 mg/kg bw/d Na2S2O5. All observed effects (occurrence of occult blood in faeces and changes in gastric morphology) were detected at higher dose levels at and above 0.5% in the diet (220 mg/kg bw/d Na2S2O5). There was no evidence of systemic toxicity following chronic treatment with sodium metabisulfite. Therefore, the NOAEL for systemic effects can be expected above the highest dose of 2% metabisulfite in the diet corresponding to 955 mg/kg bw/d of Na2S2O5.

 

Therefore, it can be concluded that based on the available animal data, Na2S2O5does not have the potential to produce significant toxicity, or to be harmful to humans, following repeated exposure at low or moderate exposure concentrations relevant for classification. This result can be read across to dipotassium disulfite without restriction.Thus, the requirements for STOT-RE classification criteria according to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – repeated exposure, oral are not met, and no classification as specific target organ toxicant is required.

 

Repeated dose toxicity, dermal

(i) Based on physico-chemical properties of dipotassium disulfite and the toxicokinetic behaviour (very limited penetration into the upper epithelial layers of the epidermis,) there are no systemic risks to humans with respect to dermal exposure to this substance.

(ii) One may assume a conservative default of 1% for dermal absorption of dipotassium disulfite, leading to the anticipation of a negligible toxicity via the dermal route.

 

Thus, it may be concluded that there will be no systemic risks to humans with respect to dermal exposure to dipotassium disulfite, and no classification for specific target organ toxicant (STOT) – repeated exposure, dermal according to regulation (EC) 1272/2008 is required for this substance or any suitable compound for read-across to this compound.

 

 

Repeated dose toxicity, inhalation

According to regulation (EC) 1272/2008, a classification for specific target organ toxicity – repeated exposure shall be taken into account only when reliable evidence associating repeated exposure to the substance with a consistent and identifiable toxic effect demonstrates support for the classification. However, there is no data or information available to evaluate a potential for specific organ toxicity following repeated inhalation exposure, and thus classification is not required.