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Key value for chemical safety assessment

Effects on fertility

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 substances 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-+ H2S2O3 HS3O3- + SO2+ H2O

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

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

One key study (Til 1972) and one supportive study (Lockett 1960) were identified to evaluate the effects sodium metabisulphite on fertility and reproduction. In both studies, male and female rats received different dietary dose levels of up to 2% Na2S2O5for periods of about 2 years over three successive generations. The results of these studies did not show evidence of a treatment-related effect on fertility and reproduction. Thus, the NOAEL for fertility can be expected above the highest dose of 2% sodium metabisulphite, corresponding to 955 mg/kg bw/d of Na2S2O5.

However, there was a slight growth retardation during lactation in offspring of the highest dose level of 2%, corresponding to a dose of 955 mg/kg bw/d Na2S2O5.


Short description of key information:
One key study (Til 1972) and one supportive study (Lockett 1960) were identified to evaluate the effects sodium metabisulphite on fertility and reproduction.

Effects on developmental toxicity

Description of key information
The folowing developmental toxicity studies were identified as key studies:
- sodium metabisulphite in rabbits (NTIS_1974)
- potassium metabisulphite in rats (Anonymous_1975)
- potassium metabisulphite in rats (Ema_1985) - diet study
- potassium metabisulphite in mice ((Anonymous_1975)
- sodium sulphite heptahydrate in rats (Itami_1989) - diet study
- sodium bisulphite in mice, rats and hamsters (NTIS_1972)
- sodium bisulphite in rabbits (NTIS_ 1974)
- sodium thiosulphate in mice, rats and hamsters (Anonymous_1972)
- sodium thiosulphate in rabbits (Anonymous_1974)
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 substances 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-+ H2S2O3 HS3O3- + SO2+ H2O

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

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

In none of the studies conducted in preganat rats, mice, hamsters and rabbits with oral administration of sodium bisulfite, sodium metabisulfite, potassium metabisulfite or sodium thiosulfate by gavage during the phase of organogenesis clear evidence of discernible effect on nidation or on maternal or foetal survival were observed. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls. Thus, the NOAELs for maternal and developmental toxicity can be expected above the highest dose levels investigated:

- sodium metabisulfite in rabbits: > 123 mg/kg bw/d

- potassium metabisulfite in rats: > 155 mg/kg bw/d

- potassium metabisulfite in mice: > 125 mg/kg bw/d

- sodium bisulfite in mice: > 150 mg/kg bw/d

- sodium bisulfite in rats: > 110 mg/kg bw/d

- sodium bisulfite in hamsters: > 120 mg/kg bw/d

- sodium bisulfite in rabbits: > 100 mg/kg bw/d

- sodium thiosulfate in mice: > 550 mg/kg bw/d

- sodium thiosulfate in rats: > 400 mg/kg bw/d

- sodium thiosulfate in hamsters: > 400 mg/kg bw/d

- sodium thiosulfate in rabbits: > 580 mg/kg bw d

In two other studies with potassium metabisulfite and sodium sulfite heptahydrate in rats given at high dietary dose levels during the phase of organogenisis, maternal toxicity evidenced by reduction in maternal body weight gain during pregnancy and food intake was observed in the highest dose groups, resulting in NOAELs of 1320 mg/kg bw/d for potassium metabisulfite or 850 mg/kg bw/d for sodium sulfite heptahydrate.

The postnatal survival rate of the offspring of the 10% potassium metabisulfite group was slightly decreased, most probably related to maternal malnutrition. Thus, the NOAEL for fetotoxicity was established at a dose level of 1320 mg K2S2O5/kg bw/d. There was no clear evidence for fetal toxicity in the study conducted with sodium sulfite heptahydrate, but slight fetal growth retardation was observed in all dose groups (at and above approx. 100 mg/kg bw/d Na2SO3x 7 H2O). However, there was no clear dose-relationship and this effect was not observed in the live-birth part of the study and was therefore not considered as of toxicological relevance.

External, skeletal and internal examinations of the fetuses revealed no evidence of teratogenesis in any of the groups.

Justification for classification or non-classification

All available animal data did not show evidence of effects on fertility, toxicity to reproduction, developmental toxicity or teratogenicity of sodium metabisulfite or any suitable substance for read-across to this substance. Thus, based on the lack of any effects on reproductive performance and organs, the reproductive tract is not considered to represent a target organ of toxicity.

Therefore the requirements according to regulation (EC) 1272/2008 for classification for the hazard class Reproductive Toxicity are not fulfilled andclassification is not proposed for sodium metabisulfite and read-across substances.