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Description of key information

Short description of key information on bioaccumulation potential result: 
Sulfites, hydrogensulfites and metabisulfites are present in dissociated form in aqueous solutions, depending on solution pH. Dithionites disproportionate in water to form hydrogen sulfites and thiosulfates. Thiosulfates also disproportionate in acidic aqueous solution to form polythionic acids and SO2 (HSO3-). For these reasons, extensive read-across between these substances is considered justified.
Inhalation absorption: based on particle size dependant deposition modelling (MPPDl), an inhalation absorption factor of 47.3% was derived for potassium metabisulfite.
Dermal absorption: in the absence of measured data on dermal absorption, dermal absorption factors of 1% (exposure to liquid media) and 0.1% (exposure to dry solids/dust) are assumed (HERAG).
Oral absorption: according to animal toxicokinetic data (70-95% absorption), an oral absorption factor of 100% was derived.
Metabolism: inorganic substances such as sulfites are not subject to metabolism as such; however, these substances are known to undergo oxidative transformation under physiological circumstances.
Distribution and elimination: upon systemic uptakey, sulfites are distributed widely between tissues because of their high solubility/bioavailability, and are cleared almost exclusively by oxidation to sulfate with subsequent renal excretion.
Short description of key information on absorption rate:
Measured data on the dermal absorption of the substances are not available. In the absence of such data, the assignment of default absorption factors of 1% (from exposure to liquid/wet media) and 0.1% (from exposure to dry dust/solids) respectively is considered appropriate, as outlined in the methodology proposed in HERAG guidance for metals and their inorganic substances (HERAG, 2007).

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

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

 

Absorption, distribution, metabolism and elimination

Inhalation absorption

Data on inhalation absorption of sulfite substances is scarce, and can be summarised as follows:

- a significant increase of the contents of sulfite in brain, heart, and lung tissues was caused by exposure to SO2(p < 0.05) compared with the control groups, and the sulfite content was increased in a dose-dependent manner (r > 92). Sulfite contents in lung tissues were the highest, the contents in the brain tissues were the lowest, and heart tissues were between them. The results indicated that SO2transforms into sulfitein vivoafter inhalation, and distributes into lungs and other organs such as brain and heart. Thus, it can offer a support for the viewpoint that SO2is a systemic toxic agent (Meng, 2005).

- minor pathological changes were seen in the tracheas and bronchi of rats exposed by inhalation to sulfur dioxide, while comparable tissues in sulfite oxidase -deficient rats were unchanged by exposure to high concentrations of endogenously generated sulfite. The histological damage was attributed to hydrogen ions stemming from inhaled SO2, not to the sulfite/bisulfite ions that are also a product of inhaled SO2. The distribution of sulfite from inhaled sulfur dioxide in sulfite oxidase-competent rats was restricted largely to the major airways of the lung. There was no evidence for exposure of lung parenchymal tissue to sulfite or for exposure of more distal tissues via the bloodstream. In contrast, endogenously generated sulfite resulted in significant systemic exposure in the highly sulfite oxidase-deficient groups. The histological data and results of gross pathological examinations indicate that all organs except the testicles were refractory to theses high concentrations of sulfite (Gunnison, 1987).

In view of the lack of reliable quantitative in-vivo data on inhalation absorption of sulfite substances, the following approach was adopted for the derivation of inhalation absorption factors, in line with the HERAG approach for metals and their inorganic substances:

After completion of a testing programme on dustiness testing and particle size analysis of the airborne fraction on commercially available sulfite substances, the collected information can be used to estimate inhalation absorption factors based on a prediction of deposition patterns in the respiratory tract (MPPD model).

The fate and uptake of deposited particles depends on the clearance mechanisms present in the different parts of the airway. In the head region, most material will be cleared rapidly, either by expulsion or by translocation to the gastrointestinal tract. A small fraction will be subjected to more prolonged retention, which can result in direct local absorption. More or less the same is true for the tracheobronchial region, where the largest part of the deposited material will be cleared to the pharynx (mainly by mucociliary clearance) followed by clearance to the gastrointestinal tract, and only a small fraction will be retained (ICRP, 1994). Once translocated to the gastrointestinal tract, the uptake will be in accordance with oral uptake kinetics.

In consequence, the material deposited in the head and tracheobronchial regions would be translocated to the gastrointestinal tract, where it would be subject to gastrointestinal uptake at a ratio of 100%. The material that is deposited in the pulmonary region may be assumed by default to be absorbed to 100%. This absorption value is chosen in the absence of relevant scientific data regarding alveolar absorption although knowing that this is a conservative choice. Thus, the following predicted inhalation absorption factors can be derived (for further information on particle size and dustiness, see IUCLID section 4.5):

Absorption factors (rounded values):

Test item

absorption factor via inhalation [%]

Potassium metabisulfite

 47.30

Dermal absorption

There is no publicly available or other scientific information concerning dermal absorption of sulfite substances.

In the absence of measured data on dermal absorption, previous guidance primarily directed at organic chemicals with a defined lipophilicity and corresponding percutaneous transfer potential, suggests the assignment of either 10% or 100% default dermal absorption rates. In contrast, the currently available scientific evidence on dermal absorption of inorganic ionic substances (predominantly based on the experience from previous EU risk assessments on metals and their inorganic substances) yields substantially lower figures, which can be summarised briefly as follows:

Measured dermal absorption values for metal cations and their inorganic substances in studies corresponding to the most recent OECD test guidelines are typically 1 % or even less. Therefore, the use of a 10 % default absorption factor is not scientifically supported for such ionic species. This is corroborated by conclusions from previous EU risk assessments (Ni, Cd, Zn, Sb, Pb, Cu), which have derived dermal absorption rates of 2 % or far less (but with considerable methodical deviations from existing OECD methods) fromliquidmedia.

However, considering that under industrial circumstances many applications involve handling of dry powders, substances and materials, and since dissolution is a key prerequisite for any percutaneous absorption, a factor 10 lower default absorption factor may be assigned to such “dry” scenarios where handling of the product does not entail use of aqueous or other liquid media. This approach was taken in the EU RA on zinc. A reasoning for this is described in detail elsewhere (Cherrie and Robertson, 1995), based on the argument that dermal uptake is dependent on the concentration of the material on the skin surface rather than it’s mass.

Consistent with the methodology proposed in HERAG guidance for metals and their inorganic substances (HERAG fact sheet - assessment of occupational dermal exposure and dermal absorption; EBRC Consulting GmbH / Hannover /Germany; August 2007), the following default dermal absorption factors for inorganic substances have therefore been proposed (reflective of full-shift exposure, i. e. 8 hours):

From exposure to liquid/wet media: 1.0 %

From dry (dust) exposure: 0.1 %

Given that the primary cause between the lack of percutaneous transfer is considered to be the ionic nature, it is proposed to assume similar behaviour for sulfite anions as for metal cations.

 

Oral absorption

Following oral administration of 10 or 50 mg SO2/kg (as NaHSO3mixed with Na235SO3), 70-95% of the35S was absorbed from the intestine and voided in the urine of mice, rats and monkeys within 24 hours. The majority of the remaining 35S was eliminated via faeces, the rate being species-dependent. Only 2% or less of35S remained in the carcass after one week. Free sulfite was not detected in rat urine even after a single oral dose of 400 mg SO2/kg. Neither could induction of liver sulfite oxidase be demonstrated either after single, or 30 daily doses of 200 mg SO2/kg/day (Gibson & Strong, 1973).

In conclusion, soluble sulfite substances may be considered to be readily absorbed from the digestive tract of mice and rats; these studies also showed that only small amounts of ingested SO2are eliminated via exhalation. Given the somewhat variable but high extent of oral absorption (70-95%), it appears most appropriate to conservatively assume 100% absorption of sulfite substances after ingestion.

 

Metabolism

For inorganic substances such as sulfites, metabolism in its true sense is not applicable. However, sulfites are known to undergo oxidative transformation under physiological circumstances, which has previously been reported as follows:

Sulfites are oxidised in the body to sulfate. In turn, the acute effects of sulfite in foods are conventionally related to the amount and concentration of free sulfur dioxide, and to the speed at which it is released from serum proteins to which it becomes bound upon systemic uptake. Sulfite may also react reversibly with disulfide linkages in proteins. The disulfide is split into one part containing a thiol group and another part with an S-sulfonic acid group (Swan, 1957).

Four rats given oral doses of sodium metabisulfite as a 0.2% solution eliminated 55% of the sulfur as sulfate in the urine within the first four hours (Bhagat & Locket, 1960). A rapid and quantitative elimination of sulfites as sulfate was also observed in man and dog (Rost, 1933). Sulfite is a strong inhibitor of some dehydrogenases, e.g. lactate dehydrogenase (heart) and malate dehydrogenase; 50% inhibition by about 10-5M sulfite (Pfleiderer et al., 1956).

 

Distribution and elimination

The available information on the distribution and elimination of sulfite substances can be summarised as follows:

- sulfites are cleared almost exclusively by oxidation to sulfate. The sulfate producedin vivofrom injected sulfite is not instantanelously accessible to plasma, since plasma sulfate appearance lags considerably behind sulifte disappearance after equilibrium of an injected sulfite dose (Gunnison, 1976).

- hydrogen sulfites (HSO3-) can be absorbed after ingestion. They are efficiently metabolised with the major part being rapidly excreted as sulfate via urine. A rapid and quantitative elimination of disodium disulfite as sulfate was observed in man and dog (Rost, 1993). When sulfite is present in tissues in sufficiently high concentrations, it may be metabolised to inorganic thiosulfate which is also excreted via urine.

- in human polymorphonuclear leukocytes, two different oxidation routes of sulfite to sulfate have been identified. Besides the well known pathway via sulfite oxidase another route of oxidation via a one electron oxidation step with an intermediate formation of sulfur trioxide radicals has been identified. The contribution of the different pathways is expected to vary substantially due to the great interindividual variation in sulfite oxidase activity. The contribution of the trioxide radical pathway is expected to be high in individuals with low sulfite oxidase activity. The identified radical mechanism may promote the activation of certain carcinogens and may also increase the risk of amino acid destruction, degradation of DNA and lipid peroxidation (Constantin, 1994).

- the main decomposition product of sodium dithionite, i. e. hydrogen sulfite, can be absorbed from the rat gastrointestinal tract. It is oxidised in vivo to sulfate, principally by hepatic sulfite oxidase (cytochrom-c oxidoreductase), with lesser amounts metabolised by the kidneys, intestines, heart, and lungs. About 70 to 95 % of the radioactivity associated with a 50 mg/kg bw oral hydrogen sulfite dose appeared in rodent and monkey urine within 3 days as sulfate. Only a small fraction (8 - 10%) of the absorbed hydrogen sulfite was eliminated intact (ACGIH, 1991; Gunnison, Bresnahanand Chiang, 1977). Physiologically, sulfite oxidase is involved in the methionine and cysteine metabolism. The endogenous sulfite body burden resulting from amino acid degradation is in the range of 0.3 - 0.4 mmol/kg bw/day, which is reported to be about 15 - to 130 - fold higher than the estimated value for exogenous sulfite exposure (Institute of Food Technologists and Committee on Public Information, 1976).In conclusion, sodium dithionite is not stable under physiological conditions, with the rate of decomposition increasing with increasing acidity. Upon contact with moisture, it is oxidised to hydrogen sulfite (HSO3-), sulfite (SO32-) and hydrogen sulfate (HSO4-), and under strongly acidic conditions it may liberate sulfur dioxide. Under anaerobic conditions (such as in the lower gastrointestinal tract), hydrogen sulfite (HSO3-) and thiosulfate (S2O32-) may be formed.

- thiosulfate is eliminated mainly unchanged via renal excretion, but a certain amount is enzymatically oxidised in the liver to sulfate. This latter fraction increases as the dose of thiosulfate decreases (JECFA, 1983). In anaesthetised rats with pre- and post-hepatic cannulation for blood withdrawal, blood levels of free sulfite in portal blood increased within minutes after intraduodenal administration of 100 mg Na2SO3/kg (approx. 65 mg sulfite). The pre-hepatic plasma peak after 10 to 20 min represented about 1 mg/ml sulfite (12.5 to 13.5 μmol/ml). No free sulfite was detected in the general circulation (post-hepatic). It was concluded that sulfite was efficiently eliminated from blood (Wever, 1985).

Discussion on bioaccumulation potential result:

Bioaccumulation:

Under physiologically relevant conditions, the substance readily dissociates in aqueous solution to sulfite and hydrogensulfite anions.

Bioaccumulation is not expected because of the strong anionic and hydrophilic nature of the substance, as well as its experimentally verified rapid oxidation in vivo to sulfate with subsequent renal elimination.