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Description of key information

In total six reliable in-vivo studies for skin irritation were identified that are considered adequate (read-across) information and thus rated as key studies. The tests on skin irritation show a negative response, thus, based on read-across, calcium sulfite does not require classification as skin irritant. 
For the endpoint eye irritation in total three in-vivo study reports were identified as adequate read-across information. The results of the eye irritation studies indicate clear eye irritation properties for the substances sodium metabisulfite and potassium disulfite, whereas sodium sulfite is not considered to be an eye irritant.

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

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

Skin irritation:

In total six studies were identified that are considered adequate (read-across) information and thus rated as key studies. One in vivo study (Kirsch, 1989) on dermal irritation of potassium sulfite was identified which was conducted according to OECD guideline 404. The test item showed no skin irritating properties. No erythema or oedema were seen in any of the rabbits at 24, 48, 72 hours after the beginning of the study. Very slight erythema was observed in two animals at the 4-hour reading, which had disappeared at the 24 hour reading.

One further in-vivo study for sodium sulfite (Grundler, 1981) equivalent or similar to OECD 404, used for read-across is available. No skin irritating properties of sodium sulfite could be determined.

Three study reports equivalent or similar to OECD 404, prepared by Consonni (2004) for the substances ammonium hydrogensulfite, sodium hydrogensulfite and potassium hydrogensulfite indicated no irritation properties when applied as aqueous solution (70%, 40% and 32%; substances as such are not existent in dry form). Erythema and edema scores were zero after 24, 48 and 72h for all substances.

Sodium metabisulfite solution was tested for skin irritation properties in a single 4h dermal application (Broughton, W.S., 1973, NTIS-OTS 572413) according to the criteria of the Federal Hazardous Substances Act, Section 191.11. The animals were immobilised in restrainers and their trunks were wrapped in a nonabsorbent binder for the exposure period. Application of 0.5 mL of the substance (aqueous solution) under gauze patches (1 inch square) to intact skin sites on the back of albino rabbits (New Zealand White, six animals) afforded no signs of irritation (Draize scoring) after 4, 24 and 48 hours. According to OECD guideline 404 examination for signs of erythema and oedema and the responses should be scored at 30 -60 minutes, and then at 24, 48, and 72 hours after patch removal. Despite minor reporting and experimental deficiencies/deviations in study design, thereference fulfils the basic requirements for scientific data used in chemicals risk assessment.

Supporting studies (Zeller & Hofmann, 1974; reliability 3) for the test substance potassium metabisulfite and sodium metabisulfite could be identified. Although one animal exposed for 20 h showed marginal erythema at 24 h and desquamation at the end of the 8 day observation period, the other animal showed no signs of irritation. In addition to the extended length of application, these data were not sufficient for classification as irritant to skin.

For some references, only short abstracts/summaries are available. Due to the limited information content, these references were not considered for hazard assessment purposes and rated with reliability 4 “not assignable” (Bomhard, E.; et al., 2000 (sodium sulfite);Bomhard, E.; et al., 2000(sodium hydrogenulfite);Edwards, D., 1974; Topping, D.C., 1980.

 

Eye irritation:

One in-vivo study for sodium metabisulfite, according to OECD guideline 405 is available (Kieczka, 1984). During the 1-hour reading slight corneal opacity was seen in one animal. Also, at the 1-hour observation well-defined conjunctivae redness and severe chemosis were observed in all animals. At the 1-hour reading detachment of the cornea was seen in one male. At the 24-hour and 48-hour readings suppuration was seen in all rabbits. At the 72-hour reading suppuration and contracted pupils were observed in the female and one male. On day 8 contracted pupils, detachment of the cornea, small retractions in the eyelids and marginal vascularization of the cornea were observed in the female rabbit. On day 8 detachment of the cornea, small retractions in the eyelids, marginal vascularization of the cornea and pannus were observed in one male rabbit. The other male rabbit was free of ocular effects on day 8. It was observed that the cornal opacitiy worsened in two animals by day 8. It changed from slight opacity to well-defined opacitiy. Also, it was observed that the well-defined conjunctival redness in two animals, which was seen at the 1, 24, 48, and 72 hours- readdings, was still seen on the last day of observations. The chemosis disappeared in one animal completely by day 8. In the two remaining animals the chemosis became better, but was still seen on day 8.

One in-vivo study, equivalent or similar to OECD guideline 405 is available (Kieczka, 1984). During the 1-hour reading slight corneal opacity was seen in one animal. Also, at the 1-hour reading well-defined conjunctival redness and severe chemosis were observed in all animals. Detachment of the cornea and discharge of blood were observed in one male at the 1-hour reading. At the 24-hour reading suppuration in two animals was observed. At the 48 hour reading suppuration was observed in all animals. At the 72 hour reading suppuration was observed in one male and suppuration, small retractions in the eyelids, and pupil contration were observed in one female. On day 8, the corneal opacitiy worsened in all animals. The conjunctival redness (well-defined) remained the same throughout the observation period, except for one animal in which slight conjunctival redness was observed on day 8. The chemosis was not fully reversed in any of the animals on day 8, but became better. On day 8 marginal vascularization of the cornea and small retractions in the eyelids were observed in one female. In addition, marginal vascularization of the cornea was observed in the male rabbit. Furthermore, marginal vascularization of the cornea, small retractions in the eyelids, suppuration, and pupil contration were observed in the remaining female.

One in-vivo study for sodium sulfite (CAS 7757 -83 -7), equivalent or similar to OECD guideline 405 is available (Grundler, O.J., 1981). During the 1-hour observation: in all animals clear conjunctival redness and chemosis (up to score 2) and slight secretion could be observed.

Based on the outcome of this study, sodium sulfite is considered as not irritating to the eye.

Justification for classification or non-classification

Skin irritation:

References Kirsch, J. (1989), Grundler, O.J. (1981), Consonni (2004, three in total) and Broughton, W.S., (1973) are considered as key studies for skin irritation and will be used for classification. The overall irritation results are as follows:

 

Kirsch, J. (1989):

(for additional information, see `discussion´)

Erythema, edema, 24, 48, 72h after application: max score = 0.                                                       

According to the criteria specified by Directive 67/548/EEC and subsequent regulations, the test item is not classified as skin irritant. According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item is not classified as skin irritant.

 

Grundler, O.J. (1981):

(for additional information, see `discussion´)

Erythema, 24, 48, 72h after application: max score =1, mean score = 0.33.

Edema, 24, 48, 72h after application: max score = 0

According to the criteria specified by Directive 67/548/EEC and subsequent regulations, the test item is not classified as skin irritant. According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item is not classified as skin irritant.

 

Consonni (2004):

Three study reports equivalent or similar to OECD 404, prepared by Consonni (2004) for the substances ammonium hydrogensulfite, sodium hydrogensulfite and potassium hydrogensulfite indicated no irritation properties when applied as aqueous solution (70%, 40% and 32%; substances as such are not existent in dry form). Erythema and edema scores were zero after 24, 48 and 72h for all substances.

According to the criteria specified by Directive 67/548/EEC and subsequent regulations, the test item is not classified as skin irritant. According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item is not classified as skin irritant.

 

Broughton, W.S., (1973):

No signs of irritation (Draize scoring) after 4, 24 and 48 hours. According to OECD guideline 404 examination for signs of erythema and oedema and the responses should be scored at 30 -60 minutes, and then at 24, 48, and 72 hours after patch removal. Despite minor reporting and experimental deficiencies/deviations in study design, the reference fulfils the basic requirements for scientific data used in chemicals risk assessment.

According to the criteria specified by Directive 67/548/EEC and subsequent regulations, the test item is not classified as skin irritant. According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item is not classified as skin irritant.

 

Eye irritation:

The reference Kieczka (1984) is considered as key study and will be used for classification. The overall results are as follows:

Sodium metabisulfite:

Animal #1:

Corneal opacity: mean score, 24, 48 and 72h after application = 0.67

Iris: mean score, 24, 48 and 72h after application = 0

Chemosis: mean score, 24, 48 and 72h after application = 2.33

Conjunctivae, 24, 48 and 72h after application: mean score = 2

 

Animal #2:

Corneal opacity: mean score, 24, 48 and 72h after application = 0.33

Iris: mean score, 24, 48 and 72h after application = 0.67

Chemosis: mean score, 24, 48 and 72h after application = 1.67

Conjunctivae, 24, 48 and 72h after application: mean score = 2

 

Animal #3:

Corneal opacity: mean score, 24, 48 and 72h after application = 0.67

Iris: mean score, 24, 48 and 72h after application = 0

Chemosis: mean score, 24, 48 and 72h after application = 2.33

Conjunctivae, 24, 48 and 72h after application: mean score = 2

 

potassium metabisulfite:

Animal #1:

Corneal opacity: mean score, 24, 48 and 72h after application = 0.67

Iris: mean score, 24, 48 and 72h after application = 0

Chemosis: mean score, 24, 48 and 72h after application = 2

Conjunctivae, 24, 48 and 72h after application: mean score = 2

 

Animal #2:

Corneal opacity: mean score, 24, 48 and 72h after application = 1

Iris: mean score, 24, 48 and 72h after application = 0.33

Chemosis: mean score, 24, 48 and 72h after application = 2

Conjunctivae, 24, 48 and 72h after application: mean score = 2

 

Animal #3:

Corneal opacity: mean score, 24, 48 and 72h after application = 0.67

Iris: mean score, 24, 48 and 72h after application = 0

Chemosis: mean score, 24, 48 and 72h after application = 2

Conjunctivae, 24, 48 and 72h after application: mean score = 2

Reference Grundler, O.J. (1981) is considered as key study and will be used for classification. The overall results are as follows:

 

Animal #1:

Corneal opacity: mean score, 24, 48 and 72h after application = 0

Iris: mean score, 24, 48 and 72h after application = 0

Chemosis: mean score, 24, 48 and 72h after application = 0.33

Conjunctivae, 24, 48 and 72h after application: mean score = 1.67

 

Animal #2:

Corneal opacity: mean score, 24, 48 and 72h after application = 0

Iris: mean score, 24, 48 and 72h after application = 0

Chemosis: mean score, 24, 48 and 72h after application = 0.67

Conjunctivae, 24, 48 and 72h after application: mean score = 0.67

 

Animal #3:

Corneal opacity: mean score, 24, 48 and 72h after application = 0

Iris: mean score, 24, 48 and 72h after application = 0

Chemosis: mean score, 24, 48 and 72h after application = 0

Conjunctivae, 24, 48 and 72h after application: mean score = 0.33

 

Animal #4:

Corneal opacity: mean score, 24, 48 and 72h after application = 0

Iris: mean score, 24, 48 and 72h after application = 0

Chemosis: mean score, 24, 48 and 72h after application = 0.33

Conjunctivae, 24, 48 and 72h after application: mean score = 1.33

 

Animal #5:

Corneal opacity: mean score, 24, 48 and 72h after application = 0

Iris: mean score, 24, 48 and 72h after application = 0

Chemosis: mean score, 24, 48 and 72h after application = 1

Conjunctivae, 24, 48 and 72h after application: mean score = 1.33

 

Animal #6:

Corneal opacity: mean score, 24, 48 and 72h after application = 0

Iris: mean score, 24, 48 and 72h after application = 0

Chemosis: mean score, 24, 48 and 72h after application = 0.67

Conjunctivae, 24, 48 and 72h after application: mean score = 0.33

 

Mean eye irritation scores of all animals combined:

Corneal opacity: mean score, 24, 48 and 72h after application = 0

Iris: mean score, 24, 48 and 72h after application = 0

Chemosis: mean score, 24, 48 and 72h after application = 0.5

Conjunctivae, 24, 48 and 72h after application: mean score = 0.9

 

According to the criteria specified by Directive 67/548/EEC and subsequent regulations, the test item is not classified as eye irritant.

 

Respiratory irritation:

The classification as respiratory irritant is covered under the endpoint specific target organ toxicity- single exposure and repeated exposure. Please refer to the endpoint summaries on acute toxicity (endpoint 7.2) and repeated dose toxicity (endpoint 7.5) for further information.