Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
2009-01-27 to 2009-02-11
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Read-across
The basis for the read-across concept for this project is the equilibrium between sulfites, hydrogensulfites, and metabisulfites in aqueous solutions depending on pH value which is clearly described in published literature and summarised in the following equations:[1],[2]
SO2 + H2O <->`H2SO3´ H2SO3<->H+ + HSO3- <-> 2H+ +SO32- 2HSO3- <->H2O +S2O52 –
As the nature of the cation should make no significant difference in this case concerning toxicity and solubility (all compounds are very soluble in water), only the chemical and biological properties of the anion are considered relevant. Based on the described equilibrium correlations, we propose unrestricted read-across between the groups of sulfites, hydrogensulfites and metabisulfites. Additionally, it is known that sodium dithionite disproportionates in water to form sodium hydrogen sulfite and sodium thiosulfate (equation II) so that this substance can also be added to the read-across concept.[2],[1]
It is expected for this case that the substance is not stable enough under physiological conditions to fulfil the requirements of study guidelines and so the products of decomposition have to be considered.
2 S2O42-+ H2O→2HSO3-+ S2O32 -

All sulfite, hydrogensulfite and metabisulfite substances are highly soluble in water, establishing upon dissolution an equilibrium that depends on solution pH as follows: ,

1. SO2 + H2O <-> H2SO3
2. H2SO3 <-> H+ + HSO3- <-> 2H+ + SO32-
3. 2 HSO3- <-> H2O + S2O52-

Under oxidising conditions, e.g., in surface waters, sulfite is oxidized to sulfate catalytically by (air) oxygen or by microbial action. A half-life of 77 hour was measured in deionized water, already suggesting substantial abiotic degradation. However, the presence of metal cations in the environment, such as copper, iron and manganese, accelerates the oxidation rate. In soils, HSO3- and SO32- ions are unstable and quickly oxidise. Further, because of the instability of SO32-, metal sulfites are generally too soluble to persist in soils. Thus, the most stable and predominant sulfur form in freshwater and in all but highly reduced environments is sulfate (SO42-). In highly reduced soils and sediments, sulfites may be reduced to sulfides (Lindsay, 1979; OECD SIDS, 2012).

Only the properties of the sulfite anion are considered relevant determinants of environmental toxicity since respective cations, i.e. ammonium, calcium, magnesium, sodium and potassium, are not assumed to contribute substantially to differences therein. Sulfite, although naturally present in the environment and also a metabolite and intermediate of sulfur-containing amino acids in organisms, may have an impact on the environment at elevated levels. Sulfites do not bioaccumulate.

In sum, unrestricted read-across between the sulfites, hydrogensulfites and metabisulfites is justified.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report Date:
2009

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
1987-02-24
Deviations:
yes
Remarks:
, - Solid test substance was applied as a solution; - Humidity range (animal housing): 20- 80 %
GLP compliance:
yes (incl. certificate)
Remarks:
signed 2008-04-17
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Details on test material:
- Name of test material (as cited in study report): Natriumsulfit wasserfrei food grade (E221)/(PRD30042389)
- Physical state: Solid / white
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature; under N2; protect against humidity

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Wiga GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: Young adult animals (male animals approx. 8 weeks, female animals approx. 12 weeks)
- Weight at study initiation: Animals of comparable weight (+/- 20% of the mean weight); mean weights males: 255 g; mean weights females: 218 g
- Housing: The animals were housed individually. The animals were housed in fully air-conditioned rooms. Type of cage: Makrolon cage, type III. Bedding: H 15005-29; Ssniff, Spezialitäten GmbH (Experimental Animal Diets Inc., 59494 Soest, Germany).
- Diet: VRF1(P); SDS Special Diets Services, 67122 Altrip, Germany.
- Water (ad libitum): Tap water
- Acclimation period: At least 5 days before the beginning of the experimental phase; during the acclimatization period, the animals were accustomed to the environmental conditions of the study and to the diet
- Enrichment: NGM E-022; ABEDD®LAB & VET Service GmbH, Hasnerstraße 84/6; 1160 Wien - Austria

ENVIRONMENTAL CONDITIONS
- Temperature: 22 – 26°C
- Relative humidity: 20 – 80%
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
water
Details on dermal exposure:
TEST SITE
- Area of exposure: About 24 hours before administration the fur was clipped. Then a single application to the clipped epidermis (dorsal and dorsolateral parts of the trunk) was applied.
- % coverage: At least 10 % of the body surface (about 40 cm^2)
- Type of wrap: Covering of the application site with a semi-occlusive dressing (the bandage consists of four layers absorbent gauze, Ph. Eur. Lohmann GmbH & Co. KG and Fixomull stretch (adhesive fleece), Beiersdorf AG) for 24 hours, afterwards removal of the dressing.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Rinsing of the application site with warm water.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10 ml/kg (application volume)
- Concentration: 20 g/100 ml
- Constant volume or concentration used: yes, constant volume
- For solids, paste formed: No, a solution was used for application. The test substanc epreparation was produced for the application group shortly before application by stirring with a magnetic stirrer.
VEHICLE: Doubly distilled water
Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 males / 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Body weight determination: Individual body weights shortly before administration (day 0), weekly thereafter and on the last day of observation.
- Signs and symptoms: Recording of signs and symptoms several times on the day of application, at least once each workday for the individual animals.
- Scoring of skin findings: Individual readings 30 – 60 minutes after removal of the semi-occlusive dressing (day 1), as a rule weekly thereafter and on the last day of observation.
- Mortality: A check for any dead or moribund animal was made twice each workday and once on weekends and on public holidays, these records are archived by Bioassay.
- Pathology: Necropsy with gross-pathology examination on the last day of the observation period after sacrifice with CO2 in a chamber with increasing concentrations over time.
Assessment of skin reactions: The evaluation of skin reactions was performed according to Draize, J.H. (1959): Appraisal of the safety of chemicals in foods, drugs and cosmetics. The association of food and drug officials of the United States Austin, Texas. Descriptions of any dermal findings not covered by this scale were recorded.

Statistics:
The means and standard deviation were calculated by using MS Excel 2003.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
No systemic clinical observations were observed during clinical examination. No local effects were observed.
Body weight:
The mean body weights of the male animals increased throughout the study period. Mean body weights of the female animals decreased during the first post-exposure observation week, probably due to the bandage procedure, but increased during the second week.
Gross pathology:
No macroscopic pathologic abnormalities were noted in the animals (5 males and 5 females) examined on the last day of observation.
Other findings:
No data

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
LD50 (male and female rats) > 2000 mg/kg bw
According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item is not classified as acute toxic via the dermal route.