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Acute Toxicity: oral

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Endpoint:
acute toxicity: oral
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Study period:
1987-08-05 to 1987-09-04
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Stability of the test material was missing.
Justification for type of information:
The basis for the read-across concept for this project is the equilibrium between sulfites, hydrogensulfites, and metabisulfites in aqueous solutions depending on pHvalue 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 -
 
Not completely included in this read-across concept is the substance class of thiosulfates. Although thiosulfates may also disproportionate in aqueous solution to form polythionic acids and SO2(HSO3-), the required conditions are somewhat different (more acidic) and are therefore not strictly comparable with physiological conditions, except for the case of oral application where read-across should be considered unrestricted due to the strongly acidic conditions in the stomach:
       HS2O3-+ H2S2O3→HS3O3- + SO2 + H2O
Nevertheless, read-across for all other routes (dermal, inhalation) should also be considered.
The proposed read-across concept only applies to toxicological and ecotoxicological/environmental fate endpoints.
[1]Hollemann Wiberg, Lehrbuch der Anorganischen Chemie, 101.Auflage
[2]Handbook of Chemistry and Physics, Ed. Lide, DR, 88thedition, CRC Press

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1987
Report date:
1987

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
, adopted 1987-02-24
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Constituent 1
Reference substance name:
Disodium disulphite
EC Number:
231-673-0
EC Name:
Disodium disulphite
Cas Number:
7681-57-4
Molecular formula:
Na2S2O5
IUPAC Name:
disodium disulphite
Test material form:
other: solid: microcrystalline powder
Details on test material:
- Name of test material (as cited in study report): Natriumbisulfit-Pulver (Sodium disulfite- powder)
- Chemical description: Sodium pyrosulfit
- Molecular formula: Na2S2O5
- Molecular weight: 190.12 g/mol
- Physical state: white, microcrystalline powder
- Analytical purity: at least 96% Na2S2O5
- Impurities (identity and concentrations): Na2SO3 and Na2SO4
- Composition of test material: 96% Na2S2O5, 2% Na2SO3, 2% Na2SO4
- Lot/batch No.: AZBP 005
- Storage condition of test material: In the dark in a fume hood at 22°C
- Use: Preserving agent, bleaching agent, and reducing agent
- Decomposition temperature: > 150°C
- Density: 1.48 kg/l
- pH-value in water: 4.4 - 4.9 (20%)
- Solubility: 650 g/l in water

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: HOECHST AG, Kastenfrund, SPF-Breed
- Age at study initiation: Males: ca. 7 weeks; females: ca.8 weeks
- Weight at study initiation: Males (n = 15): Mean weight: 195 g +/- 13 g (max. 215 g, min. 179 g); females (n = 15): Mean weight: 178 g +/- 5 g (max. 185 g, min. 168 g)
- Fasting period before study: Ca. 16 hours before administration and 3-4 hours after administration.
- Housing: Animals were housed in groups of five in Makroloncages (Type 4) on granulat of softwood.
- Diet (ad libitum): Rat diet Altromin 1324 (Altromin-GmbH, Lage/Lippe)
- Water (ad libitum): Tap water in plastic drinking bottles
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS - fully airconitioned rooms
- Temperature:: 22+/- 3°C
- Relative humidity: 50% +/- 20%
- Photoperiod (hrs dark / hrs light): 12/12
No further information on the test animals was stated.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
deionised water
Details on oral exposure:
RANGE-FINDING STUDY:
Doses of the main study were selected based on a range-finding studies. The following doses were tested in one male and one female: 500, 1000, and 2000 mg/kg bw in deionised water (25% Concentration).
The following findings were made:
Both male and female died 120 minutes after the administration of 2000 mg/kg bw.
On the application day the animals showed reduced spontaneous activity, crouching, drawn in flanks, long-legged gait and irregular breatching. The symptoms of surviving animals were reversible from Day 1 on.
The animals, which died during the study had reddened mucous coat of the stomach as well as haematoma in the gastro-intestinal tract. The macroscopically examined animals, which were killed at the end of the study showed no changes.

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg bw.

DOSAGE PREPARATION: Sodium disulfite was dissolved in deionised water.
Concentrations:
8.0% (w/v) (Dose: 800 mg/kg bw.)
12.5% (w/v) (Dose: 1250 mg/kg bw.)
16.0% (w/v) (Dose: 1600 mg/kg bw.)
20.0% (w/v) (Dose: 2000 mg/kg bw.)
No further information on the oral exposure was stated.
Doses:
Males: 1250, 1600, and 2000 mg/kg bw
Females: 800, 1250, and 1600 mg/kg bw
No. of animals per sex per dose:
Males: 5 per dose
Females: 5 per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The body weight of the animals were recorded weekly. The clinical signs and mortality were observed at least 10 and 30 minutes after administration, and 1, 2, 4 and 6 hours after administration. Afterwards the clinical signs and mortality were observed daily.
- Necropsy of survivors performed: Yes
The animals, which died during the study, were dissected and macrosopically examined. The animals, which survived until the end of the observation period, were killed with carbon dioxide. They were also dissected and macroscopically examined.
- Examinations performed: The symptoms and the mortality were recorded.
No further information on the study design was stated.
Statistics:
The LD50, the confidence interval, and the equation of the grade of the probit were calculated from the observed death rates using a probit analysis.

Results and discussion

Effect levelsopen allclose all
Sex:
female
Dose descriptor:
LD50
Effect level:
1 420 mg/kg bw
Based on:
test mat.
95% CL:
>= 1 040 - <= 2 110
Remarks on result:
other: Confidence interval: P = 0.05
Sex:
male
Dose descriptor:
LD50
Effect level:
1 630 mg/kg bw
Based on:
test mat.
95% CL:
>= 1 210 - <= 2 260
Remarks on result:
other: Confidence interval: P = 0.05
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 540 mg/kg bw
Based on:
test mat.
95% CL:
>= 1 290 - <= 1 960
Remarks on result:
other: Confidence interval: P = 0.05
Mortality:
The following death rates were observed:
800 mg/kg bw.: Females: 0/5 (0%)
1250 mg/kg bw.: Males: 1/5 (20%; death after 60 minutes of administration); Females: 1/5 (20%; death after 70 minutes of administration)
1600 mg/kg bw.: Males: 2/5 (40%; death after 75 and 180 minutes of administration, respectively); Females: 4/5 (80%, death after 60 minutes of administration)
2000 mg/kg bw.: Males: 4/5 (80%; death after 70 minutes of administration)
Clinical signs:
The following clinical signs were observed in the males and females, respectively: reduced spontaneous activity, crouching, flanks drawn-in, ruffled fur, irregular breathing, and long-legged gait. In addition, latero-abdominal position, constricted palpebral fissure, and drowsiness were observed in the males receiving 1600 and 2000 mg/kg bw. The clinical signs of the surviving animals were reversible from the first day on.

Body weight:
An impairment of the development of the body weight was not observed.
Gross pathology:
The macroscopically examination of the males and females, which died during the study, showed the following:
- gastro-intestinal tract filled with blood (Males in the 1250, 1600 and 2000 mg/kg bw. dose; females: 1250 and 1600 mg/kg bw. dose)
- Mucous coat of the stomach reddened (Males in the 1250 and 2000 mg/kg bw. dose; females: 1250 and 1600 mg/kg bw. dose)
- Liver dark discoloured (Males in the 1250, 1600 and 2000 mg/kg bw. dose; females: 1600 mg/kg bw. dose)
- Marked liver lobules (Females: 1600 mg/kg bw. dose
The animals, which were killed at the end of the observation period, were free of macroscopical changes.

Any other information on results incl. tables

The following clinical signs were observed.

Clinical sigs of the males:

1250 mg/kg bw.:

- Reduced spontaneous activity: One male after at least 30 minutes and four males after 1 hour of administration until Day 1 after administration.

- Long-legged gait: Four males at least 30 minutes after administration until Day 1 after administration.

- Crouching: Four males at least 30 minutes after administration until Day 1 after administration.

- Irregular breathing: Four males 1 hour after administration until Day 1 after administration.

- Ruffled fur: Two males 2 hours after administration.

1600 mg/kg bw.:

- Reduced spontaneous activity: Five males after at least 30 minutes, four males after 1 hour and three males after 2 hour of administration until Day 1 after administration.

- Long-legged gait: Two males at least 30 minutes and three males 1 hour after administration until Day 1 after administration.

- Crouching: Five males at least 30 minutes, four males 1 hour and 3 males 2 hours after administration until Day 1 after administration.

- Irregular breathing: Four males 1 hour after administration until 2 hours after administration.

- Ruffled fur: Two males 2 hours after administration.

- Flank drawn-in: 3 males after at least 30 minutes after administration until Day 1 after administration.

- Constricted palpebral fissure: 1 male after 1 hour of administration until 2 hours after administration

- Abdominal or lateral position: 1 male at 2 hours after administration

-Drowsiness: 1 male at 2 hours after administration

2000 mg/kg bw.:

- Reduced spontaneous activity: Five males after at least 30 minutes, one male after 1 hour of administration until 4 hours after administration.

- Crouching: Four males at least 30 minutes, and one male 1 hour after administration until 4 hours after administration.

- Irregular breathing: Four males at least 30 minutes, five males 1 hour, and onemale 2 hours after administration until 4 hours after administration.

- Ruffled fur: One male 4 hours after administration.

- Flank drawn-in: Four males after at least 30 minutes and one male 1 hour after administration until Day 1 after administration.

- Constricted palpebral fissure: 1 male at least 30 miuntes after administration until 1 hour after administration

- Abdominal or lateral position: Four males at 1 hour after administration

-Drowsiness: Four males at 4 hours after administration

Clinical sigs of the females:

800 mg/kg bw.:

- Reduced spontaneous activity: five females after 1 hour of administration until Day 1 after administration.

1250 mg/kg bw.:

- Reduced spontaneous activity: Five females after at least 30 minutes and four females after 1 hour of administration until Day 1 after administration.

- Crouching: Two females after at least 30 minutes and four females after 1 hour of administration until Day 1 after administration.

- Flank drawn-in: Two females after at least 30 minutes and four females after 1 hour of administration until Day 1 after administration.

- Irregular breathing: Two females after at least 30 minutes and four females after 1 hour of administration until Day 1 after administration.

- Ruffled fur: One female after 2 hours of administration until 4 hours after administration.

1600 mg/kg bw.:

- Reduced spontaneous activity: One female after at least 30 minutes of administration until Day 1 after administration.

- Long-legged gait: Five females at least 30 minutes and 1 female after 1 hour of administration until Day 1 after administration.

- Crouching: One females after at least 30 minutes of administration until Day 1 after administration.

- Flank drawn-in: One females after at least 30 minutes of administration until Day 1 after administration.

- Irregular breathing: One females after 2 hours of administration until Day 1 after administration.

- Ruffled fur: One females after 2 hours of administration until Day 1 after administration.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item is classified as Category 4.