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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
not specified
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
see attachment “Read-across concept – Human Health/Environment - Category approach for Inorganic sulfites/thiosulfates/dithionite" in section 13.

Data source

Reference
Reference Type:
publication
Title:
Teratologic evaluation of compound FDA 71-22 (sodium metabisulfite) in rabbits
Author:
Anonymous
Year:
1974
Bibliographic source:
PB-267 194, National Technical Information Service (NTIS), U.S. Department of Commerce, Springfield, VA. 22161

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
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:
solid: crystalline
Details on test material:
- Name of test material (as cited in study report): sodium metabisulfite, FDA 71-22
- Physical state: white crystalline material
Specific details on test material used for the study:
not specified

Test animals

Species:
rabbit
Strain:
Dutch
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: virgin, adult females
- Housing: individually housed in mesh bottom cages
- Diet: ad libitum
- Water (ad libitum): tap water

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
VEHICLE
- Amount of vehicle (if gavage): doses administered as a water solution.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: artificial insemination.
- On day 0, each doe was given an injection of 0.4 mL of human chorionic gonadotropin (400 IU) via the marginal ear vein.
- Three hours later, each doe was inseminated artificially with 0.3 mL of diluted semen from a proven donor buck using approximately 20 x 10^6 motile sperm according to the procedure described by Vogin et al. (Pharmacologist 11, 282 (1969)).
Duration of treatment / exposure:
gestation days 6 to 18
Frequency of treatment:
daily
Duration of test:
until day 29 of gestation
Doses / concentrationsopen allclose all
Dose / conc.:
1.23 mg/kg bw/day (actual dose received)
Dose / conc.:
5.71 mg/kg bw/day (actual dose received)
Dose / conc.:
26.5 mg/kg bw/day (actual dose received)
Dose / conc.:
123 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
15 to 20 mated females
Control animals:
yes, concurrent vehicle
other: positive control: 2.5 mg/kg body weight of 6-aminonicotinamide dosed on Day 9
Details on study design:
not specified

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked: mortality, appearance and behaviour

DETAILED CLINICAL OBSERVATIONS:No data

BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 6, 12, 18 and 29 of gestation.

FOOD CONSUMPTION: Yes
- Time schedule: daily

WATER CONSUMPTION: No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- all does were subjected to Caesaren section under surgical anesthesia.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
- Number of live and dead foetuses: Yes
Fetal examinations:
External examinations: Yes
- all foetuses underwent a detailed gross examination for the presence of external congenital abnormalities.

Soft tissue examinations: Yes
- live foetuses of each litter were then placed in an incubator for 24 hours for evaluation of neonatal survival.
- all surviving pups were sacrificed, and all pups examined for visceral abnormalities (by dissection).

Skeletal examinations: Yes
- all fetuses were cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal defects (sternebrae, ribs, vertebrae, skull, extremities and miscellaneous)

Head examinations: No data

- Body weights of the live pups were recoded.
- Sex of the foetuses was recorded

Statistics:
not specified
Indices:
not specified
Historical control data:
not specified

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, non-treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
- survival of pregnant females was not affected by treatment with sodium metabisulfite.
- maternal body weights and weight gains were comparable among groups.

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
no effects observed
Other effects:
not specified
Details on maternal toxic effects:
- The pregnancy rates was comparable among groups (control group: 14 pregnant rabbits; 1.23 mg/kg bw/d: 13 pregnant rabbits; 5.71 mg/kg bw/d: 12 pregnant rabbits; 26.5 mg/kg bw/d: 12 pregnant rabbits; 123.0 mg/kg bw/d: 14 pregnant rabbits).
- There were no treatment-related effects on the number of abortions, corpora lutea, implantation sites, live litters and resorptions.




Effect levels (maternal animals)

Key result
Remarks on result:
not determinable due to absence of adverse toxic effects

Maternal abnormalities

Abnormalities:
not specified

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
not specified
Changes in postnatal survival:
no effects observed
External malformations:
not specified
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
- The number of live and dead foetuses, sex ratio and average foetal weight was not affected by treatment of dams with sodium metabisulfite.
- 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.

Effect levels (fetuses)

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Dose descriptor:
NOAEL
Remarks:
teratogenicity
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The administration of up to 123 mg/kg bw/d of sodium metabisulfite to pregnant rabbits for 13 consecutive days had no clearly discernible effect on nidation or on maternal or foetal survival. 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 NOAEL for maternal and developmental toxicity can be expected above the highest dose of 123 mg/kg body weight sodium metabisulfite in this rabbit study.