Sodium sulphite

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

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 1

Reference Type:

publication

Title:

Evaluation of teratogenic potential of sodium sulfite in rats.

Author:

Itami, T. et al.

Year:

1989

Bibliographic source:

Drug Chem. Toxicol., 12: 123-135. (cited in OECD SIDS sodium dithionite, Oct. 2004)

Reference 2

Reference Type:

review article or handbook

Title:

Occupational Exposures to Mists and Vapours from Strong Inorganic Acids and Other Industrial Chemicals.

Author:

Anonymous

Year:

1992

Bibliographic source:

IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol. 54, 131 - 188, International Agency for Research on Cancer, Lyon

Reference 3

Reference Type:

review article or handbook

Title:

Safety evalutation of certain food additives. Sulfur dioxide and sulfites (addendum).

Author:

Anonymous

Year:

1999

Bibliographic source:

WHO Food Additives Series 42: 95-116.

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Sodium sulphite

EC Number:

231-821-4

EC Name:

Sodium sulphite

Cas Number:

7757-83-7

Molecular formula:

NA2SO3

IUPAC Name:

disodium sulfate

Test material form:

solid: crystalline

Details on test material:

- Supplier: Katayama Chemical Industries Co. LTD (Tokyo, Japan)- State of aggregation: colourless, efflorescent crystalline compound

Specific details on test material used for the study:

not specified

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: KEARI Co. Ltd, Osaka, Japan.
- Weight at study initiation: 237 ± 2 g on day 0 of pregnancy.
- Housing: housed individually in wire-mesh cages.
- Diet (ad libitum): basal diet CE-2, Clea Japan Inc., Tokyo)
- Water (ad libitum): tap water

ENVIRONMENTAL CONDITIONS
- Temperature: 24 - 25 °C
- Relative humidity: 50 - 60 %
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

DIET PREPARATION
- diet was prepared to contain the different concentrations of the test item in the basal diet.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

not specified

Details on mating procedure:

- Impregnation procedure: cohoused; virgin female rats were caged with male rats overnight.
- Proof of pregnancy: vaginal plug and sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

gestation day 8 to gestation day 20

Frequency of treatment:

ad libitum

Duration of test:

Either until gestation day 20 (10 to 12 dams per group) or until weaning on day 21 post partum (4 - 5 dams of control, 0.32% and 5% groups).

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0.32 other: %

Remarks:

approx. 200 mg sodium sulfite heptahydrate/kg bw/day (equivalent to approx. 100 mg sodium sulfite/kg bw/day or approx. 50 mg/kg bw/day SO2 equivalent)

Doses / concentrations 2

Dose / conc.:

0.63 other: %

Remarks:

approx. 400 mg sodium sulfite heptahydrate/kg bw/day (equivalent to approx. 200 mg sodium sulfite/kg bw/day or approx. 100 mg/kg bw/day SO2 equivalent)

Doses / concentrations 3

Dose / conc.:

1.25 other: %

Remarks:

approx. 900 mg sodium sulfite heptahydrate/kg bw/day (equivalent to approx. 450 mg sodium sulfite/kg bw/day or approx. 225 mg/kg bw/day SO2 equivalent)

Doses / concentrations 4

Dose / conc.:

2.5 other: %

Remarks:

approx. 1750 mg sodium sulfite heptahydrate/kg bw/day (equivalent to approx. 850 mg sodium sulfite/kg bw/day or approx. 440 mg/kg bw/day SO2 equivalent)

Doses / concentrations 5

Dose / conc.:

5 other: %

Remarks:

approx. 2900 mg sodium sulfite heptahydrate/kg bw/day (equivalent to approx. 1450 mg sodium sulfite/kg bw/day or approx. 725 mg/kg bw/day SO2 equivalent)

No. of animals per sex per dose:

10 - 12 dams/group (exception: 14 to 17 dams/group in the control, 0.32% and 5% groups)

Control animals:

yes, plain diet

Details on study design:

not specified

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked: clinical signs

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule for examinations: daily
- Net amounts of sodium sulfite uptake were calculated from the food consumption.

WATER CONSUMPTION: No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20; 10 or 12 pregnant rats in each group were sacrificed by cervical dislocation.

OTHER:
- 4 or 5 dams in 5%, 0.32% and control groups were individually housed and were allowed to give birth.
- After completion of delivery, maternal rats were fed basal diet without sodium sulfite; the day of delivery was designated as day 0 after birth.
- At birth, the number of live and dead newborns were recorded.
- Pups were sexed, weighed, examined for external malformations, marked for identification and allowed to suckle their own mother.
- Pups were weaned day 21 after birth.
- The body weights of maternal rats and pups were measured and clinical signs of toxicity were noted during this period.

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: No data
- Number of implantations: Yes
- Number and position of resorptions: Yes
- Examination for the presence and position of foetuses (dead or alive)

Fetal examinations:

- External examinations: Yes, each foetuses.
- Soft tissue examinations: Yes, half per litter
- Skeletal examinations: Yes, half per litter
- Head examinations: No data

Further examinations:
- each live foetus was weighed and sexed.

Statistics:

Statistical analysis of the fetal data was based on the litter as the experimental unit. The maternal body weight gain and food consumption during pregnancy, the number of implantations, live fetuses, live newborns per litter, the weights of the fetuses and offspring were analysed using the Student's t-test. The incidence of postimplantation loss, skeletal and internal variations, delayed ossification, the live birth index, the survival rate of offspring and sex ratio of live fetuses were analysed non-parametricallly using the Wilcoxon's rank sum test, the chi-square test with Yates' correction or Fischer's exact probability test. In all cases, P<0.05 was chosen as the level of significance.

Indices:

Percent of intrauterine death: (No. of resorptions and dead foetuses/No. of implantation) x 100
Live birth index (%): (No. of live newborns at birth / No. of implantation remnants) x 100
Survival rate (%): (No. of live offspring on indicated day after birth / No. of offspring at birth) x 100

Historical control data:

not specified

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

- 5 % group: significantly (p<0.05) decreased body weight gain

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

- 5 % group: food intake of the pregnant rats was low when compared to the control group (day 9 - 20; p < 0.05; -26 %).

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:

- neither mortality nor clinical signs of toxicity were observed in any group.
- 0.32, and 0.63 % groups: food intake of the pregnant rats was low when compared to the control group (p < 0.05).
- no differences between the control and other sodium sulfite-treated groups were observed.

Observation in groups of dams (0.32%, 5% and control) that were allowed to deliver and rear their offspring
- maternal body weight gain three weeks after delivery was not significantly affected by treatment during GD 8-20.

Maternal developmental toxicity

Number of abortions:

not specified

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

not specified

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in pregnancy duration:

not specified

Changes in number of pregnant:

not specified

Other effects:

not specified

Details on maternal toxic effects:

- at sacrifice on day 20 of pregnancy, the reproductive parameters obtained such as the numbers of implants, live foetuses and intrauterine death (resorptions and dead foetuses) were found not significantly different between the control and sodium sulfite-treated groups.

Effect levels (maternal animals)

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 1 750 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

food consumption and compound intake

Remarks on result:

other: The NOAEL for maternal toxicity can be established at 2.5% in the diet (approx. 1750 mg/kg bw/d Na2SO3 x 7 H2O, approx. 850 mg/kg bw/d Na2SO3 or approx. 440 mg/kg bw/d as SO2 equivalents).

Maternal abnormalities

Abnormalities:

not specified

Results (fetuses)

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

- foetal body weights in all of the sodium sulfite-treated groups except 2.5 % group (females only) were significantly lower than in the control group (p < 0.05).

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:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

no effects observed

Other effects:

no effects observed

Details on embryotoxic / teratogenic effects:

Observation at day 20 of pregnancy (0.32-5% and control):
- at sacrifice on day 20 of pregnancy, the sex ratios of foetuses were found not significantly different between the control and test item-treated groups.

Fetal examinations:
- External, skeletal and internal malformations of the foetuses were not observed at any dose level.
- several types of foetal skeletal variations such as lumbar ribs, hypoplastic rib and delayed ossifications were observed in the test item-treated groups, except for the 1.25 % group. The differences were found not significant in comparison with the control group.
- degree of delayed ossification was slightly, but not significantly increased by high doses of the test item.
- few foetuses with dilatation of the renal pelvis (reduction of renal papilla) and lateral ventricle were observed, but there was no significant dose-dependence.

Observation in groups of dams (0.32%, 5% and control) that were allowed to deliver and rear their offspring
- The live birth index and survival rate (day 7 and 28) of offspring was not affected by treatment.
- Pup body weight gain at 3 weeks after birth were not affected by the sodium sulfite-treatment.

Effect levels (fetuses)

1

Key result

Dose descriptor:

NOAEL

Remarks:

teratogenicity

Remarks on result:

not determinable due to absence of adverse toxic effects

2

Remarks on result:

other: Some evidence of growth retardation was observed in all groups at & above a dietary dose of 0.32% (approx. 200 mg/kg bw/d Na2SO3 x 7 H2O, approx. 100 mg/kg bw/d Na2SO3); no dose-relationship was seen. Effects were not observed in the live-birth part.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Treatment of pregnant Wistar rats with diets containing 0, 0.32, 0.63, 1.25, 2.5 and 5% Na2SO3 * 7H2O in the diet from GD 8 to GD 20 resulted in effects on body weight gain and food consumption at 5%, but no clinical signs of toxicity were recorded. Some evidence of growth retardation was observed in all treatment groups, but there was no dose-relationship and these effects were not observed in the live-birth part of the study, which was indicated by a lack of changes in male and female pups 3 weeks after birth. These effects were considered as might be related to maternal malnutrition and/or disturbance in metabolism by liberated sulfur dioxide. No evidence of teratogenicity was seen in the study.
Thus, the NOAEL for maternal toxicity can be established at 2.5% in the diet (approx. 1750 mg/kg bw/d Na2SO3 x 7 H2O, approx. 850 mg/kg bw/d Na2SO3 or approx. 440 mg/kg bw/d as SO2 equivalents). There was no clear evidence for foetal toxicity, but slight fetal growth retardation was observed at dietary doses at and above 0.32% (approx. 200 mg/kg bw/d Na2SO3 x 7 H2O, approx. 200 mg/kg bw/d or approx. 50 mg/kg bw/d as SO2 equivalents).