Magnesium thiosulphate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

no data available

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well-documented study.

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 substances 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

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1975

Report date:

1975

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

not specified

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Dipotassium disulphite

EC Number:

240-795-3

EC Name:

Dipotassium disulphite

Cas Number:

16731-55-8

IUPAC Name:

dipotassium disulphite

Constituent 2

Reference substance name:

Dipotassium disulfite

IUPAC Name:

Dipotassium disulfite

Constituent 3

Reference substance name:

dipotassium disulfite

IUPAC Name:

dipotassium disulfite

Details on test material:

- Name of test material (as cited in study report): Potassium metabisulfite (FDA 71-21)
- Substance type: pure substance
- Physical state: solid, white granular substance
No further details are given.

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: adult female albino rats
- Housing: individually housed in mesh bottom cages
- Diet: ad libitum
- Water: ad libitum
No further details are given

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

VEHICLE
- Amount of vehicle (if gavage): doses administered as a water solution of 1 mL/kg body weight.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

no data

Details on mating procedure:

- Impregnation procedure: cohoused.
- Females were mated with young adult males.
- Observation of the vaginal sprem plug was considered day 0 of gestation.
- One male was not permitted to impregnate more than one female per group.

Duration of treatment / exposure:

from day 6 to 15 of gestation

Frequency of treatment:

daily

Duration of test:

until day 20 of gesation

No. of animals per sex per dose:

22-25 animals per group

Control animals:

yes, sham-exposed

other: positive control: 250 mg/kg body weight of Aspirin

Details on study design:

No further details are given.

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: all animals were observed daily for appearance and behaviour.

BODY WEIGHT: Yes
- Time schedule for examinations: recorded on days 0, 6, 11, 15 and 20 of gestation.

FOOD CONSUMPTION: Yes
- Time schedule: all animals were observed daily for food consumption.

WATER CONSUMPTION: No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: 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 and sex of live and dead fetuses: Yes

Fetal examinations:

External examinations: Yes
- Body weights of the live pups were recoded.
- All fetuses underwent a detailed gross examination for the presence of external congenital abnormalities. .

Soft tissue examinations: Yes
- One-third of the fetuses of each litter underwent detailed visceral examinations employing 10x magnification.

Skeletal examinations: Yes
- Two-third of the 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

Statistics:

no data

Indices:

no data

Historical control data:

no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
- The pregnancy rates was comparable among groups and survival of pregnant females was not affected by treatment with potassium metabisulphite.
- Maternal body weights and weight gains were comparable among groups.
- There were no treatment-related effects on the number of abortions, corpora lutea, implantation sites, live litters and resorptions.

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

> 155 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Remarks on result:

not determinable

Remarks:

no NOAEL identified

2

Dose descriptor:

NOAEL

Effect level:

> 155 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
- The number of live and dead fetuses, sex ratio and average fetal weight was not affected by treatment of dams with potassium metabisulphite.
- 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)

Dose descriptor:

NOAEL

Effect level:

> 155 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The administration of up to 155 mg/kg bw/d of potassium metabisulfphite to pregnant rats for 10 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 155 mg/kg body weight potassium metabisulphite in this rat study.