Disodium disulphite

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

key study

Study period:

no data available

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

key study

Study period:

no data available

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Objective of study:

absorption

excretion

Qualifier:

no guideline followed

Principles of method if other than guideline:

The fate of ingested sulfite was investigated in mice using dose levels of 50 mg SO2/kg administered as NaHSO3 mixed with Na2[35]SO3.

GLP compliance:

no

Specific details on test material used for the study:

not specified

Radiolabelling:

yes

Remarks:

[35]SO3

Species:

mouse

Strain:

other: albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: C.L. Rolfsmeyer Co., Madison, Wisc.
- Weight at study initiation: 15 g
- Housing: Animals were housed in stainless-steel metabolism cages, with a screen attached to the cage bottom beneath the existing wire floor to facilitate separation of food, urine and faeces.
- Individual metabolism cages: yes
- Diet: e.g. ad libitum; Wayne Lab-Blox
- Water: ad libitum
No further details are given.

Route of administration:

oral: feed

Vehicle:

water

Remarks:

0.5 mL

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: NaHSO3 was mixed with tracer amounts of Na2[35]SO3.

DIET PREPARATION
no details

VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: 0.5% glucose solution
- Amount of vehicle (if gavage): 5.0 mL

Duration and frequency of treatment / exposure:

24, 48 hours, 1 week and 2 weeks

Dose / conc.:

50 other: mg SO2/kg

Remarks:

giving 3.37 x 10^7 count/minute

No. of animals per sex per dose / concentration:

groups of 6 to 8 mice were used

Control animals:

yes

Positive control reference chemical:

No positive control substance was tested.

Details on study design:

no data

Details on dosing and sampling:

Sulfite in aqueous solution was assayed either by colorimetric method based on pararosaniline, or by iodometric titration. A third method of sulfite analysis, using radioactive N-[1-[14C]]ethylmaleimide was used for urine samples.

Groups of 6-8 mice were killed at the end of 24 and 48 hours from the time of administration, during which period urine and faeces were collected, and the remaining two groups of three rats were killed 1 and 2 weeks after dosing. All animals were killed by a blow on the head and were frozen whole prior to the determination of the radioactivity remaining in the carcass.
For the determination of levels of activity in the urines and faeces, food was separated from the faeces manually and from urine by filtration. The cage floor, screen and funnel were washed with distilled water and the washings were added to the urine. Any food that might have been contaminated with urine was soaked in water and filtrated and the filtrate was also added to the urine.

Statistics:

no data

Type:

absorption

Results:

Most (70-95%) of the ingested [35S]sulfite was absorbed from the intestine and voided in the urine within 24 hours.

Type:

excretion

Results:

Most of the remaining [35]S was eliminated in the faeces.

Type:

other:

Results:

Residual [35]S in the animal carcasses after 1 week accounted for 2% or less of the administered dose.

Details on absorption:

No further details are reported.

Details on distribution in tissues:

No further details are reported.

Details on excretion:

As might be expected from their faster metabolic rate, mice eliminated sulfite more quickly than did rats (see IUCLID section 7.1.1 k_Gibson_1973 (rats)). Both sexes appeared to behave identically in these experiments.

Metabolites identified:

no

Details on metabolites:

no data

Conclusions:

Sulfite is readily absorbed from the digestive tract of mice. The studies in mice showed that very little, if any, ingested SO2 is eliminated by exhalation.

Cross-reference 2

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

key study

Study period:

no data available

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Objective of study:

absorption

excretion

Qualifier:

no guideline followed

Principles of method if other than guideline:

The fate of ingested sulfite was investigated in monkeys using dose levels of 50 mg SO2/kg administered as NaHSO3 mixed with Na2[35]SO3.

GLP compliance:

no

Specific details on test material used for the study:

not specified

Radiolabelling:

yes

Remarks:

[35]SO3

Species:

monkey

Strain:

other: Rhesus

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Primate Research Center, Madison, Wisc.
- Weight at study initiation: approximately 6 kg
- Housing: Animals were housed in stainless-stell metabolism cages, which permitted separation of urine and faeces.
- Individual metabolism cages: yes
- Diet: ad libitum
- Water: ad libitum
No further details are given.

Route of administration:

oral: gavage

Vehicle:

other: glucose

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: 15 mL of a Na2[35]SO3-NaHSO3 solution (3.3 x 10^8 counts/minute) in 0.5% glucose.

DIET PREPARATION
no details

VEHICLE
no details

Duration and frequency of treatment / exposure:

5 days

Dose / conc.:

50 other: mg SO2/kg

No. of animals per sex per dose / concentration:

5 females and 1 male

Control animals:

no

Positive control reference chemical:

No positive control substance was tested.

Details on study design:

no data

Details on dosing and sampling:

Sulfite in aqueous solution was assayed either by colorimetric method based on pararosaniline, or by iodometric titration. A third method of sulfite analysis, using radioactive N-[1-[14C]]ethylmaleimide was used for urine samples.

Urine and faeces were colleceted at 24-hour intervals for 5 days and analysed for radioactivity. The collection funnel was rinsed with water after each daily collection and the rinsings were added to the urine samples. At the end of the experiment, each cage was washed thoroughly, the washings were separated into a solid and liquid fraction by filtration, and the solid and liquid fractions were tabulated respectively as part of the faeces and urine collected on day 5.

Statistics:

no data

Type:

absorption

Results:

Most (70-95%) of the ingested [35S]sulfite was absorbed from the intestine and voided in the urine within 24 hours.

Type:

excretion

Results:

All of the [35]S was eliminated from the body in 3 days. An efficient voidance of the dose via the urinary tract was demonstrated in the first 24 hours.

Type:

excretion

Results:

The greatest cumulative amount found in the faeces of the 6 monkeys was 6%, the remainder being recovered in the urine.

Details on absorption:

no data

Details on distribution in tissues:

no data

Details on excretion:

no data

Metabolites identified:

no

Details on metabolites:

no data

Data source

Reference

Reference Type:

publication

Title:

Metabolism and Elimination of Sulphite by rats, Mice and Monkeys

Author:

Gibson W.B.& Strong, F.M.

Year:

1973

Bibliographic source:

Fd Cosmet. Toxicol., 11: 185-198.

Materials and methods

Objective of study:

absorption

excretion

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The fate of ingested sulfite was investigated in rats using dose levels of 10 and 50 mg SO2/kg administered as NaHSO3 mixed with Na2[35]SO3.
Additional, it was tryed to define what level of ingested sulfite could be tolerated by rats before they would start to excrete unaltered sulfite in their urine.

GLP compliance:

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 sulfite

Test material form:

solid

Details on test material:

- Name of test material (as cited in study report): Sodium sulfite
- Molecular formula (if other than submission substance): Na2SO3
- Physical state: solid

Radiolabelling:

yes

Remarks:

[35]SO3

Test animals

Species:

rat

Strain:

other: albino

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Holtzman Co., Madison, Wisc.
- Weight at study initiation: 90-100 g
- Housing: Animals were housed in stainless-steel metabolism cages, with a screen attached to the cage bottom beneath the existing wire floor to facilitate separation of food, urine and faeces.
- Individual metabolism cages: yes
- Diet: e.g. ad libitum; Wayne Lab-Blox
- Water: ad libitum

No further details are given.

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: glucose

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: NaHSO3 was mixed with tracer amounts of Na2[35]SO3.

DIET PREPARATION
no details

VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: 0.5% glucose solution
- Amount of vehicle (if gavage): 5.0 mL

Duration and frequency of treatment / exposure:

24, 48 hours, 1 week and 2 weeks

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

10 other: mg SO2/kg

Doses / concentrations 2

Dose / conc.:

50 other: mg SO2/kg

Remarks:

giving 3.37 x 10^7 count/minute

No. of animals per sex per dose / concentration:

12 rats

Control animals:

no

Positive control reference chemical:

No positive control substance was tested.

Details on study design:

no data

Details on dosing and sampling:

Sulfite in aqueous solution was assayed either by colorimetric method based on pararosaniline, or by iodometric titration. A third method of sulfite analysis, using radioactive N-[1-[14C]]ethylmaleimide was used for urine samples.

Groups of 3 rats were killed at the end of 24 and 48 hours from the time of administration, during which period urine and faeces were collected, and the remaining two groups of three rats were killed 1 and 2 weeks after dosing. All animals were killed by a blow on the head and were frozen whole prior to the determination of the radioactivity remaining in the carcass.
For the determination of levels of activity in the urines and faeces, food was separated from the faeces manually and from urine by filtration. The cage floor, screen and funnel were washed with distilled water and the washings were added to the urine. Any food that might have been contaminated with urine was soaked in water and filtrated and the filtrate was also added to the urine.

Sulfite excretion in urine:
A) 100-g rats were fed daily for 5 days with 5 mL of either 0.5% glucose, 5 mg SO2 as NaHSO3 in 0.5% glucose, or 20 mg SO2 as NaHSO3 in 0.5% glucose. These doses (0, 50 and 200 mg/kg) were given each morning. A 10 µL sample of freshly voided urine was taken when each rat had consumed 90-100% of the dose. These samples, obtained on days 1, 2, 3 and 5 were treated with [14]C-NEM for sulfite analysis.
B) Groups of 6 rats were fed doses of NaHSO3 daily for 30 days at a level of 50 or 200 mg SO2/kg. On day 30, the rats were given their usual dose and from each dose group, as well as from a control group, 2 rats (male and female) that had finished at least 50% of their daily dose in 4 hours, were sampled for urinary sulfite content.
C) A short-term study was carried out in which 2 rats were each given by stomach tube a 400 mg SO2/kg dose of NaHSO3 in 0.5% glucose. Urine samples of 25 µL were obtained at 30 minutes and 1, 2 and 3 hours after dose administration and were assayed for sulfite.

Statistics:

no data

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Most (70-95%) of the ingested [35S]sulfite was absorbed from the intestine and voided in the urine within 24 hours.

Main ADME results 2

Type:

excretion

Results:

Most of the remaining [35]S was eliminated in the faeces.

Main ADME results 3

Type:

other:

Results:

Residual [35]S in the animal carcasses after 1 week accounted for 2% or less of the administered dose in all cases.

Main ADME results 4

Type:

other:

Results:

No free sulfite was detected in rat urine even after administration of a single oral dose as high as 400 mg/ SO2/kg.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Rats given a single dose of 50 mg SO2/kg: Three experiments of this type have given similar results, in that 70-80% of the dose appeared in the urine in 24 hour and the carcass contained on average about 15% after 24 hours, 6% after 48 hours, 2% after 1 week and 1% after 2 weeks. The overall recovery for each of the rats for which this was determined was 100 +/- 8%.

Details on distribution in tissues:

no further details

Details on excretion:

The experiments were carried out at a dose level of 10 as well as 50 mg/SO2/kg. A comparison of these results shows a similar rate of elimination at both dose levels.

Sulfite in urine: It was of interest to try to define what level of ingested sulfite could be tolerated by rats before they would start to excrete unaltered sulfite in their urine. No indication of any sulfite excretion was found in rats given up to 200 mg SO2/kg/day either for 5 or for 30 days. In the short term study carried out to investigate the possibility that in the previous experiments sulfit present in the urine could have been voided before sampling time, chromatography of urine samples taken 30 minutes to 3 hours after dosing revealed no detectable increases in sulfite excretion compared with samples taken before SO2 administration. Control reaction mixtures, to which excess sulfite was added at the end of the 3-hour study, indicated that if sulfite were indeed present, it would form the [14]C-NEM-SO3- product under these conditions.
Therefore it was concluded, that at no time during the course of these experiments the animals' ability to oxidise the administered sulfite was saturated.

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

no data

Applicant's summary and conclusion

Conclusions:

Sulfite is readily absorbed from the digestive tract of rats.The studies in rats showed that very little, if any, ingested SO2 is eliminated by exhalation.