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Basic toxicokinetics

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basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
no data available
Reason / purpose:
reference to same study

Data source

Reference Type:
Metabolism and Elimination of Sulphite by rats, Mice and Monkeys
Gibson W.B.; Strong, F.M.
Bibliographic source:
Fd Cosmet. Toxicol., 11, 185-198.

Materials and methods

Objective of study:
Test guideline
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:

Test material

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
No further details are given.

Test animals

other: albino
not specified
Details on test animals and environmental conditions:
- 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
other: glucose
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: NaHSO3 was mixed with tracer amounts of Na2[35]SO3.

no details

- 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:
10 mg SO2/kg
50 mg SO2/kg (giving 3.37 x 10^7 count/minute)
No. of animals per sex per dose:
12 rats
Control animals:
Positive control:
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.
no data

Results and discussion

Main ADME resultsopen allclose all
Most (70-95%) of the ingested [35S]sulfite was absorbed from the intestine and voided in the urine within 24 hours.
Most of the remaining [35]S was eliminated in the faeces.
Residual [35]S in the animal carcasses after 1 week accounted for 2% or less of the administered dose in all cases.
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:
Details on metabolites:
no data

Applicant's summary and conclusion

Interpretation of results (migrated information): other:
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.