Potassium thiosulphate

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

repeated dose toxicity: inhalation

Remarks:

combined repeated dose and carcinogenicity

Type of information:

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

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well-documented paper primarily directed to study the effect of SO2 on the induction of squamous cell carcinoma (SQCA) by inhaled benzo(a)pyrene.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

The effect of inhaled sulfur dioxide and systemic sulfite on the induction of lung carcinoma in rats by benzo[a]pyrene.

Author:

Gunnison, A.F.; et al.

Year:

1988

Bibliographic source:

Environ. Res. 46, 59-73

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Male Sprague-Dawley CD rats were exposed in chambers to nominal concentrations of 0, 10 or 30 ppm SO2 for 6 hr per day, 5 days per weeks for 21 weeks. Thereafter, the rats were observed for the development of tumours in the respiratory tract for 737 days.
Systemic exposure to sulphite/bisulphite was accomplished by inducing sulphite oxidase deficiency by means of high tungsten to molybdenum ratio in the diet. Sulphite oxidase deficiency results in an accumulation of endogenously generated sulphite.
Complete necropsy was performed on all animals with particular attention given to the respiratory tract.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Sulphur dioxide

EC Number:

231-195-2

EC Name:

Sulphur dioxide

Cas Number:

7446-09-5

Molecular formula:

SO2

Details on test material:

- Name of test material (as cited in study report): sulfur dioxide
- Molecular formula (if other than submission substance): SO2
- Molecular weight (if other than submission substance): 64.07 g/mol
- Physical state: colourless gas
No further information given.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Wilmington, MA facility
- Age at study initiation: 9 weeks
- Housing: housed in wire cages suspended in racks
- Diet: Ourina Laboratory Chow, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 3 weeks

ENVIRONMENTAL CONDITIONS
- Humidity (%): 61 +/- 10 %
- Air changes (per hr): 5 air changes /min

Administration / exposure

Route of administration:

inhalation: gas

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

MMAD / GSD: not applicable

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Animals were exposed to SO2 in stainless-steel/plexiglass dynamic chambers.
- Air change rate: 5 air changes/min.
- Air supply passed through a high efficiency particulate filter capable of removing particles of 0.3 µm in diameter.

Detailed method description in "Gunnison, A.F.; et al. (1987): The distribution, metabolism and toxicity of inhaled sulfur dioxide and endogenously-generated sulfite in the respiratory tract of normal and sulfite oxidase-deficientrats. J. Toxicol. Environ. Health 21, 141-162."

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

- Actual chamber concentrations were determined by a rapid iodine titration method.
- Concentrations of SO2 were 10.0 +/- 0.4 and 29.6 +/- 0.6 ppm; daily standard variations average approximately 11 % of the mean concentration.

Duration of treatment / exposure:

21 weeks (101 exposure days)

Frequency of treatment:

6 hr per day, 5 days per weeks

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
10 ppm SO2
Basis:
nominal conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
30 ppm SO2
Basis:
nominal conc.

No. of animals per sex per dose:

- 20 animals per group (exposure groups)
- 46 colony control animals (exposure to room air)

Control animals:

yes, concurrent no treatment

Details on study design:

Rationale for animal assignment: randomly

Positive control:

no data

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: weekly or biweekly during the experimental period and monthly later

FOOD CONSUMPTION: No data

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

SACRIFICE
- Animals were allowed to die naturally or were sacrificed if moribund until 737 days.
- All remaining animals were sacrificed after 737 days.

GROSS PATHOLOGY: Yes
- Complete necropsy was performed on all animals with particular attention given to the respiratory tract.

HISTOPATHOLOGY: Yes
- All organs were fixed in 10 % neutral buffered formalin.
- Histologic sections were prepared from each lobe of the lung, the trachea, larynx, and other organs where gross pathology was present.

Other examinations:

- In the systemic erxposure series, systemic exposure was acomplished by inducing sulfite oxidase deficiency, thus allowing endogenously generated sulfite to accumulate to concentrations that were greatly elevated compared to "normal" rats.
- The level of sulfite exposure was controlled by regulation of the degree of sulfite oxidase deficiency. Enzyme deficiency was induced by maintaining high tungsten (W) to molybdenum (Mo) ratio in rats' diet.
- Detailed method description in "Gunnison, A.F.; et al. (1987): The distribution, metabolism and toxicity of inhaled sulfur dioxide and endogenously-generated sulfite in the respiratory tract of normal and sulfite oxidase-deficient rats. J. Toxicol. Environ. Health 21, 141-162."

Statistics:

no data

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
- Survival was not altered by SO2 inhalation.

BODY WEIGHT AND WEIGHT GAIN
- Exposure of rats to 10 or 30 ppm SO2 did not affect the body weight gain.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
- Exposure to SO2 did not result in tumour formation in the lung (squamous cell carcinoma, mixed carcinoma, adenocarcinoma, papilloma, adenoma, or fibrosarcoma).
- A statistically insignificant increase in the incidence of mammary tumours (fibroadenoma and adenocarcinoma) was observed in the sulphite oxidase-deficient rats.

Effect levels

Dose descriptor:

NOAEC

Remarks on result:

not determinable

Remarks:

no NOAEC identified

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

No NOAEC could be derived from the study. No significant adverse effects have been reported from SO2 exposure.