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Toxicological information

Genetic toxicity: in vivo

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Administrative data

Endpoint:
in vivo mammalian germ cell study: cytogenicity / chromosome aberration
Remarks:
Type of genotoxicity: chromosome aberration
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Although the overall reporting quality fulfils the criteria for its use in the chemicals safety assessment, the method is of limited relevance (test guidance has been withdrawn and superseded by more up-to-date guidelines). Thus, the reference is considered reliable with restriction but only as supporting information in a weight of evidence assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1979
Report Date:
1979

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
In a dominant lethal assay, the induction of dominant lethal mutations in rat after sodium bisulfite administration was investigated. Male Sprague-Dawley rats (53 to 62 days old, bodyweight 247-339 g) were given sodium bisulfite in diet, ad libitum at doses of 45, 15 and 4.5 mg/kg/day over a period of 10 weeks. Animals in the positive control group received triethylenemelamine (TEM). After the 10-week treatment period, 40 male rats from the vehicle control group and 20 male rats from each treatment group were selected and mated with two adult virgin females for seven days. These females were replaced with two new females for an additional 7-day mating period. Each female was sacrificed 15-19 days after the first day of cohabitation.
GLP compliance:
not specified
Type of assay:
rodent dominant lethal assay

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: granular
Details on test material:
- Name of test material (as cited in study report): sodium bisulfite (76-72)(prepared by J.T. Baker Chemical Comany, Phillipsburg, New Jersey)
- Physical state: granular compound

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Simonsen Laboratories, Gilroy, California
- Age at start of treatment: 53 to 62 days old
- Weight at start of treatment: between 247 and 339 g
- Housing: housed in shoebox cages with hardwood chip bedding. Males were housed three per cage during the treatment phase.
- Diet (ad libitum)
- Water (ad libitum)

Administration / exposure

Route of administration:
oral: feed
Vehicle:
- Vehicle(s)/solvent(s) used: corn oil
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): ground laboratory chow (finely Purina rat diet supplemented with 50 mg thiamine per kg of finished diet)
The compound was added to a finely ground commercial diet. Concentrations of compound in the diet were adjusted weekly to achieve the dose levels.
Individual body weight and food consumption were used to to calculate the concentration of compound to be mixed into each kilogram of diet to achieve the desired dose levels.
The test compound was incorporated into a ground laboratory chow on a weight-to-weight basis. To ensure adequate distribution in the diet, the compound was initially suspended in corn oil. The compound-corn oil mixture was then added to the diet. The final concentration of corn oil was 3% in all diet levels.

- Storage temperature of food: excess was stored at 4°C to minimize compound loss
Duration of treatment / exposure:
10 weeks
Frequency of treatment:
ad libitum
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
4.5, 15, and 45 (maximum tolerated dose) mg/kg bw/day
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
4.43, 14.76, and 44.23 mg/kg/day (average actual)
Basis:
analytical conc.
No. of animals per sex per dose:
Treatment groups: 20 male rats
Positive control group: 20 male rats
Vehicle control group: 40 male rats
Control animals:
yes, concurrent vehicle
Positive control(s):
Triethylenemelamine (TEM)
- Route of administration: drinking water
- Doses / concentrations: approximately 0.04 mg/kg/day

The positive control group received the positive control substance, administered in the drinking water at a concentration of 0.60 mg/liter throughout the 10-week treatment period. Solutions were preapred fresh daily and the previous day's water was discarded. Based on the average rat weight of 369 g for the 10-week exposure period and an estimated intake of approximately 25 mL per rat per day, the average TEM dose was approximately 0.04 mg/kg/day.

Examinations

Tissues and cell types examined:
no data
Details of tissue and slide preparation:
CRITERIA FOR DOSE SELECTION:
Before initiating the dominant lethal study of sodium bisulfite (76-72), the specific dosage information was reviewed.

METHOD:
After the 10-week treatment period, 40 male rats from the vehicle control group and 20 male rats from each experimental level (including the positive reference control group) were selected and housed individually. Each male was then mated with two adult virgin females (age: 70- to 94- days; weight: between 240 and 300 g) for seven days. These females were replaced with two new females for an additional seven-day mating period. Following mating, females were housed four per cage to await necropsy. Each female was sacrificed by carbon dioxide asphyxiation 15 to 19 days after the first day of cohabitation.
At sacrifice , the following data were collected and reported: number of pregnant females per number of mated females, number of total implants per pregnant female, number of live and dead implants per pregnant female, number of corpora lutea per pregnant female, number of females with one or more dead implants, and number of females with two or more dead implants. Deaths were classified as early or late.
In addition to the uterine evaluation, females were examined for the presence of intercurrent infections; infected animals were excluded from the study.

The following parameters were examined for an indication of a dominant lethal effect: total implants (live foetuses plus early and late deaths), total dead implants (early and late foetal deaths), live implants (total implants minus dead implants), dead implants per total implants, and preimplanatation loss (calculated as the difference between total corpora lutea and total implants). Total corpora lutea were also recorded, since a significant increase (or decrease) in this measure influences the statistical significance of the preimplantation loss.
The data on the proportion of females with one or more dead implants and the proportion with two or more dead implants were evaluated.

OBSERVATIONS:
All animals were observed daily for activity, health, behaviour, food and water intake, and mortality. Individual body weights of males were recorded initially and then weekly throughout the 10-week treatment period. During this phase, food consumption was also measured weekly by cage.
Evaluation criteria:
no data
Statistics:
The t-test was applied to determine significant differences between the average number of live implantations per pregnant female at a dose level and the average for the control. A regression fit of the average number of live implantations was made for both the arithmetic and logarithmic dose to determine which was better. The data on dead implants per pregnant female were evvaluated by the t-test on Freeman-Tukey Square Root transformed data.

Results and discussion

Test results
Sex:
male
Genotoxicity:
negative
Toxicity:
no effects
Vehicle controls validity:
not specified
Negative controls validity:
not examined
Positive controls validity:
valid
Additional information on results:
The dose of 76-72 received over the 10-week treatment period was greater than 98% of the intended dose for all three levels.

RESULTS OF DEFINITIVE STUDY
- body weight: body weight gains were comparable for control and treated groups -- 104, 108, and 97% of controls for the low, mid, and high dose levels. respectively. The TEM group gained significantly less than the vehicle control group.
- food consumption: values were within normal limits, with low- and mid-dose test groups comparable to the control group. High-dose animals consumed slightly less food each week and gained slightly less weight.
- water consumption: water intake were generally normal (treated animals did not differ from the controls).
- activity, physiological and behavioural responses: generally normal (treated animals did not differ from the controls).
- mortality: one high dose male died after 9 weeks of treatment.
- no females were found to have any intercurrent infections.
- the biological criteria used to evaluate mutagenic effects in the rat showed no consistent responses that could be attributed to treatment.
- statistical evaluation: there were occasional statistical differences between control and sodium bisulfite-treated groups, but they were generally random and did not suggest a time or dose-response effect.
- the positive reference control (TEM group showed significant effects during both weeks of breeding.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative
The dominant lethal test produced no consistent responses to suggest that sodium bisulfite is mutagenic to rats.