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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Limited study summary. Study predates approved guidelines, minimal data provided on study design and results, no GLP.

Data source

Reference Type:
Report of carcinogenesis bioassay of sodium benzoate in rats: absence of carcinogenicity of sodium benzoate in rats
Sodemoto Yukio, Enomoto Makoto
Bibliographic source:
Journal of Environmental Pathology and Toxicology, 4: 87 - 95.
Report date:

Materials and methods

Test guideline
no guideline followed
Principles of method if other than guideline:
Study predates approved guidelines.
The chronic toxicity study of the test substance was examined in Fischer 344 rats. The test substance was administered in the diet for 18 to 24 months at two dose levels.
GLP compliance:
not specified
Limit test:

Test material

Constituent 1
Reference substance name:
Sodium benzoate
EC Number:
EC Name:
Sodium benzoate
Cas Number:
sodium benzoate
Test material form:
not specified
Details on test material:
not specified

Test animals

Fischer 344
Details on test animals or test system and environmental conditions:
- Source: Provided by Japan CLEA Co. Ltd.
- Age at study initiation: 4-5 weeks old
- Weight at study initiation: 110-150 g
- Housing: Five in each cage
- Diet (ad libitum): CE-2 pellets
- Water (ad libitum): tap water

- Temperature (°C): 22-23 °C

Administration / exposure

Route of administration:
oral: feed
unchanged (no vehicle)
Details on oral exposure:
None stated
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
18-24 months
Frequency of treatment:
Doses / concentrationsopen allclose all
Dose / conc.:
1 other: % (nominal in diet)
equivalent to 10000 mg/kg food or 500 mg/kg bw/day
Dose / conc.:
2 other: % (nominal in diet)
equivalent to 20000 mg/kg food or 1000 mg/kg bw/day
No. of animals per sex per dose:
Test group: 50 males and 52 females per dose
Control group: 25 males and 43 females
Control animals:
yes, plain diet
Details on study design:
Both male and female rats were divided into three groups and maintained on the diet containing 2 or 1% of the test substance or basal diet for 18 to 24 months. The animals were maintained on a free choice diet, but amount of diet was adequately controlled to avoid excess. Tap water was freely offered to all animals. The rats were weighed weekly, and food intake was measured daily.
Positive control:
None stated


Observations and examinations performed and frequency:
Mortality, growth, food intake, behavior and general status were observed in the experimental period.
Sacrifice and pathology:
In the middle of the experimental period, several animals from each groups selected at random were sacrificed for morphologic examination. All surviving animals were killed between 18 to 25 months. For morphologic examination, autopsy was carried out in all animals and paraffin sections of various organs were prepared and stained (hematoxylin and eosin).
Other examinations:
None stated

Results and discussion

Results of examinations

Clinical signs:
no effects observed
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified
Details on results:
Clinical signs and mortality:
During the first 16 months of the experimental period, the average mortality rate of all animals was 14.5%. Except for myeloproliferative disorder developed in one female control rat, all the dead animals showed pneumonia with abscess. Around 100 rats including those of the control groups died after 16 months of hemorrhagic pneumonia with edema which was probably induced by mixed infection of sialodacryoadenitis and mycoplasma. However, no differences in mortality rates between treated and control groups were observed throughout the experimental course.

Body weight gain and food intake:
Nor were there any significant differences in growth and food intake between groups of rats.

Most developed tumours were benign, such as interstitial cell tumour of the testes and endometrial polyp of the uterus. However, a small number of malignant neoplasms including leukemia was also observed. Differences in numbers of tumor-bearing animals and time-to-tumor development between control and treated gorups were not significant (t-test). No specific toxic effect induced by the test substance was observed.

Effect levels

Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

From the results of this study, it may be concluded that the test substance was not toxic for male and female Fischer 344 rats after 18 to 24-month dietary exposure.
Executive summary:

The chronic toxicity study of the test substance was examined in Fischer 344 rats. The test substance was administered in the diet for 18 to 24 months at two dose levels.

No adverse clinical signs directly attributable to the compound were observed in treated animals. Differences in the average body weight, and mortality rates between treated and control groups were negligible. The results of the statistical test for dose-related trends were significant (p<0.05). Although a variety of tumors occurred among test and control rats of each sex, tumors appearing in treated rats were similar in type and number to those in controls. It was concluded that no evidence of carcinogenicity in rats from the test substance was demonstrated.