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Toxicological information

Carcinogenicity

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Description of key information

1) A carcinogenicity study (Sodemoto, 1979) is available which is key study. This study showed that the test substance was not carcinogenic.

2) A tumorigenicity study (Toth, 1984) is available which is supporting study. It is concluded that the test substance was not carcinogenic.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
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.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Study predates approved guidelines.
The carcinogenicity 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
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Provided by Japan CLEA Co. Ltd.
- Age at study initiation: 4-5 weeks old
- Weight at study initiation: 110-150 g
- Fasting period before study:
- Housing: Five in each cage
- Diet (e.g. ad libitum): CE-2 pellets
- Water (e.g. ad libitum): tap water
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-23℃
- Humidity (%): 55%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):

IN-LIFE DATES: From: To:
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
18-24 months
Frequency of treatment:
Daily
Post exposure period:
Immediately
Remarks:
Doses / Concentrations:
1 or 2%
Basis:
nominal in diet
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.
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
Statistics:
T-test
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):
no effects observed
Food efficiency:
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
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:
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.

Histopathology:
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.
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No findings of toxicological significance at 1000 mg/kg bw/day.
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Conclusions:
From the results of this study, it may be concluded that the test substance was not carcinogenic for male and female Fischer 344 rats after 18 to 24-month dietary exposure.
The reliability of this study should be defined as 2 (reliable with restrictions) due to minimal data on study design and results and no GLP.
Executive summary:

The carcinogenicity 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.

The reliability of this study should be defined as 2 (reliable with restrictions) due to minimal data on study design and results and no GLP.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
2 (reliable with restrictions)

Additional information

1) A carcinogenicity study was conducted using rats exposed via diet (Sodemoto, 1979). Key study.

This study showed that the test substance was not carcinogenic, and resulted a NOAEL value of >1000 mg/kg bw/day (2% in food).

2) A tumorigenicity study was conducted using mice exposed via drinking water (Toth, 1984). Supporting study.

It is concluded that the test substance was not carcinogenic, and resulted a NOAEL value of >4000 mg/kg bw/day. This study should be a supporting study due to the test substance was administered as a 2% solution in drinking water.

Justification for selection of carcinogenicity via oral route endpoint:

This study was conducted according to a reliable method using Fischer 344 rats. The test substance was administered in the diet for 18 to 24 months at two dose levels.

Justification for classification or non-classification

The test substance was not carcinogenic to rats and mice at doses of 1000 mg/kg bw and above.

Therefore in accordance with Regulation (EC) No. 1272/2008 Tables 3.6.1 the substance is not classified for carcinogenesis.