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Description of key information

The carcinogenicity in the rat was determined (no guideline followed) in a 24 month feeding study. No test material related tumor induction was observed and a NOAEL was set at 200 mg/kg body weight (nominal in diet, only concentration tested) in rats.

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:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose for cross-reference:
reference to same study
Qualifier:
no guideline followed
Principles of method if other than guideline:
Carcinogenicity was examined in Wistar rats over 24 months. Limitations: TS purity and composition not specified, limited documentation, only one dose group, only 20 animals per sex; examinations limited to body weight, mortality, haematology, gross pathology and histopathology (non-neoplastic & neoplastic).
GLP compliance:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: own bred
- Diet: artificial Laccassagne MAB 1 diet; ad libitum

ENVIRONMENTAL CONDITIONS
The animals held in well acclimatised and aerated room.

No additional details provided.
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Remarks:
in diet
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): not specified
- Mixing appropriate amounts with (Type of food): test substance was mixed with normal feed at 2 g TS per kg feed.
- Storage temperature of food: not specified.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
24 months
Frequency of treatment:
Continuously in diet.

OTHER: after 3 months on treatment, 1 male was mated with 5 females and further examined for reprotoxicity.
Post exposure period:
None.
Dose / conc.:
200 mg/kg bw/day (nominal)
Remarks:
the nominal concentration of TS in diet was selected based on presumed food consumtion to achieve as final daily dose of 200 mg/kg bw
No. of animals per sex per dose:
20
Control animals:
yes, plain diet
yes, historical
Details on study design:
No additional details provided.
Positive control:
None.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes; for mortality
- Time schedule: not specified

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: at necropsy for all animals.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination
No further details provided

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes at death or sacrifice; survival animals were sacrificed after 24 months treatment.
HISTOPATHOLOGY: Yes, a complete histology of all relevant organs was conducted for all animals at sacrifice or at spontaneous death.
Other examinations:
None
Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
7 male and 1 female animals died during the treatment period.
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
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
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
At necropsy, mean liver weights of 14.3±2.1 g (12-19) and 12.9±2.5 g (10-22) were measured respectively for male and female animals, and were in the range of the negative control animals (10.5-22 g for both male and female animals)
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
At necropsy, mean body weights of 267.5±71.5 g (250-520) and 276.5±42.2 g (210-260) were measured respectively for male and female animals, and were in the range of the negative control animals (260-430 and 230-300 g respectively).
All pathological observations were equally distributed between control and treated animals, and in the range of the historical control values.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
A total of 3 malignant tumours (tumour rate: 7.5%) were found in the treatment group:
- 3 intestinal tumours were observed: a fusocellular Sarcoma in the caecum in one animal, an atypical intestinal epithlioma in one animal, and a differentiated intestinal reticulosarcoma (caecum) in one animal.
- One breast cancer (benign adenofibroma) was observed in one animal.
- One benign lymph node lymphocytoma of one animal.

A total of 8 malignant tumours (tumour rate: 4,87%) were found in the control group:
- One pulmonary edenocarcinoma,
- One abdominal reticulosarcoma,
- 2 parietal abdominal fuso-cellular sarcoma,
- 4 abdominal fibrosarcoma
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No test substance related adverse effects were observed.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
chronic
Species:
rat

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data was used for the purpose of classification under Regulation (EC) No.1272/2008. Based on the data, classification for carcinogenicity is not warranted.

Additional information

The carcinogenicity of the test substance was determined in rats. 20 Wistar rats per sex and dose group were fed with food containing the test compound in a dose of 200 mg/kg body weight (target dose; the nominal concentration of the test substance in the diet was selected based on presumed food consumption). The control animals were fed plain diets. During exposure the rats were observed for mortalities. Body weight, haematology, organ weights, gross pathology and histopathology were examined at the end of the study. 7 males and 1 female died during the treatment period. At necropsy, mean body weights of 267.5 ± 71.5 g (250-520) and 276.5 ± 42.2 g (210-260) were measured respectively for male and female animals, and were in the range of the negative control animals (260-430 and 230-300 g respectively). Mean liver weights of 14.3 ± 2.1 g (12-19) and 12.9 ± 2.5 g (10-22) were measured respectively for male and female animals, and were in the range of the negative control animals (10.5-22 g for both male and female animals). All pathological observations were equally distributed between control and treated animals, and in the range of the historical control values. A total of 3 malignant tumours (tumour rate: 7.5%) were found in the treatment group: 3 intestinal tumours (a fusocellular sarcoma in the caecum in one animal, an atypical intestinal epithlioma in one animal, and a differentiated intestinal reticulosarcoma (caecum) in one animal), one breast cancer (benign adenofibroma) was observed in one animal, and one benign lymph node lymphocytoma of one animal. In control animals a total of 8 malignant tumours (tumour rate: 4,87%) were found: One pulmonary edenocarcinoma, one abdominal reticulosarcoma, 2 parietal abdominal fuso-cellular sarcoma, and 4 abdominal fibrosarcoma. All induced tumours were common sarcoma to the rat strain used, in the range of the historical and negative control, and therefore not related to the treatment. Based on these findings, a NOAEL was set at 200 mg/kg body weight in rats, which was the only concentration tested in this study.

The findings are supported by the results from a BALB/3T3 assay (for reference see chapter 7.6.1), which determined morphological changes due to transformation in mammalian cells in vitro. No test material induced cell transformation was detected under the experimental conditions chosen.