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Carcinogenicity

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Description of key information

Feeding Study: Dose dependent inhibition of growth and food consumption in both sexes at 0.25 & 0.5% when administered in feed for 78-weeks. No significant differences in survival rates and mean survival times between dose groups, compared either to each other or to controls. Swelling of centrilobular hepatocytes, as observed in the subchronic toxicity study, was evident only in male mice at 0.5%. No significant differences in total tumor incidences were observed between groups of either sex. All “tumours were considered to be spontaneous because their incidences were essentially similar to those of spontaneous neoplastic lesions reported previously…” Compound administration “neither increased the incidences of such spontaneous tumours nor induced any unusual neoplasms.” The study authors concluded that under the conditions of this bioassay, the test compound “exerts no carcinogenic activity in B6C3F1mice.

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:
weight of evidence
Study period:
83 weeks total duration; 78 weeks active feeding of test substance.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No GLP statement. Insufficient details of experimental conduct/results. Not a Guideline study.
Principles of method if other than guideline:
Administration of test material in the daily diet over a range of concentrations for more than 80% of the expected lifetime of the test animals, combined with daily, weekly and end of life observations for clinical signs. at end of life, necropsy and microscopic evaluation of selected tissue.
GLP compliance:
not specified
Remarks:
Though no statement of GLP compliance is addressed in the published report, this study was conducted by the Division of Pathology of the Japanese National Institiute of Health Sciences with funding from the Grant-in-Aid for Safety Evaluation of Existing C
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
M/F B6C3F1 mice; Charles River ; 6wk at start of study. Maintained on basal diet (MF Oriental) & tap water, ad lib, up to start of study. Housed 10/plastic cage, with soft-wood chips as bedding. Room Temp. 23±2 C°, humidity 55±5%, 12hr light cycle.
Route of administration:
oral: feed
Details on exposure:
Test substance added to powdered basal diet (MF Oriental) at 0, 0.25, or 0.5%, available, along with water, ad lib, throughout the study. Feeding with test substance continued for 78 weeks. Test article administration was discontinued at 78 weeks, but surviving animals were maintained on basal diet through 83 weeks, at which point survivors were euthanized.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
78 weeks.
Frequency of treatment:
Daily. (though not explicitly stated, this would appear to have been 7 days per week.
Post exposure period:
5 weeks ("After 78 wk, the administration of BBTC was stopped and mice were then maintained on the powdered basal diet until wk 83 when all surviving animals were killed.")
Remarks:
Doses / Concentrations:
0, 0.25, or 0.5%
Basis:
nominal in diet
based on animal weight and food consumption data, the authors reported the following mean test substance intake: Males - 0, 187, and 373 g/kg body weight/78wk; Females - 0, 280, 576 g/kg body weight/78wk. Precisely how these figures were derived is not st
No. of animals per sex per dose:
50 males and 50 females (100 total per dose group).
Control animals:
yes, plain diet
Details on study design:
Mice divided randomly into three groups of 50 males and 50 females (100 total per dose group). Test substance added to powdered basal diet (MF) at 0, 0.25, or 0.5%, available, along with water, ad lib, throughout the study. Feeding with test substance continued for 78 weeks, with food intake monitoring to calculate actual intake of test article. Daily observations for clinical signs. Body wt monitored throughout study. Test article administration was discontinued at 78 weeks, but surviving animals were maintained on basal diet through 83 weeks, at which point survivors were euthanized. All mice were necropsied and ‘organs’ fixed in 10% formalin, sectioned, and stained with hematoxylin & eosin.
Positive control:
none
Observations and examinations performed and frequency:
Daily observations for clinical signs. Body wt monitored throughout study. All mice were necropsied and ‘organs’ fixed in 10% formalin, sectioned, and stained with hematoxylin & eosin.
Sacrifice and pathology:
All mice, those dying or sacrificed in extremis or that survived till week 83, were necropsied and ‘organs’ fixed in 10% formalin, sectioned, and stained with hematoxylin & eosin. no specific list of tissues examined is provided. however, see Table 2 (attached report) of tumors identified as a partial list of the breadth of histopathology.
Statistics:
Data were analysed for statistical significance by Fisher's exact probability test and the chi-square test.
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
Dose dependent inhibition of growth and food consumption in both sexes at 0.25 & 0.5%. No significant differences in survival rates and mean survival times between dose groups, compared either to each other or to controls. Swelling of centrilobular hepatocytes, as observed in the subchronic toxicity study, was evident only in male mice at 0.5%. No significant differences in total tumor incidences were observed between groups of either sex. All “tumours were considered to be spontaneous because their incidences were essentially similar to those of spontaneous neoplastic lesions reported previously…” Compound administration “neither increased the incidences of such spontaneous tumours nor induced any unusual neoplasms.” The study authors concluded that under the conditions of this bioassay, the test compound “exerts no carcinogenic activity in B6C3F1 mice.
Effect level:
> 0.5 other: percent in diet
Sex:
male/female
Basis for effect level:
other: No significant differences in total tumor incidences were observed between groups of either sex. The study authors concluded that under the conditions of this bioassay, the test compound “exerts no carcinogenic activity in B6C3F1 mice.
Remarks on result:
other: Effect type: carcinogenicity (migrated information)

Dose dependent inhibition of growth and food consumption in both sexes at 0.25 & 0.5%. No significant differences in survival rates and mean survival times between dose groups, compared either to each other or to controls. Swelling of centrilobular hepatocytes, as observed in the subchronic toxicity study, was evident only in male mice at 0.5%. No significant differences in total tumor incidences were observed between groups of either sex. All “tumours were considered to be spontaneous because their incidences were essentially similar to those of spontaneous neoplastic lesions reported previously…” Compound administration “neither increased the incidences of such spontaneous tumours nor induced any unusual neoplasms.” The study authors concluded that under the conditions of this bioassay, the test compound “exerts no carcinogenic activity in B6C3F1 mice.

Conclusions:
No significant differences in total tumor incidences were observed between groups of either sex. The study authors concluded that under the conditions of this bioassay, the test compound “exerts no carcinogenic activity in B6C3F1 mice.
Executive summary:

Dose dependent inhibition of growth and food consumption in both sexes at 0.25 & 0.5%. No significant differences in survival rates and mean survival times between dose groups, compared either to each other or to controls. Swelling of centrilobular hepatocytes, as observed in the subchronic toxicity study, was evident only in male mice at 0.5%. No significant differences in total tumor incidences were observed between groups of either sex. All “tumours were considered to be spontaneous because their incidences were essentially similar to those of spontaneous neoplastic lesions reported previously…” Compound administration “neither increased the incidences of such spontaneous tumours nor induced any unusual neoplasms.” The study authors concluded that under the conditions of this bioassay, the test compound “exerts no carcinogenic activity in B6C3F1mice.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
No GLP statement. Insufficient details of experimental conduct/results. Not a Guideline study. However, it confirms the lack of carcinogenic lesions in a 52-week repeat dose oral gavage rat study.

Additional information

Feeding Study: Dose dependent inhibition of growth and food consumption in both sexes at 0.25 & 0.5% when administered in feed for 78-weeks. No significant differences in survival rates and mean survival times between dose groups, compared either to each other or to controls. Swelling of centrilobular hepatocytes, as observed in the subchronic toxicity study, was evident only in male mice at 0.5%. No significant differences in total tumor incidences were observed between groups of either sex. All “tumours were considered to be spontaneous because their incidences were essentially similar to those of spontaneous neoplastic lesions reported previously…” Compound administration “neither increased the incidences of such spontaneous tumours nor induced any unusual neoplasms.” The study authors concluded that under the conditions of this bioassay, the test compound “exerts no carcinogenic activity in B6C3F1mice.

Justification for selection of carcinogenicity via oral route endpoint:

Only available carcinogenicity study.  

Justification for classification or non-classification

In a 78-week feeding study at 0.25 and 0.5% in feed, no significant differences in total tumor incidences were observed between groups of either sex.All “tumours were considered to be spontaneous because their incidences were essentially similar to those of spontaneous neoplastic lesions reported previously…”Compound administration “neither increased the incidences of such spontaneous tumours nor induced any unusual neoplasms.” The study authors concluded that under the conditions of this bioassay, the test compound “exerts no carcinogenic activity in B6C3F1mice.