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EC number: 214-787-5 | CAS number: 1194-65-6
Carcinogenicity
Administrative data
Description of key information
The test material was determined to have no carcinogenic effects according to rat and hamster studies performed in line with EPA Guideline 83-2. The test material was determined to show evidence of tumourigenic potential that was considered to be based on toxicologically significant non-neoplastic hepatic changes rather than any effect of the test material in a further study performed in line with EPA Guideline 83-2.
In addition, two in vitro cell transformation screens performed using BALB/c-3T3 cells (performed to a method similar to the cell transformation assay validated by ECVAM) demonstrated that the test material was inactive in the transformation assay.
Key value for chemical safety assessment
Carcinogenicity: via oral route
Link to relevant study records
- Endpoint:
- carcinogenicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 11 April 1980 to 30 November 1983
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Reason / purpose for cross-reference:
- reference to other study
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 83-2 (Carcinogenicity)
- Deviations:
- not specified
- GLP compliance:
- yes
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: five weeks old
- Weight at study initiation: 82-102 g (male); 74-92 g (female)
- Housing: individual feeding cages
- Diet: ad libitum
- Water: city water ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature: 23 ± 1 °C
- Humidity: 55 ± 5 %
- Air changes: 20 times per hour
- Photoperiod: 12 hours light; 12 hours dark - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 110 weeks (10 animals of each sex sacrificed from each group at weeks 52 and 78).
- Frequency of treatment:
- Daily
- Dose / conc.:
- 50 ppm (nominal)
- Dose / conc.:
- 400 ppm (nominal)
- Dose / conc.:
- 3 200 ppm (nominal)
- No. of animals per sex per dose:
- Seventy
- Control animals:
- yes, plain diet
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (at scheduled sacrifice and sacrifice of moribund animals).
- Organ weight was measured at weeks 52, 78 and 110 for brain, heart, lungs, liver, kidneys, adrenals, spleen, testes, ovaries, thyroid, thymus and pituitary. Ratio of organ weight to body weight was calculated.
HISTOPATHOLOGY: Yes
- for organs detailed under Gross Pathology and spinal cord, eyes, salivary gland, lungs, trachea, oesophagus, stomach, large and small intestine, pancreas, prostate, uterus and cervical canal, lymph nodes, femur, femoralis muscle, skin, sciatic nerve and mammary gland. - Statistics:
- Incidence of tumours was analysed by Peto's analysis method.
- Relevance of carcinogenic effects / potential:
- The test material has no obvious carcinogenic effect.
- Key result
- Dose descriptor:
- other: NOEL
- Effect level:
- 50 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Toxicity. 50 ppm is equal to 3.18 mg/kg bw/day for males and 3.16 mg/kg bw/day for females
- Conclusions:
- Under the conditions of the test, there was no effect upon the total tumours observed, a negative trend being apparent in 21/40 tumour types tested. The test material has no obvious carcinogenic effect. A slight excess of tumours occurred only at the notably toxic 3200 ppm dose level.
- Executive summary:
In a GLP compliant study conducted in line with standardised guideline EPA OPP 83-2 (as part of a combined chronic toxicity/carcinogenicity study), the effects of the carcinogenicity of the test material over 52, 78 and 110 weeks was determined in the rat.
Rats were administered the test material by oral (diet) at 0, 50, 400 and 3200 ppm. There was no effect upon the total tumours observed, a negative trend being apparent in 21/40 tumour types tested. The test material has no obvious carcinogenic effect. A slight excess of tumours occurred only at the notably toxic 3200 ppm dose level.
The NOEL for chronic toxicity was determined to be 50 ppm (3.18 mg/kg bw/day for males; 3.16 mg/kg bw/day for females).
- Endpoint:
- carcinogenicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 01 December 1987 to 27 October 1991
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 83-2 (Carcinogenicity)
- Deviations:
- yes
- Remarks:
- (at necropsy stage, two group 3 males were found to be transposed. It was not certain at which time point transposition occurred. As both animals are from the same group, all group mean and incidence data remain unaltered)
- Qualifier:
- according to guideline
- Guideline:
- other: OECD 'Short Term and Long Term Toxicology Group Guidelines' published in the Chemical Regulations Reporter, 14th August 1981
- Deviations:
- not specified
- Qualifier:
- according to guideline
- Guideline:
- other: Requirements for safety evaluation of agricultural chemicals published in 59 Nohsan No. 4200, Ministry of Agriculture, Forestry and Fisheries dated 28th January 1985
- Deviations:
- not specified
- GLP compliance:
- yes
- Species:
- hamster, Syrian
- Strain:
- other: Bio F1D Alexander
- Sex:
- male/female
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 88 weeks (males); 80 weeks (females)
- Frequency of treatment:
- Daily
- Dose / conc.:
- 5 ppm
- Dose / conc.:
- 26 ppm
- Dose / conc.:
- 132 ppm
- Dose / conc.:
- 675 ppm
- No. of animals per sex per dose:
- 100 controls (male and female) and 132 and 675 ppm for males; 50 for all other test groups
- Control animals:
- yes, plain diet
- Description (incidence and severity):
- No apparent clinical signs of a reaction to treatment were noted. There were no apparent treatment-related ante-mortem clinical signs.
- Description (incidence):
- In both sexes, the administration of test material was not considered to have affected the distribution or rate of mortalities.
- Description (incidence and severity):
- During the period of maximal growth (weeks 0 to 6) males receiving 675 mg/kg diet showed slightly lower than control body weight gain. Subsequently, during the body weight decline/plateau phase after week 8, animals receiving 675 mg/kg diet showed a higher rate of mean body weight loss, when compared with the controls; females receiving 132 mg/kg diet were similarly affected, but the difference did not achieve statistical significance. Additionally, the overall body weight change (weeks 0 to 88) of males receiving 675 mg/kg diet was lower than control (see Table 2).
- Description (incidence and severity):
- During the first 6 weeks of treatment lower food consumption values were obtained for males receiving 675 mg/kg diet. Subsequently, the values obtained for this group were comparable with the controls. The food consumption values of the remaining treated groups were considered to be unaffected by treatment (see Table 3). The overall (weeks 1 to 8) food utilisation efficiency was considered to be unaffected by treatment. The achieved intakes followed the expected pattern for a fixed dietary level study.
- Description (incidence and severity):
- Examination of the blood smears for differential white cell counts did not reveal any treatment-related effects.
- Description (incidence and severity):
- Analysis of organ weights obtained from females killed after 80 weeks revealed slightly higher than control liver weights in the high dose females. In males killed after completion of 88 weeks of treatment, there were no statistical differences from the control (see Table 4).
- Description (incidence and severity):
- Macroscopic pathology of animals killed or dying during the treatment period, or killed at termination, revealed pitting of the liver of terminal females receiving 675 mg/kg diet. A reduction of adipose tissue was also noted in the decedent males. In addition, the following findings were also noted in the high dose group, but were unassociated with notable microscopic pathological change: uniform cortical scarring in the kidneys of the terminal females and pallor of the kidneys and small testes in the terminal males.
- Description (incidence and severity):
- Examination of animals killed or dying during the treatment period, or killed at termination, revealed notable non-neoplastic findings in females only (see Table 6):
• Liver: the number of animals involved is small and the toxicological importance of this finding is unclear.
• Adrenals: the toxicological importance of this finding is unclear. - Description (incidence and severity):
- Microscopic pathology revealed that there was no evidence of tumourigenic potential in this study (see Table 5).
- Relevance of carcinogenic effects / potential:
- There was no evidence of tumorigenic potential at the dose levels used in this study.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 132 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- gross pathology
- other: Lower bodyweight and feed consumption in high dose males, with a reduction in adipose tissue of decedent males. Pitted liver and centrilobular hepatocyte enlargement and cortical hyperplasia in the adrenals of high dose females.
- Conclusions:
- Under the conditions of the study, there was no evidence of tumourigenic potential of the test material. Treatment related changes were primarily confined to the high dose level. In the high dose males these changes included initial impairment of body weight gain together with associated lower food consumption, and lower overall body weight change together with the macroscopic pathological finding of a reduction in the adipose tissue in the male decedents. Although there were no pathological findings of clear toxicological importance, the changes in the liver (slightly higher weights, pitted liver, and centrilobular hepatocyte enlargement) and adrenals (cortical hyperplasia) of the high dose females are of note. The NO(A)EL for toxicity has been determined to be 132 mg/kg diet.
- Executive summary:
In a GLP compliant study conducted in line with standardised guideline EPA OPP 83-2, the carcinogenicity of the test material over 80 weeks (females) and 88 weeks (males) was determined in the hamster.
Hamsters were administered the test material orally (via diet) at 0, 5, 26, 132 and 675 ppm. There was no evidence of tumourigenic potential of the test material. Treatment related changes were primarily confined to the high dose level; in males these changes included initial impairment of body weight gain together with associated lower food consumption, and lower overall body weight change together with the macroscopic pathological finding of a reduction in the adipose tissue in the male decedents. Although there were no pathological findings of clear toxicological importance, the changes in the liver (slightly higher weights, pitted liver, and centrilobular hepatocyte enlargement) and adrenals (cortical hyperplasia) of the high dose females are of note.
The NO(A)EL (for toxicity) has been determined to be 132 mg/kg diet.
- Endpoint:
- carcinogenicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 17 February 1989 to 10 February 1992
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 83-2 (Carcinogenicity)
- Deviations:
- yes
- Remarks:
- (during week 23, a female in group 2 was found to be pregnant and in the cage of a male from group 3. The male was re-housed and food and body weight data for weeks 18-22 excluded. The female was sacrificed and all data from week 18 onwards excluded).
- Qualifier:
- according to guideline
- Guideline:
- other: OECD 'Short Term and Long Term Toxicology Group Guidelines' published in the Chemical Regulations Reporter, 14th August 1981
- Deviations:
- not specified
- Qualifier:
- according to guideline
- Guideline:
- other: Requirements for safety evaluation of agricultural chemicals published in 59 Nohsan No. 4200, Ministry of Agriculture, Forestry and Fisheries dated 28th January 1985
- Deviations:
- not specified
- GLP compliance:
- yes
- Species:
- hamster, Syrian
- Strain:
- other: Bio F1D Alexander
- Sex:
- male/female
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 91 weeks (males); 78 weeks (females)
Termination was initiated when mortality in the respective control group attained 50 % - Frequency of treatment:
- Daily
- Dose / conc.:
- 675 mg/kg diet
- Dose / conc.:
- 1 500 mg/kg diet
- Dose / conc.:
- 3 375 mg/kg diet
- No. of animals per sex per dose:
- 100 (controls); 50 (all treatment groups)
- Control animals:
- yes, plain diet
- Description (incidence and severity):
- There were no clinical signs of a reaction considered attributable to treatment throughout the treatment period. There were no apparent treatment-related ante-mortem clinical signs.
- Description (incidence):
- The administration of the test material was not considered to have affected the distribution or incidence of mortalities in the males. The females of the highest dose group showed a lower mortality than the other groups, possibly as a consequence of their reduced food intake (see Table 1).
- Description (incidence and severity):
- During the first two weeks of treatment, group mean body weight loss occurred amongst animals receiving 3375 mg/kg diet and males receiving 1500 mg/kg diet, whilst lower weight gain was recorded for all other treatment animals when compared to controls. Lower weight gain persisted up to week 18 for females receiving 3375 mg/kg diet. Subsequent to these initial effects group mean body weight changes were essentially comparable with controls although parity with controls was not regained at any treatment level (see Table 2).
- Description (incidence and severity):
- Cumulative group mean food intake was slightly but consistently lower than controls for all treated males, although not dose-related in degree, and for females receiving 3375 mg/kg diet throughout the treatment period. Food consumption was also reduced during the first two weeks of treatment for females receiving 1500 mg/kg diet; thereafter being comparable with controls. Food intake of females receiving 675 mg/kg diet was considered to be unaffected by treatment (see Table 3). The efficiency for food utilisation (weeks 1-18) was innpaired for all treated groups during the first two weeks of treatment. During weeks 3 to 18 food utilisation was marginally improved for males receiving 3375 mg/kg diet, but remained impaired for females receiving 3375 mg/kg diet, whilst values for animals receiving 675 or 1500 mg/kg diet were comparable with concurrent controls. The mean achieved intakes over the treatment period were 51, 117 and 277 mg/kg bw/day for males and 55, 121 and 277 mg/kg bw/day for females with both sexes receiving 675, 1500 and 3375 mg/kg diet.
- Description (incidence and severity):
- Examination of the blood smears for differential white cell counts did not reveal any treatment-related effects.
- Description (incidence and severity):
- There was a dose-related increase in liver weight for all treated groups; attaining statistical significance (when adjusted for body weight) in all treated female groups and for males at 1500 and 3375 mg/kg diet, when compared with controls. Slightly lower than control testes plus epididymides weights were noted for all treated male groups; attaining statistical significance (when adjusted for body weight) in males at 1500 and 3375 mg/kg diet. A dose-related decrease in heart weights was also noted in all treated groups. However, in the absence of corroborative macropathological significance or micropathological changes these differences were considered attributable to the inter-group differences in body weight. (see Table 4).
- Description (incidence and severity):
- Macroscopic pathology revealed enlargement of the liver in both sexes receiving 3375 mg/kg diet, together with a slightly increased incidence of liver masses in males receiving the same dose. A slight increase in the incidence of pale areas on the liver together with a reduction in adipose tissue was also noted in all treated male groups. In addition, increased incidences of the following findings were noted in the high dose male group when compared with controls, but were unassociated with any notable microscopic pathological change: decreased size and pallor of the spleen, urinary bladder distension and protrusion of the penis.
- Description (incidence and severity):
- Non-neoplastic findings considered to be of toxicological relevance were recorded for all treatment levels, and all confinded to the liver (see Table 7).
- Description (incidence and severity):
- Neoplastic findings during microscopic pathology revealed that treatment resulted in an increased incidence of benign liver cell tumours in males receiving 1500 or 3375 mg/kg diet (see Tables 5 and 6).
No liver cell tumours were reported in females. - Description (incidence and severity):
- Several other incidental and spontaneous pathological findings were reported in control and treated animals of both sexes, however were considered to be of no toxicological significance.
No treatment related findings were seen among the factors contributory of death reported in decedent males and females. - Relevance of carcinogenic effects / potential:
- Dietary administration of the test material at 675, 1500 and 3375 mg/kg diet for 78 weeks in females and 91 weeks in males resulted in evidence of tumourigenicity amongst males receiving 3375 mg/kg diet manifest as increased incidence of benign liver tumours. A single malignant tumour was also recorded for males at this treatment level, whilst a single benign liver tumour was also recorded amongst males receiving 1500 mg/kg diet. It was considered that the occurrence of tumours amongst males receiving 1500 or 3375 mg/kg diet resulted from the spectrum of toxicologically significant non-neoplastic hepatic changes rather than any direct effect of the test material.
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 675 mg/kg diet
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: equivalent to 51 mg/kg bw/d
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 3 375 mg/kg diet
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: equivalent to 266 mg/kg bw/d
- Conclusions:
- Under the conditions of the test, dietary administration of the test material at 675, 1500 or 3375 mg/kg diet for 78 weeks in females and 91 weeks in males resulted in evidence of tumourigenicity amongst males receiving 3375 mg/kg diet, manifest as an increased incidence of benign liver tumours. A single malignant tumour was also recorded for males at this treatment level, whilst a single benign liver tumour was also recorded amongst males receiving 1500 mg/kg diet. There was no evidence of tumourigenicity amongst males receiving 675 mg/kg diet or any treated females. Non-neoplastic changes were evident in the liver. It was considered that the occurrence of tumours amongst males receiving 1500 or 3375 mg/kg diet resulted from the spectrum of toxicologically significant non-neoplastic hepatic changes rather than any direct effect of the test material. In addition to hepatotoxicity, evident at all treatment levels, toxicity was also manifest as impaired body weight gain and food intake amongst all treated males and for females receiving 3375 mg/kg diet. Initial impaired body weight gain was also evident for females receiving 1500 mg/kg diet. Thus, 675 mg/kg diet for males (equalling 51 mg/kg bw/day) and 3375 mg/kg diet for females (equalling 277 mg/kg bw/day) was considered to be the no observable effect level in respect of tumourigenicity, however, none of the treatment levels investigated was considered to be a no observable effect level.
Additional data on the incidence of spontaneously occurring tumours in hamsters of the Bio FiD Alexander Syrian strain, supplied by Bio Breeders Inc (USA) were obtained in a separate study. This information was for the provision of background data in support of two previous studies in this strain of test animal, performed at Huntingdon Research Centre Ltd., to assess the potential tumourigenic effects of the test material. Thus, the conditions and procedures used in this study were designed to duplicate those of the aforementioned investigations. - Executive summary:
In a GLP compliant study conducted in line with standardised guideline EPA OPP 83-2, the carcinogenicity of the test material over 78 weeks (females) and 91 weeks (males) was determined in the hamster.
Hamsters were administered the test material by oral (diet) at 0, 675, 1500 and 3375 ppm. Evidence of tumourigenicity amongst males receiving 3375 mg/kg diet, manifest as an increased incidence of benign liver tumours was observed. A single malignant tumour was also recorded for males at this treatment level, whilst a single benign liver tumour was also recorded amongst males receiving 1500 mg/kg diet. There was no evidence of tumourigenicity amongst males receiving 675 mg/kg diet or any treated females. Non-neoplastic changes were evident in the liver. It was considered that the occurrence of tumours amongst males receiving 1500 or 3375 mg/kg diet resulted from the spectrum of toxicologically significant non-neoplastic hepatic changes rather than any direct effect of the test material. In addition to hepatotoxicity, evident at all treatment levels, toxicity was also manifest as impaired body weight gain and food intake amongst all treated males and for females receiving 3375 mg/kg diet. Initial impaired body weight gain was also evident for females receiving 1500 mg/kg diet. Thus, 675 mg/kg diet for males (equalling 51 mg/kg bw/day) and 3375 mg/kg diet for females (equalling 277 mg/kg bw/day) was considered to be the no observable effect level in respect of tumourigenicity, however, none of the treatment levels investigated was considered to be a no observable effect level.
Referenceopen allclose all
At the 3200 ppm dose level organic disturbances attributable to pathological changes due to the test material were observed as chronic renal disturbances in many males and in less than half of the females. Furthermore swelling of parathyroid, renal osteodystrophy and calcification in bloods vessels and gastric mucosa were observed in both sexes. The changes were more appreciable in the males and from around week 78 up to week 102 all males died at this dose level. Diffuse development in the increase in amount of lipids in liver tissues was noted. Some animals, both males and females, demonstrated aggregated acidophile "oxyphilic cells" near Langerhans islets in the pancreas. At the 400 ppm dose level some animals showed the same chronic renal disturbances and aggregated "oxyphilic cells". At the 50 ppm dose level no changes attributable to the test material were noted.
Selected information on tumours can be found in Tables 1 to 3.
Information on historical control data versus results from the study can be found in Table 4. The incidence rate of hepatic adenoma in females is slightly higher than lab and breeder historical controls but within historical controls for NTP (US National Toxicology Program). This supports the claim that the adenomas seen are not treatment related but are on the high side of spontaneous range for hepatic adenomas. The incidence rate for carcinomas is well within the historical control range. When adenomas and carcinomas are considered concurrently, the incidence rate remains the same (4.0 %).
Table 1: Selected histopathological findings at week 52 (number of findings per group of 10 animals)
| Dose level (ppm) | 0 | 50 | 400 | 3200 | |
| Sex | M/F | M/F | M/F | M/F | |
| Organ | Finding | ||||
| Liver b.t. | + Adenoma | 1 ' / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
| Testis | + Interstitial cell tumour | 0 / 0 | 0 / 0 | 0 / 0 | 1 ' / 0 |
Grade of findings: 0 = normal; ' = slight
+ = non-neoplastic tumour
Table 2: Selected histopathological findings at week 78 (number of findings per group of 10 animals)
| Dose level (ppm) | 0 | 50 | 400 | 3200 | |
| Sex | M/F | M/F | M/F | M/F | |
| Organ | Finding | ||||
| Lung | + Adenoma | 0 / 0 | 0 / 0 | 1 ' / 0 | 0 / 0 |
| Kidney | * Adenocarcinoma | 0 / 0 | 0 / 0 | 0 / 0 | 1 ' / 0 |
| Adrenal | + Pheochromo-cytoma | 1 ' / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
| Liver b.t. | * Hepatocellular carcinoma | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 1 ' |
| Spleen | * Malignant lymphoma | 0 / 0 | 0 / 0 | 1 ' / 0 | 0 / 0 |
| Thyroid | + Adenoma | 1 ' / 0 | 0 / 0 | 1 ' / 0 | 0 / 0 |
| Testis | + Interstitial cell tumour | 4 / 0 | 5 ' / 0 | 6 ' / 0 | 6 ' / 0 |
| Pituitary | + Adenoma | 1 ' / 0 | 0 / 1 ' | 1 ' / 0 | 1 ' / 1 ' |
| Bone | + Osteoma | 0 / 0 | 0 / 0 | 0 / 0 | 1 ' / 0 |
| Uterus | + Leiomyoma | 0 / 1 ' | 0 / 0 | 0 / 0 | 0 / 1 1' |
| + Fibrosarcoma | 0 / 1 ' | 0 / 0 | 0 / 0 | 0 / 0 | |
Grade of findings: 0 = normal; ' = slight
+ = non-neoplastic tumour; * neoplastic tumour
Table 3: Selected histopathological findings at week 110
| Dose level (ppm) | 0 | 50 | 400 | 3200 | |
| Sex | M/F | M/F | M/F | M/F | |
| Organ | Finding | ||||
| Number of animals examined | 47/47 | 47/47 | 47/47 | 50/47 | |
| Lung | + Adenoma | 0 / 0 | 0 / 0 | 0 / 1 ' | 0 / 0 |
| Number of animals examined | 45/47 | 46/45 | 44/47 | 50/47 | |
| Thymus | * Malignant lymphoma | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 1 ' |
| Number of animals examined | 47/47 | 47/47 | 47/47 | 50/47 | |
| Kidney | * Adenocarcinoma | 0 / 0 | 0 / 0 | 0 / 0 | 2 ' / 1 ' |
| + Hamartoma | 0 / 0 | 0 / 0 | 0 / 0 | 1 ' / 0 | |
| Number of animals examined | 47/47 | 47/46 | 47/47 | 50/47 | |
| Adrenal | + Pheochromocytoma | 6 ' / 1 ' | 6 ' / 1 ' | 6 ' / 0 | 0 / 0 |
| Number of animals examined | 47/47 | 47/47 | 47/47 | 50/47 | |
| Liver / b.t. | + Adenoma | 0 / 0 | 0 / 0 | 0 / 2 ' | 4 ' / 6 ' |
| + Leiomyoma | 2 ' / 0 | 0 / 0 | 0 / 0 | 0 / 0 | |
| * Hepatocellular carcinoma | 0 / 0 | 0 / 0 | 0 / 0 | 1 ' / 1 ' | |
| Number of animals examined | 46/47 | 47/47 | 46/47 | 50/47 | |
| Spleen | * Malignant lymphoma | 1 ' / 2 ' | 0 / 0 | 1 ' / 3 ' | 0 / 1 ' |
| * Angiosarcoma | 0 / 0 | 1 ' / 0 | 0 / 0 | 0 / 0 | |
| Number of animals examined | 47/47 | 47/47 | 47/47 | 50/47 | |
| Islets | + Islet cell adenoma | 1 ' / 1 ' | 2 ' / 1 ' | 0 / 1 ' | 0 / 0 |
| * Squamous cell carcinoma | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 1 ' | |
| CNS | * Astrocytoma | 0 / 0 | 0 / 0 | 1 ' / 0 | 0 / 0 |
| Number of animals examined | 47/47 | 47/47 | 46/47 | 50/47 | |
| Stomach | + Papilloma | 0 / 0 | 1 ' / 0 | 0 / 0 | 2 ' / 0 |
| Number of animals examined | 47/47 | 47/47 | 47/47 | 50/47 | |
| Small intestine | * Undifferentiated sarcoma | 0 / 0 | 1 ' / 0 | 0 / 0 | 0 / 0 |
| * Malignant lymphoma | 0 / 0 | 0 / 0 | 0 / 0 | 1 ' / 0 | |
| Number of animals examined | 45/47 | 47/46 | 47/47 | 47/47 | |
| Lymph | * Malignant lymphoma | 2 ' / 3 ' | 1 ' / 1 ' | 2 ' / 3 ' | 0 / 6 ' |
| Number of animals examined | 44/47 | 45/47 | 46/47 | 48/46 | |
| Thyroid | + C-cell adenoma | 1 ' / 5 ' | 5 ' / 2 ' | 3 ' / 1 ' | 0 / 2 ' |
| + Adenoma | 4 ' / 0 | 1 ' / 0 | 0 / 1 ' | 2 ' / 1 ' | |
| * Adenocarcinoma | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 1 ' | |
| Number of animals examined | 47/47 | 47/46 | 47/46 | 48/46 | |
| Skin / sc | + Keratocanthoma | 5 ' / 3 ' | 1 ' / 0 | 2 ' / 0 | 2 ' / 1 ' |
| + Fibroma | 2 ' / 1 ' | 1 ' / 1 ' | 1 ' / 1 ' | 1 ' / 0 | |
| * Malignant fibrous histiocytoma | 0 / 0 | 0 / 2 ' | 1 ' / 1 ' | 0 / 0 | |
| + Papilloma | 0 / 1 ' | 0 / 0 | 0 / 0 | 1 ' / 1 ' | |
| * Undifferentiated sarcoma | 0 / 0 | 1 ' / 0 | 1 ' / 0 | 0 / 1 ' | |
| * Basal cell carcinoma | 0 / 1 ' | 0 / 2 ' | 0 / 0 | 0 / 0 | |
| + Leiomyoma | 1 ' / 1 ' | 0 / 0 | 0 / 0 | 0 / 0 | |
| + Lipoma | 0 / 0 | 0 / 0 | 1 ' / 0 | 0 / 0 | |
| Number of animals examined | 46/47 | 47/47 | 47/45 | 50/46 | |
| Marrow | * Malignant lymphoma | 0 / 0 | 0 / 2 ' | 0 / 3 ' | 0 / 0 |
| Number of animals examined | 47/0 | 47/0 | 47/0 | 50/0 | |
| Testis | + Interstitial cell tumour | 38 ' / 0 | 33 ' / 0 | 43 ' / 0 | 35 ' / 0 |
| Number of animals examined | 2/0 | 1/0 | 2/0 | 1/0 | |
| Epididymis | * Mesothelioma | 1 ' / 0 | 1 ' / 0 | 2 ' / 0 | 1 ' / 0 |
| Number of animals examined | 24/44 | 23/44 | 30/46 | 33/47 | |
| Mammary | + Fibroadenoma | 0 / 3 ' | 0 / 5 ' | 0 / 7 ' | 0 / 3 ' |
| * Adenocarcinoma | 0 / 2 ' | 0 / 1 ' | 1 ' / 0 | 0 / 0 | |
| * Adenocanthoma | 0 / 0 | 1 ' / 0 | 0 / 1 ' | 0 / 0 | |
| + Fibroma | 1 ' / 0 | 0 / 0 | 0 / 0 | 0 / 0 | |
| * Carcinosarcoma | 0 / 1 ' | 0 / 0 | 0 / 0 | 0 / 0 | |
| Number of animals examined | 47/47 | 46/46 | 47/46 | 49/46 | |
| Pituitary | + Adenoma | 11 ' / 14 ' | 4 ' / 11 ' | 7 ' / 10 ' | 0 / 7 ' |
| * Adenocarcinoma | 0 / 5 ' | 0 / 1 ' | 0 / 1 ' | 0 / 0 | |
| Number of animals examined | 47/0 | 47/0 | 47/0 | 50/0 | |
| Prostate | * Squamous cell carcinoma | 1 ' / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
| Number of animals examined | 45/47 | 47/47 | 47/47 | 50/47 | |
| Bladder | * Transitional cell carcinoma | 0 / 0 | 0 / 0 | 0 / 1 ' | 0 / 0 |
| Number of animals examined | 46/47 | 47/47 | 47/46 | 50/46 | |
| Bone | * Osteogenic sarcoma | 0 / 0 | 1 ' / 0 | 0 / 0 | 0 / 0 |
| Number of animals examined | 0/1 | 3/1 | 2/1 | 2/5 | |
| Blood | * Leukemia | 0 / 1 ' | 3 ' / 1 ' | 2 ' / 1 ' | 2 ' / 5 ' |
| Number of animals examined | 0/47 | 0/47 | 0/46 | 0/47 | |
| Uterus | + Polyp | 0 / 2 ' | 0 / 3 ' | 0 / 0 | 0 / 0 |
| * Fibrosarcoma | 0 / 1 ' | 0 / 0 | 0 / 1 ' | 0 / 2 ' | |
| * Fibromyxoma | 0 / 1 ' | 0 / 1 ' | 0 / 1 ' | 0 / 0 | |
| + Leimyoma | 0 / 0 | 0 / 1 ' | 0 / 0 | 0 / 0 | |
| * Adenocarcinoma | 0 / 0 | 0 / 0 | 0 / 1 ' | 0 / 0 | |
| Number of animals examined | 0/0 | 0/0 | 0/0 | 0/1 | |
| Vagina | * Undifferentiated sarcoma | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 1 ' |
Grade of findings: 0 = normal; ' = slight
+ = non-neoplastic tumour; * neoplastic tumour
Table 4: Overview of historical control data versus test material
| Laboratory | AN-PYO | Charles River | NTP | ARegDoc 12564 | ||||
| No. animals/total no. examined | % | No. animals/total no. examined | % | No. animals/total no. examined | % | No. animals/total no. examined | % | |
| Adenoma | ||||||||
| Male | 5/569 | 0.9 | 8/956 | 0.8 | 23/1002 | 2.3 | 0/50 | 0.0 |
Female |
2/573 |
0.3 |
8/954 |
0.8 |
4/1000 |
0.4 |
2/50 |
4.0 |
Carcinoma |
||||||||
Male |
3/569 |
0.5 |
6/956 |
0.6 |
7/1002 |
0.7 |
0/50 |
0.0 |
Female |
1/573 |
0.2 |
2/954 |
0.2 |
1/1000 |
0.1 |
0/50 |
0.0 |
Combined |
||||||||
Male |
8/569 |
1.4 |
14/956 |
1.5 |
30/1002 |
3.0 |
0/50 |
0.0 |
Female |
3/573 |
0.5 |
10/954 |
1.0 |
5/1000 |
0.5 |
2/50 |
4.0 |
Overall range |
0 -7.7% |
0 -4.3% |
0 -10% |
4% |
||||
Table 1: Mortality
| Dose group (ppm) | ||||||
| Sex | Week | 0 | 5 | 26 | 132 | 675 |
| Male | 4 | 0/100 | 0/50 | 0/50 | 0/100 | 0/100 |
| 41 | 2/100 | 1/50 | 1/50 | 0/100 | 0/100 | |
| 60 | 2/98 | 0/49 | 0/49 | 1/100 | 4/100 | |
| 70 | 8/96 | 3/49 | 6/49 | 4/99 | 5/96 | |
| 80 | 14/88 | 6/46 | 6/43 | 5/95 | 4/91 | |
| 88 | 24/74 | 10/40 | 13/37 | 8/90 | 8/87 | |
| Total dead / % mortality | 50/50 | 20/40 | 26/52 | 18/36 | 21/42 | |
| Female | 4 | 0/100 | 1/50 | 0/50 | 0/50 | 0/50 |
| 40 | 3/100 | 0/49 | 0/50 | 0/50 | 1/50 | |
| 60 | 3/97 | 2/49 | 3/50 | 3/50 | 2/49 | |
| 70 | 22/94 | 5/47 | 14/47 | 9/47 | 7/47 | |
| 75 | 10/72 | 9/42 | 6/33 | 10/38 | 7/40 | |
| 80 | 20/62 | 11/33 | 6/27 | 13/28 | 5/33 | |
| Total dead / % mortality | 58/58 | 28/56 | 29/58 | 35/70 | 22/44 | |
Table 2: Statistical analysis of body weight gain (g)
| Dose group (ppm) | ||||||
| Sex | Week range | 0 | 5 | 26 | 132 | 675 |
| Male | 0-6 | 31.7 | 35.5 | 31.3 | 30.8 | 26.6** |
| 0-8 | 31.5 | 32.7 | 33.3 | 32.3 | 31.2 | |
| 8-80 | -11.1 | -11.2 | -12.3 | -12.8 | -27.8** | |
| 0-80 | 20.1 | 20.9 | 20.3 | 19.5 | 3.2** | |
| 8-88 | -14.1 | -9.8 | -13.8 | -14.6 | -30.1** | |
| 0-88 | 16.6 | 21.9 | 19.5 | 17.7 | 0.7** | |
| Female | 0-6 | 43.3 | 41.8 | 43.7 | 44.9 | 42.9 |
| 0-8 | 40.8 | 42.2 | 41.7 | 42.1 | 45.7** | |
| 8-80 | -9.8 | -12.1 | -11.6 | -18.5 | -20.1** | |
| 0-80 | 30.0 | 29.7 | 26.8 | 19.7 | 24.4 | |
**P<0.01 in comparison to control
Table 3: Statistical analysis on food consumption (g/hamster/period)
| Dose group (ppm) | ||||||
| Sex | Week range | 0 | 5 | 26 | 132 | 675 |
| Male | 1-6 | 473 | 460* | 448** | 461** | 435** |
| 7-80 | 4545 | 4514 | 4539 | 4727 | 4464 | |
| 1-80 | 5018 | 4978 | 4984 | 5189 | 4899 | |
| 7-88 | 5006 | 4955 | 5065 | 5224 | 4871 | |
| 1-88 | 5482 | 5414 | 5507 | 5689 | 5307* | |
| Female | 1-6 | 479 | 471 | 466 | 470 | 486 |
| 7-80 | 4739 | 4690 | 4581 | 4727 | 4940** | |
| 1-80 | 5213 | 5159 | 5032 | 5198 | 5422** | |
*P<0.05 in comparison to control; P<0.01 in comparison to control
Table 4: Mean group organ weights, absolute (g)
| Dose group (ppm) | ||||||
| Sex | Organ | 0 | 5 | 26 | 132 | 675 |
| Male | Brain | 1.055 | 1.067 | 1.052 | 1.063 | 1.038 |
| Heart | 0.894 | 0.929 | 0.902 | 0.861 | 0.850 | |
| Liver | 6.87 | 6.62 | 6.74 | 6.66 | 6.64 | |
| Kidneys | 1.721 | 1.786 | 1.867 | 1.667 | 1.551 | |
| Adrenals | 0.0285 | 0.0240 | 0.0286 | 0.0243 | 0.0243 | |
| Testes | 3.411 | 3.713 | 3.280 | 3.525 | 2.482 | |
| Female | Brain | 1.043 | 1.070 | 1.060 | 1.036 | 1.040 |
| Heart | 0.977 | 0.971 | 1.019 | 0.944 | 0.886 | |
| Liver | 8.67 | 9.19 | 7.89 | 8.41 | 9.77** | |
| Kidneys | 1.995 | 1.952 | 1.976 | 1.933 | 1.886 | |
| Adrenals | 0.0214 | 0.0207 | 0.0178 | 0.0233 | 0.0219 | |
** P<0.01 in comparison to control
Table 5: Microscopic pathology - inter-group comparison of tumour incidence
| Dose group (ppm) | ||||||
| Sex | Type of tumour | 0 | 5 | 26 | 132 | 675 |
| Animals completed (decedent / terminal) | 51 / 49 | 20 / 30 | 26 / 24 | 20 / 30 | 22 / 28 | |
| Number of tumour bearing animals | 21 / 21 | 10 / 8 | 11 / 12 | 4 / 6 | 7 /13 | |
| Males | Malignant | 10 / 6 | 7 / 3 | 6 / 5 | 3 / 4 | 4 / 4 |
| Benign | 15 / 16 | 5 / 6 | 6 / 9 | 2 / 2 | 4 / 10 | |
| Multiple | 4 / 8 | 4 / 2 | 2 / 3 | 2 / 0 | 1 / 2 | |
| Single | 17 / 13 | 6 / 6 | 9 / 9 | 2 / 6 | 6 / 11 | |
| Multiple malignant | 0 / 0 | 1 / 0 | 0 / 0 | 1 / 0 | 0 / 1 | |
| Multiple benign | 1 / 7 | 1 / 1 | 1 / 1 | 0 / 0 | 0 / 0 | |
| Metastatic | 2 / 0 | 1 / 0 | 0 / 1 | 0 / 0 | 1 / 1 | |
| Animals completed (decedent / terminal) | 58 / 42 | 28 / 22 | 32 / 18 | 36 / 14 | 24 / 26 | |
| Number of tumour bearing animals | 17 / 14 | 7 / 6 | 12 / 2 | 17 / 4 | 10 / 13 | |
| Female | Malignant | 10 / 6 | 3 / 2 | 6 / 0 | 7 / 3 | 3 / 5 |
| Benign | 8 / 10 | 5 / 4 | 9 / 2 | 12 / 1 | 7 / 9 | |
| Multiple | 1 / 4 | 4 / 0 | 4 / 1 | 4 / 0 | 1 / 4 | |
| Single | 16 / 10 | 3 / 6 | 8 / 1 | 13 / 4 | 9 / 9 | |
| Multiple malignant | 0 / 0 | 1 / 0 | 0 / 0 | 1 / 0 | 0 / 0 | |
| Multiple benign | 0 / 3 | 2 / 0 | 1 / 1 | 1 / 0 | 1 / 3 | |
| Metastatic | 0 / 0 | 1 / 0 | 1 / 0 | 1 / 2 | 1 / 1 | |
Table 6: Incidence of centrilobular hepatocyte enlargement with or without rarefraction; incidence of adrenal cortical hyperplasia and adrenal cortical tumours (females)
| Dose group (ppm) | ||||||
| Findings | 0 | 5 | 26 | 132 | 675 | |
| Number of animals examined | 100 | 50 | 50 | 50 | 50 | |
| Liver | Centrolibular hepatocyte enlargement (A) | 2 | 2 | 0 | 0 | 4 |
| Centrolibular hepatocyte enlargement rarefraction (B) | 1 | 1 | 1 | 1 | 6 | |
| (A) and (B) | 2 (3) | 3 (6) | 1 (2) | 1 (2) | 10 (20) | |
| Number of animals examined | 99 | 50 | 49 | 49 | 49 | |
| Adrenals | Cortical hyperplasia | 10 (10) | 7 (17) | 3 (6) | 6 (12) | 8 (16) |
| Cortical tumours | 48 (48) | 25 (52) | 23 (58) | 29 (58) | 36 (72) | |
Numbers in brackets are the findings expressed as a percentage of the total number of animals examined.
Table 1: Mortality
| Dose group (mg/kg diet) | |||||
| Sex | Week | 0 | 675 | 1500 | 3375 |
| Male | 5 | 0/100 | 0/50 | 0/50 | 1/50 |
| 39 | 2/100 | 2/50 | 0/50 | 0/49 | |
| 60 | 0/98 | 0/48 | 0/50 | 1/49 | |
| 70 | 1/98 | 1/48 | 1/50 | 3/48 | |
| 78 | 5/97 | 9/47 | 12/49 | 10/45 | |
| 91 | 42/92 | 14/38 | 14/37 | 9/35 | |
| Total dead / % mortality | 50/50 | 26/52 | 27/54 | 24/48 | |
| Female | 5 | 1/100 | 0/50 | 0/50 | 0/50 |
| 39 | 2/99 | 2/50 | 0/50 | 1/50 | |
| 60 | 8/97 | 4/48 | 4/50 | 1/49 | |
| 70 | 12/89 | 6/44 | 7/46 | 2/48 | |
| 74 | 11/77 | 8/38 | 4/39 | 2/46 | |
| 78 | 16/66 | 3/30 | 6/35 | 5/44 | |
| Total dead / % mortality | 50/50 | 23/47 | 21/42 | 11/22 | |
Table 2: Statistical analysis of body weight gain (g)
| Dose group (mg/kg diet) | |||||
| Sex | Week range | 0 | 675 | 1500 | 3375 |
| Male | 0-2 | 5.2 | 2.1** | -1.3** | -16.7 |
| 2-18 | 14.8 | 14.9 | 13.3 | 16.5 | |
| 18-78 | -14.4 | -19.5 | -16.3 | -6.7* | |
| 0-78 | 5.5 | -2.0** | -5.4** | -5.6** | |
| 18-91 | -7.7 | -14.2 | -15.3 | -9.7 | |
| 0-91 | 11.8 | 3.8* | -4.3** | -7.8** | |
| Female | 0-2 | 5.7 | 4.5 | 2.5** | -2.8** |
| 2-18 | 17.3 | 17.2 | 16.9 | 14.0* | |
| 18-78 | 2.0 | -6.5 | -4.6 | 5.5 | |
| 0-78 | 25.0 | 16.5** | 15.8** | 17.4** | |
*P<0.05 in comparison to control; **P<0.01 in comparison to control; all week 0-2 value have Kruskal-Wallis analysis of mean ranks applied
Table 3: Statistical analysis on food consumption (g/hamster/period)
| Dose group (mg/kg diet) | |||||
| Sex | Week range | 0 | 675 | 1500 | 3375 |
| Male | 1-2 | 134 | 122** | 120** | 129** |
| 3-18 | 1055 | 1007** | 1014** | 941** | |
| 19-78 | 3970 | 3709** | 3811** | 3570** | |
| 1-78 | 5159 | 4842** | 4947** | 4639** | |
| 19-91 | 4805 | 4524** | 4536** | 4377** | |
| 1-91 | 5990 | 2654** | 5661** | 5456** | |
| Females | 1-2 | 142 | 138 | 131** | 129** |
| 3-18 | 1085 | 1089 | 1075 | 1042** | |
| 19-78 | 4316 | 4201 | 4231 | 4097** | |
| 1-78 | 5536 | 5417 | 5438 | 5269** | |
*P<0.05 in comparison to control; P<0.01 in comparison to control (Williams test); males in weeks 1-2 and 3-18 had Kruskal-Wallis analysis of mean ranks applied; analysis on females weeks 3-18 was performed in log-transformed data
Table 4: Mean group organ weights, absolute (g) during 78/91 week feeding study
| Dose group (mg/kg diet) | |||||
| Sex | Organ | 0 | 675 | 1500 | 3375 |
| Male | Brain | 1.059/1.049 | 1.056/1.056 | 1.032/1.040 | 1.021/1.032 |
| Heart | 0.940 | 0.885* | 0.855** | 0.841** | |
| Liver | 6.33/5.95 | 6.22/6.17 | 6.52/6.75 | 8.54/9.08** | |
| Kidneys | 1.640/1.551 | 1.581/1.580 | 1.473/1.548 | 1.475/1.576 | |
| Adrenals | 0.0205 | 0.0206 | 0.0216 | 0.0205 | |
| Testes and epididymides | 1.199/1.160 | 1.126/1.125 | 0.944/1.026* | 0.961/1.004** | |
| Female | Brain | 1.055/1.046 | 1.048/1.054 | 1.036/1.042 | 1.054/1.058 |
| Heart | 0.964 | 0.916 | 0.899 | 0.864** | |
| Liver | 7.70/7.34 | 7.73/7.98* | 8.80/9.02* | 11.57/11.70** | |
| Kidneys | 2.041 | 1.900 | 1.854 | 2.095 | |
| Adrenals | 0.0184 | 0.0181 | 0.0183 | 0.0181 | |
*P<0.05 in comparison to control; ** P<0.01 in comparison to control (Williams test)
Table 5: Microscopic pathology - inter-group comparison of tumour incidence
| Dose group (mg/kg diet) | |||||
| Sex | Type of tumour | 0 | 675 | 1500 | 3375 |
| Animals completed (decedent / terminal) | 55 / 45 | 27 / 23 | 28 /22 | 26 /240 | |
| Number of tumor bearing animals | 14 / 20 | 3 / 6 | 8 /5 | 9 / 7 | |
| Male | Malignant | 5 / 5 | 1 / 2 | 1 / 0 | 3 / 2 |
| Benign | 10 / 15 | 2 / 4 | 7 / 5 | 6 / 6 | |
| Multiple | 1 / 2 | 0 / 0 | 0 / 0 | 2 / 3 | |
| Single | 13 / 18 | 3 / 6 | 8 / 5 | 7 / 4 | |
| Multiple malignant | 0 / 0 | 0 / 0 | 0 / 0 | 1 / 2 | |
| Multiple benign | 0 / 2 | 0 / 0 | 0 / 0 | 1 / 2 | |
| Metastatic | 0 / 0 | 0 / 1 | 1 / 0 | 0 / 0 | |
| Animals completed (decedent / terminal) | 50 / 50 | 23 / 26 | 21 / 29 | 11 / 39 | |
| Number of tumour bearing animals | 12 / 18 | 10 / 7 | 3 / 6 | 3 / 9 | |
| Female | Malignant | 7 / 7 | 4 / 3 | 3 / 1 | 1 /2 |
| Benign | 5 / 11 | 6 / 4 | 0 / 5 | 3 / 7 | |
| Multiple | 1 / 0 | 1 / 0 | 0 / 0 | 1 / 1 | |
| Single | 11 / 18 | 9 / 7 | 3 / 6 | 2 / 8 | |
| Multiple malignant | 1 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | |
| Multiple benign | 0 / 0 | 1 / 0 | 0 / 0 | 0 / 1 | |
| Metastatic | 1 / 0 | 1 / 0 | 0 / 0 | 0 / 0 | |
Table 6: Incidence of liver cell tumours in males
| Dose group (mg/kg diet) | ||||
| 0 | 675 | 1500 | 3375 | |
| Benign liver cell tumour | 0 | 0 | 1 | 6 |
| Malignant liver cell tumour | 0 | 0 | 0 | 1 |
| Total examined | 100 | 50 | 50 | 50 |
Table 7: Microscopic pathology - incidence of liver findings
| Dose group (mg/kg diet) | |||||
| Sex | Finding | 0 | 675 | 1500 | 3375 |
| Male | Eosiniophilic hepatocytes | 0 | 0 | 1 | 5 |
| Minimal centrolibular hepatocyte enlargement | 7 | 15 | 10 | 14 | |
| Hepatitis | 1 | 1 | 2 | 5 | |
| Pigmented giant cells | 10 | 4 | 5 | 20 | |
| Pigmented sinusoidal cells | 5 | 1 | 3 | 9 | |
| Brown pigment in hepatocytes | 9 | 7 | 16 | 19 | |
| Total examined | 100 | 50 | 50 | 50 | |
| Female | Minimal centrolibular hepatocyte enlargement | 7 | 5 | 5 | 11 |
| Hepatitis | 0 | 0 | 3 | 4 | |
| Pigmented sinusoidal cells | 7 | 4 | 2 | 9 | |
| Brown pigment in hepatocytes | 1 | 1 | 3 | 10 | |
| Total examined | 100 | 50 | 50 | 50 | |
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
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
In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substancec is considered to be unclassified for carcinogenicity.
Additional information
In a 110 week feeding study in rats, dose levels of 50, 400 and 3200 mg/kg food did not have an effect upon total tumours observed, a negative trend being apparent in 21/40 tumour types tested. The test material was considered to have no carcinogenic effect with a slight excess of tumours observed only at 3200 mg/kg food which is a notably toxic dose level.
In a 88-week hamster study no evidence of tumourigenic potential was found at any dose levels. Treatment-related changes were primarily confined to the high dose level, i.e. 675 mg/kg food. In the males these changes included initial impairment of body weight gain together with associated lower food consumption, and lower overall body weight change together with the macroscopic pathological finding of a reduction in the adipose tissue in the male decedents. Although there were no pathological findings of clear toxicological importance, the changes in the liver (slightly higher weights, pitted liver and centrilobular hepatocyte enlargement) and adrenals (cortical hyperplasia) of the high dose females are of note. The dose level of 132 mg/kg diet, equal to 9.39 mg/kg bw for males and 9.20 mg/kg bw for females, should be regarded as the NO(A)EL for toxicity.
In a second study with hamsters at dose levels of 675, 1500 or 3,75 mg/kg diet for 78 weeks in females and 91 weeks in males it was confirmed that 675 mg/kg diet is a Maximum Tolerated Dose for the test material in this species. This was evidenced by hepatotoxicity at all treatment levels and was also manifest as impaired body weight gain and food intake amongst all treated males and for females receiving 3375 mg/kg diet. Initial impaired body weight gain was also evident for females receiving 1500 mg/kg diet. There was no evidence of tumourigenicity amongst males receiving 675 mg/kg diet or any treated females. The occurrence of tumours amongst males receiving 1500 or 3375 mg/kg diet resulted from the spectrum of toxicologically significant non-neoplastic hepatic changes rather than any direct effect of the test material. Thus, 675 mg/kg diet for males (equalling 51 mg/kg bw/day) and 3375 mg/kg diet for females (equalling 277 mg/kg bw/day) was considered to be the no observable effect level in respect of tumourigenicity. However, none of the treatment levels investigated in this study was considered to be a no observable effect level.
Two additional in vitro screening studies performed with BALB/c-3T3 demonstrated that the test material did not transform BALB/c-3T3 cells both in the presence and absence of metabolic activation. The methods performed in both screens were almost identical, except that one was performed with metabolic activation (with a shorter incubation time) and the other performed in the absence of metabolic activation (with a longer incubation time). In both studies, After an initial preliminary toxicity screening test, tissue cultures were treated with doses of 667.0, 2667, 4000.0, 6000.0 and 7,500.0 µg/mL in the presence of metabolic activation and 240, 480, 720, 900 and 1125 µg/mL in the absence of metabolic activation administered in media. After sufficient incubation, the cell monolayers were assessed for foci and compared with negative and positive control cultures. The test material, did not induce a significant number of transformed foci in either of the two screens. The results of both screening studies are in accordance with the in vivo carcinogenicity data.
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