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EC number: - | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study without detailed documentation
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- carcinogenicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study without detailed documentation
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
- Principles of method if other than guideline:
- A combined chronic oral toxicity (14 rats/sex/dose for 52 weeks) and carcinogenicity study (50 rats/sex/dose for 104 weeks) was performed in Fischer 344/Du Crj rats.
- GLP compliance:
- not specified
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Mitsubishi-Kasei Foods Corporation
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: refrigerated storeroom
- Stability under test conditions: In an earlier sub-chronic toxicity study, the stability of the test substance was checked after 3, 10, and 18 weeks by gas chromatography.
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Final preparation of a solid: The test substance was mixed with powder feed and tested for uniformity. - Species:
- rat
- Strain:
- Fischer 344/DuCrj
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Japan, Inc.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 5 weeks
- Housing: 2 animals per cage, polycarbonate cages with hardwood chip bedding
- Diet (e.g. ad libitum): CFR-1 Oriental Yeast Co., Ltd. mixed with test substance, ad libitum, replaced weekly
- Water (e.g. ad libitum): ad libitum
DETAILS OF FOOD AND WATER QUALITY: Diet was tested for contaminants by a third-party laboratory.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25 degrees C
- Humidity (%): 40-70%
- Air changes (per hr): 12 changes/hr
- Photoperiod (hrs dark / hrs light): 12 hrs dark/ 12 hrs light - Route of administration:
- oral: feed
- Vehicle:
- other: feed
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency): every 9 weeks
- Mixing appropriate amounts with (Type of food): CFR-1
- Storage temperature of food: refrigerated
VEHICLE
- Justification for use and choice of vehicle (if other than water): The test substance is a solid with low water solubility.
- Concentration in vehicle: 0, 1, 3, and 5% of daily diet - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The test substance/diet mix was tested for uniformity. The top, middle and bottom of the mix was tested using duplicate samples. The stability of the test substance was checked in an sub-chronic toxicity study at 3, 10, and 18 weeks.
- Duration of treatment / exposure:
- Chronic oral toxicity: 52 weeks
Carcinogenicity: 104 weeks - Frequency of treatment:
- The test substance was mixed with the diet. Test animals had ad libitum access to the test substance/diet mix.
- Post exposure period:
- None
- Dose / conc.:
- 0 other: % diet
- Dose / conc.:
- 1 other: % diet
- Dose / conc.:
- 3 other: % diet
- Dose / conc.:
- 5 other: % diet
- No. of animals per sex per dose:
- 50 (104 exposure)
14 (52 week exposure) - Control animals:
- yes, plain diet
- Positive control:
- No
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: Survival, clinical signs, appearance, behaviour
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: Once a week for first 13 weeks, every 4 weeks thereafter.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
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: Yes
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Every 3 months, and within 1 week of end of treatment.
- Dose groups that were examined: All doses in the 52 week exposure groups.
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Every 3 months for satellite groups, every 6 months for main groups.
- Anaesthetic used for blood collection: No, except for collection prior to sacrifice.
- Animals fasted: Yes, 12 hrs.
- How many animals: All
- Parameters examined: Satellite groups: prothrombin time and activated partial thromboplastin time
Main groups: Erythrocyte count, leukocyte count, differential leukocyte count, platelet counts, hemoglobin, hematocrit, reticulocyte count, prothrombin time, activated partial thromboplastin time, mean corpuscular volume, and mean corpuscular hemoglobin concentration.
CLINICAL CHEMISTRY: Yes, satallite groups only.
- Time schedule for collection of blood: Every 3 months for satellite groups.
- Animals fasted: Yes, 12 hrs
- How many animals: All
- Parameters examined: toatl protein, glucose, triglycerides, total cholesterol, phospholipids, bilirubin, urea nitrogen, creatinine, calcium, inorganic phosphorous, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, albumin, albumin/globulin ratio, sodium, potassium, and chloride.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, Yes, all animals at termination
ORGAN WEIGHTS: Yes - liver, kidneys, adrenals, testes, ovaries, brain, heart, lungs, and spleen.
HISTOPATHOLOGY: Yes - on 48 tissues and organs in all control and high-dose animals and in animal tissues showing macroscopic changes in the low- and mid-dose groups: brain, pituitary, thyroid, thymus, trachea, lungs, heart, aorta, salivary glands, liver, spleen, adrenals, pancreas, testes, epididymides, prostate gland, seminal vesicle, ovaries, uterus, vagina, skin, tongue, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, kidneys, bladder, lymph nodes, mammary glands, muscle, sciatic nerve, femur, sternum, eyes, Harderian glands, spinal cord, nasal cavity, oviducts, auditory sebaceous gland, and extraorbital lacrimal gland, and any other organs and tissues with macroscopic changes. - Statistics:
- Numerical data: Bartlett's equial variance test
Data showing homogenous variance: analysis of variance (ANOVA)
Data with a signifcant difference between group: Dunnett's method (if number of animals in each group was the same), Scheffe's method (if number of animals in each group was different)
Data showing heterogenous variance: Kruskal-Wallis H test
Data with a signifcant difference between group: Dunnett-type rank sum test (if number of animals in each group was the same), Scheffe-type rank sum test (if number of animals in each group was different)
Survival ratio: Fischer exact method
Incidences of neoplasms: Armitage's X^2 test - Clinical signs:
- no effects observed
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- No significant difference was noted in the survival percentages in any treatment group as compared to controls.
Survival at 52 (100%) and 104 weeks (66-76%) was not affected by the treatment. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Males in the high-dose group showed a significant decrease in weight gain in weeks 3, 4, 5, 6, 8, 10, 17, and 49.
During the second year of the study body weight progression was normal. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Food consumption was lower in the high-dose male group, and the female medium- and high-dose groups during the first week.
- Food efficiency:
- no effects observed
- Description (incidence and severity):
- Food efficiency was not affected, but an initial reduction in food intake in males and females was observed for a few weeks in the mid- and high-dose groups.
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No toxicologically significant differences between the test groups and the control groups were observed. All differences in values between the test groups and control groups were within historical controls.
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Statistically signifcant differences were noted between the test groups and the control groups, but none of these differences were dose dependent, and are therefore considered incidental.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Males in the medium- and high-dose groups showed higher absolute and relative spleen weights at 104 weeks. Males in the high-dose group also showed higher absolute heart weights. There was also an increase in absolute and relative spleen weight, and absolute lung weight in females in the medium-dose group. High spleen weights are common in aged rats of this strain. Incidences of up to 25% are common, as this effect was not seen in animals sacrificed earlier in life, this effect is not considered treatment related.
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No statistically significant differences between the test and control groups were seen in surviving animals. In the nonsurviving animals, about 1/2 had large granular lymphocyte leukemia with associated macroscopic observations. As this was also seen in the control group, it is not considered treatment related.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- An increase in extramedullary hematopoiesis was seen in the spleen in some of the 104 week exposure groups including the control group, but these increases were not statistically significant.
- Histopathological findings: neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Large granular lymphocyte leukemia was seen in both males and females with increase with increasing dose, but this increase was not statistically significant. An increase in mesothelioma in the abdominal cavity was also not statistically significant, and was within historical controls.
- Other effects:
- not examined
- Details on results:
- At termination of the 104 weeks study absolute and relative spleen weights were significantly increased in males at 3% and 5% and in females at 3% (but not in females at 5%). The changes in spleen weight and haematological parameters were most likely caused by the occurrence of large granular lymphocyte (LGL) leukaemia. Aged rats of this strain normally have a high incidence of LGL leukaemia that can be as high as 24% for males and 25% for females. In this experiment, the LGL leukaemia frequencies in the groups receiving 0%, 1%, 3% and 5% of test material were 7/50, 9/50, 11/50 and 12/50 in males and 10/50, 7/50, 14/50 and 13/50 in females, respectively. Thus, LGL leukaemia was a common neoplasm in all groups but was slightly increased without statistical significance at the two top doses. However, when the rats that showed LGL leukaemia were removed from the spleen weight determinations, no differences were seen between treated and control rats. In that case, the spleen weights of the rats treated at concentrations of 0% 1%, 3% or 5% in the diet were 1.3, 1.3, 1.4 and 1.6 g in males 0.6, 0.7, 0.8 and 0.6 g in females, respectively. Consistent with the higher incidence of LGL leukaemia in the high-dose group, there were associated non-neoplastic findings; extramedullary haematopoiesis in the spleen and haematopoietic hyperplasia in the bone marrow was slightly (but not significantly) increased in the high-dose groups.
- Relevance of carcinogenic effects / potential:
- No statistically significant increase in neoplastic lesions was observed in the test groups.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 5 other: % in diet
- Based on:
- test mat.
- Sex:
- male/female
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 970 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Remarks on result:
- other: equivalent to 5% in diet
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 2 440 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Remarks on result:
- other: equivalent to 5% in diet
- Key result
- Critical effects observed:
- no
- Conclusions:
- The test substance is not carcinogenic.
- Executive summary:
A 2 -year chronic toxicity/carcinogenicity study was performed on male and female rats. Groups of 50 male and 50 females were fed a diet consisting of 0, 1, 3, or 5% of the test substance for 104 weeks. Other groups of 14 male and 14 female rats were fed a diet of the same concentrations for 52 weeks. No statistically significant increase in neoplastic lesions was observed in the test groups.
Data source
Referenceopen allclose all
- Reference Type:
- publication
- Title:
- Chronic toxicity and carcinogenicity of sucrose fatty acid esters in Fischer 344/DuCrj rats
- Author:
- Takeda, K., and Flood, M.
- Year:
- 2 002
- Bibliographic source:
- Regulatory Toxicology and Pharmacology 35, 157-164.
- Reference Type:
- review article or handbook
- Title:
- Sucrose esters of fatty acids, E 473 and sucroglycerides, E 474 based on a request from the Commission related to Sucrose Esters of Fatty Acids (E 473)
- Author:
- EFSA Scientific Panel
- Year:
- 2 004
- Bibliographic source:
- The EFSA Journal (2004) 106, 1-24
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 994
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
- Principles of method if other than guideline:
- A combined chronic oral toxicity (14 rats/sex/dose for 52 weeks) and carcinogenicity study (50 rats/sex/dose for 104 weeks) was performed in Fischer 344/Du Crj rats.
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Fatty acids C16-18 (even numbered), mono, di and triesters with sucrose, UVCB
- Molecular formula:
- not applicable, substance is UVCB
- IUPAC Name:
- Fatty acids C16-18 (even numbered), mono, di and triesters with sucrose, UVCB
- Test material form:
- solid: particulate/powder
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Mitsubishi-Kasei Foods Corporation
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: refrigerated store room
- Stability under test conditions: In an earlier sub-chronic toxicity study, the stability of the test substance was checked after 3, 10, and 18 weeks by gas chromatography.
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Final preparation of a solid: The test substance was mixed with powder feed and tested for uniformity.
Test animals
- Species:
- rat
- Strain:
- Fischer 344/DuCrj
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Japan, Inc.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 5 weeks
- Housing: 2 animals per cage, polycarbonate cages with hardwood chip bedding
- Diet (e.g. ad libitum): CFR-1 Oriental Yeast Co., Ltd. mixed with test substance, ad libitum, replaced weekly
- Water (e.g. ad libitum): ad libitum
DETAILS OF FOOD AND WATER QUALITY: Diet was tested for contaminants by a third-party laboratory.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25 degrees C
- Humidity (%): 40-70%
- Air changes (per hr): 12 changes/hr
- Photoperiod (hrs dark / hrs light): 12 hrs dark/ 12 hrs light
Administration / exposure
- Route of administration:
- oral: feed
- Details on route of administration:
- Test animals were fed a diet consisting of 0, 1, 3, or 5% test substance ad libitum.
- Vehicle:
- other: CRF-1, Oriental Yeast Co., Ltd.
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency): every 9 weeks
- Mixing appropriate amounts with (Type of food): CFR-1
- Storage temperature of food: refrigerated
VEHICLE
- Justification for use and choice of vehicle (if other than water): The test substance is a solid with low water solubility.
- Concentration in vehicle: 0, 1, 3, and 5% of daily diet - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The test substance/diet mix was tested for uniformity. The top, middle and bottom of the mix was tested using duplicate samples. The stability of the test substance was checked in an sub-chronic toxicity study at 3, 10, and 18 weeks.
- Duration of treatment / exposure:
- Chronic oral toxicity: 52 weeks
Carcinogenicity: 104 weeks - Frequency of treatment:
- The test substance was mixed with the diet. Test animals had ad libitum access to the test substance/diet mix.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- males and females, 0% in diet
- Dose / conc.:
- 394 mg/kg bw/day (nominal)
- Remarks:
- males, 1% in diet
- Dose / conc.:
- 1 160 mg/kg bw/day (nominal)
- Remarks:
- males, 3% in diet
- Dose / conc.:
- 1 970 mg/kg bw/day (nominal)
- Remarks:
- males 5% in diet
- Dose / conc.:
- 480 mg/kg bw/day (nominal)
- Remarks:
- females, 1% in diet
- Dose / conc.:
- 1 440 mg/kg bw/day (nominal)
- Remarks:
- females, 3% in diet
- Dose / conc.:
- 2 440 mg/kg bw/day (nominal)
- Remarks:
- females, 5% in diet
- No. of animals per sex per dose:
- Chronic oral toxicity: 14
Carcinogenicity: 50 - Control animals:
- yes, plain diet
- Positive control:
- No
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: Survival, clinical signs, appearance, behaviour
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: Once a week for first 13 weeks, every 4 weeks thereafter.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
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: Yes
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Every 3 months, and within 1 week of end of treatment.
- Dose groups that were examined: All doses in the 52 week exposure groups.
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Every 3 months for satellite groups, every 6 months for main groups.
- Anaesthetic used for blood collection: No, except for collection prior to sacrifice.
- Animals fasted: Yes, 12 hrs.
- How many animals: All
- Parameters examined: Satellite groups: prothrombin time and activated partial thromboplastin time
Main groups: Erythrocyte count, leukocyte count, differential leukocyte count, platelet counts, hemoglobin, hematocrit, reticulocyte count, prothrombin time, activated partial thromboplastin time, mean corpuscular volume, and mean corpuscular hemoglobin concentration.
CLINICAL CHEMISTRY: Yes, satellite groups only.
- Time schedule for collection of blood: Every 3 months for satellite groups.
- Animals fasted: Yes, 12 hrs
- How many animals: All
- Parameters examined: total protein, glucose, triglycerides, total cholesterol, phospholipids, bilirubin, urea nitrogen, creatinine, calcium, inorganic phosphorous, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, albumin, albumin/globulin ratio, sodium, potassium, and chloride.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, all animals at termination
ORGAN WEIGHTS: Yes, from liver, kidneys, adrenals, testes, ovaries, brain, heart, lungs, and spleen.
HISTOPATHOLOGY: Yes - on 48 tissues and organs in all control and high-dose animals and in animal tissues showing macroscopic changes in the low- and mid-dose groups:
brain, pituitary, thyroid, thymus, trachea, lungs, heart, aorta, salivary glands, liver, spleen, adrenals, pancreas, testes, epididymides, prostate gland, seminal vesicle, ovaries, uterus, vagina, skin, tongue, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, kidneys, bladder, lymph nodes, mammary glands, muscle, sciatic nerve, femur, sternum, eyes, Harderian glands, spinal cord, nasal cavity, oviducts, auditory sebaceous gland, and extraorbital lacrimal gland, and any other organs and tissues with macroscopic changes. - Statistics:
- Numerical data: Bartlett's equial variance test
Data showing homogenous variance: analysis of variance (ANOVA)
Data with a signifcant difference between group: Dunnett's method (if number of animals in each group was the same), Scheffe's method (if number of animals in each group was different)
Data showing heterogenous variance: Kruskal-Wallis H test
Data with a signifcant difference between group: Dunnett-type rank sum test (if number of animals in each group was the same), Scheffe-type rank sum test (if number of animals in each group was different)
Survival ratio: Fischer exact method
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Description (incidence):
- No significant difference was noted in the survival percentages in any treatment group as compared to controls.
Survival at 52 (100%) and 104 weeks (66-76%) was not affected by the treatment. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Males in the high-dose group showed a significant decrease in weight gain in weeks 3, 4, 5, 6, 8, 10, 17, and 49.
During the second year of the study body weight progression was normal. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Food consumption was lower in the high-dose male group, and the female medium- and high-dose groups during the first week.
- Food efficiency:
- no effects observed
- Description (incidence and severity):
- Food efficiency was not affected, but an initial reduction in food intake in males and females was observed for a few weeks in the mid- and high-dose groups.
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No toxicologically significant differences between the test groups and the control groups were observed. All differences in values between the test groups and control groups were within historical controls.
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Statistically signifcant differences were noted between the test groups and the control groups, but none of these differences were dose dependent, and are therefore considered incidental.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Males in the medium- and high-dose groups showed higher absolute and relative spleen weights at 104 weeks. Males in the high-dose group also showed higher absolute heart weights. There was also an increase in absolute and relative spleen weight, and absolute lung weight in females in the medium-dose group. High spleen weights are common in aged rats of this strain. Incidences of up to 25% are common, as this effect was not seen in animals sacrificed earlier in life, this effect is not considered treatment related.
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No statistically significant differences between the test and control groups were seen in surviving animals. In the nonsurviving animals, about 1/2 had large granular lymphocyte leukemia with associated macroscopic observations. As this was also seen in the control group, it is not considered treatment related.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- An increase in extramedullary hematopoiesis was seen in the spleen in some of the 104 week exposure groups including the control group, but these increases were not statistically significant.
- Histopathological findings: neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Large granular lymphocyte leukemia was seen in both males and females with increase with increasing dose, but this increase was not statistically significant. An increase in mesothelioma in the abdominal cavity was also not statistically significant, and was within historical controls.
- Details on results:
- At termination of the 104 weeks study absolute and relative spleen weights were significantly increased in males at 3% and 5% and in females at 3% (but not in females at 5%). The changes in spleen weight and haematological parameters were most likely caused by the occurrence of large granular lymphocyte (LGL) leukaemia. Aged rats of this strain normally have a high incidence of LGL leukaemia that can be as high as 24% for males and 25% for females. In this experiment, the LGL leukaemia frequencies in the groups receiving 0%, 1%, 3% and 5% of test material were 7/50, 9/50, 11/50 and 12/50 in males and 10/50, 7/50, 14/50 and 13/50 in females, respectively. Thus, LGL leukaemia was a common neoplasm in all groups but was slightly increased without statistical significance at the two top doses.
However, when the rats that showed LGL leukaemia were removed from the spleen weight determinations, no differences were seen between treated and control rats. In that case, the spleen weights of the rats treated at concentrations of 0% 1%, 3% or 5% in the diet were 1.3, 1.3, 1.4 and 1.6 g in males 0.6, 0.7, 0.8 and 0.6 g in females, respectively.
Consistent with the higher incidence of LGL leukaemia in the high-dose group, there were associated non-neoplastic findings; extramedullary haematopoiesis in the spleen and
haematopoietic hyperplasia in the bone marrow was slightly (but not significantly) increased in the high-dose groups.
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 5 other: % diet
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- clinical signs
- food consumption and compound intake
- food efficiency
- gross pathology
- haematology
- histopathology: neoplastic
- histopathology: non-neoplastic
- mortality
- ophthalmological examination
- organ weights and organ / body weight ratios
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 970 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Remarks on result:
- other: equivalent to 5% in diet
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 2 440 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Remarks on result:
- other: equivalent to 5% in diet
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- The test substance was not toxic at up to 5% in the diet.
- Executive summary:
A 2-year chronic toxicity/carcinogenicity study was performed on male and female rats. Groups of 50 male and 50 females were fed a diet consisting of 0, 1, 3, or 5% of the test substance for 104 weeks. Other groups of 14 male and 14 female rats were fed a diet of the same concentrations for 52 weeks. The test substance was found to be non-toxic at up to 5% in the diet.
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