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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
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- December 27, 1990-December 27, 1991
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with national standard methods
Cross-reference
- Reason / purpose for cross-reference:
- read-across source
Reference
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- December 27, 1990-December 27, 1991
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with national standard methods
- Qualifier:
- according to guideline
- Guideline:
- other: Toxicological Principles for the Safety Assessment of Direct Food Aditives and Color Additives used in Food (FDA, USA, 1982)
- Deviations:
- yes
- Remarks:
- Stability testing was performed on feed mixes containing 1 and 5% of test substane after 18 weeks, rather than feed containing 0.1 and 10% of feed after 10 weeks storage in refrigeration.
- GLP compliance:
- yes
- Limit test:
- no
- Specific details on test material used for the study:
- TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Final preparation of a solid: Mixed with basal diet feed. - Species:
- rat
- Strain:
- Fischer 344/DuCrj
- Details on species / strain selection:
- Strain chosen as it has been used extensively in long-term toxicity study, and therefore sufficient background data is available on it.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Japan, Inc.
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 5 weeks
- Weight at study initiation: 73-88 g males, 74-89 g females
- Fasting period before study: No
- Housing: 2 animals in polycarbonate cages with hardwood chip bedding
- Diet: CRF-1, Oriental Yeast Co., radition-sterilized, ad libitum
- Water: filtered, UV sterilized tap water ad libitum
- Acclimation period: 5-8 days
DETAILS OF FOOD AND WATER QUALITY: Food was analyzed by a third party to ensure contaminants were below acceptable levels. Drinking water is tested biannually.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25
- Humidity (%): 40-70
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: January 14, 1991 To: April 26, 1991 - Route of administration:
- oral: feed
- Details on route of administration:
- Since the test substance will be taken orally during actual use, it was decided to perform an oral toxicity study in feed.
- Vehicle:
- other: feed
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): radiation sterilized powdered feed for rats and mice
VEHICLE
- Justification for use and choice of vehicle (if other than water): appropriate feed for species selected
- Concentration in vehicle: 1, 3, and 5% - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples were taken from the top, middle, and bottom of the first batch of feed prepared. All lots of feed mix were analyzed. The stability of the test substance with checked after 18 weeks at 5-10 °C storage for the 1 and 5% mixtures. Analysis was done using gas chromatography.
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Animals were given feed containing the test substance ad libitum throughout the study period.
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Control group
- Dose / conc.:
- 636 mg/kg bw/day (nominal)
- Remarks:
- 1% of diet male
- Dose / conc.:
- 666 mg/kg bw/day (nominal)
- Remarks:
- 1% of diet female
- Dose / conc.:
- 1 900 mg/kg bw/day (nominal)
- Remarks:
- 3% of diet male
- Dose / conc.:
- 1 950 mg/kg bw/day (nominal)
- Remarks:
- 3% of diet female
- Dose / conc.:
- 3 240 mg/kg bw/day (nominal)
- Remarks:
- 5% of diet male
- Dose / conc.:
- 3 430 mg/kg bw/day (nominal)
- Remarks:
- 5% of diet female
- No. of animals per sex per dose:
- 20
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: 5% was the maximum dose recommended in the guideline.
- Rationale for animal assignment (if not random): random sampling based on body weight stratification
- Section schedule rationale (if not random): - 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: weekly
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: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
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: 3-1 days before study start, and 5-2 days before end of study
- Dose groups that were examined: control, high dose
HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to sacrifice at end of study
- Anaesthetic used for blood collection: Yes (sodium pentobarbital)
- Animals fasted: Yes
- How many animals: all
- Parameters checked: erythrocyte count, leucocyte count, platelet count, hemoglobin concentration, hematocrit, differential leucocyte count, reticulocyte count, prothrombin time, activated partial thromboplastin time, mean corpuscular volume, and mean corpuscular hemoglobin
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to sacrifice
- Animals fasted: Yes
- How many animals: all
- Parameters checked: total protein, glucose, triglycerides, total cholesterol, phospholipids, free fatty acids, urea nitrogen, creatinine, calcium, inorganic phosphorous, GOT, GPT, gamma-GTP, ALP, albumin, A/G ratio, sodium, potassium, and chlorine
URINALYSIS: Yes
- Time schedule for collection of urine: 4-3 days before end of study
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked: pH, occult blood, protein, glucose, ketone bodies, bilirubin, urobilirubin
NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
General examination, weights of liver, kidneys, adrenals, testes, ovaries, brain, heart, lung, and spleen
HISTOPATHOLOGY: Yes
brain, pituitary, thyroid/parathyroids, 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 gland, muscle, sciatic nerve, femur, sternum, eyes, spinal cord, any other organs with macroscopic changes - Statistics:
- Bartlett's equal variance, ANOVA for homogenous variance, Dunnett's method was used to compare mean values between groups with the same number of animals, Scheffe's method was used to compare mean values between groups with different numbers of animals, heterogeneous variance was analyzed using the Kruskal-Wallis H-test, Data from the urinalysis was analyzed using the Armitage chi-squared test
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Bilateral alopecia of the forelimbs was noted in one female in the low dose group at 10 weeks. As this was not seen in any other group, it was not considered to be related to treatment.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Suppression of weight gain was noted in the medium dose male group in the early to mid-part of the study period. As this effect was not dose dependent, it was not considered treatment related.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Males in the high dose group showed increased food consumption. The increase was not consistent, and the difference was slight. When the weight of test substance was subtracted from the total food weight, the actual consumption in this group was identical.
- Food efficiency:
- effects observed, non-treatment-related
- Description (incidence and severity):
- A decrease in food efficiency was observed in some males animals, but this effect was short-term.
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Females in the high dose group showed prolonger activated partial thromboplastin times. As the value was still within the normal range of background data, this effect was concluded to be non-treatment related.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- A significant increase in albumin, and elevation in GPT in the medium and high dose male groups. The high dose males also showed a significant increase in potassium. The increase in albumin and potassium was not considered treatment related. The female high dose group also showed significant elevation of GPT. The increase in GPT values was dose-dependent, but within the range of the control group. Since no changes were seen in the livers, this effect, though treatment related, was considered to be of minor importance. A longer term study would be needed to determine the full significance of this increase. Males in the medium dose group and females in the low dose group showed decreased levels of sodium. As this decrease was not dose-dependent, it was not considered treatment related.
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- A decrease of ketone bodies was observed in males in the high dose group. However, this effect is not considered to be toxicologically significant.
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- High and medium dose males showed a significant decrease in absolute kidney weights. A significant decrease in relative kidney weights was seen in all male treatment groups. A decrease in relative liver weight was seen in the high dose male group. These differences were 5% or less, and no other changes relating to the decrease were observed. Thus, these effects were not attributed to treatment. A significant decrease in absolute adrenal weight was seen in the medium dose male group. This decrease was attributed to the decrease in average body weight of the treatment groups, and so the effect was not considered significant.
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- One female in the medium dose group showed a unilateral ovarian cyst. Ovarian bursa cysts were also in one female in the low dose group, and two in the medium dose group. Hydrometra was seen in one female in the control, medium, and high dose groups. Partial alopecia was seen in one female in the low dose groups. As none of theses changes was dose-related, they were not considered to be treatment related.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Hyaline droplets in the epithelium of the renal uriniferous tubules were frequently found in the control and high dose male. Since there was no significant difference between the groups, this change was not considered to be treatment related. Other changes noted in various groups were focal myocardial degeneration, dilation of the tracheal glands, calcinosis of the reanal cortico-medullary junction, and regeneration fo the uriniferous tubules. These changes were not dose dependent, and therefore not considered to be treatment related. Changes noted in less than 5 males or females, and therefore not considered to be treatment related, were increased extramedullary hematopoiesis in the spleen, lymphocytic infiltration of the tracheal submucosa, cellular infiltration in Glisson's sheath and focal necrosis in the liver, interstitial ductal proliferation and lymphocytic infiltration in the pancreas, lymphocytic infiltration of the hyaline casts and interstitial tissue in the kidney, interstitial lymphocytic infiltration of the thyroid gland, and interstitial lymphocytic infiltration of the Harderian glands. Cysts formed by the dilation of the lymphatic vessels of the ovaries, hydrometra, and hair loss were also observed. These did not occur often enough to be considered treatment related.
- Histopathological findings: neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Focal osseous metaplasia of the alveolar wall was seen in less than 5 males or females.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 3 240 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Remarks on result:
- other: No adverse effects observed up to the highest dose tested.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 3 430 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Remarks on result:
- other: No adverse effects observed up to the highest dose tested.
- Key result
- Critical effects observed:
- no
- Lowest effective dose / conc.:
- 3 240 mg/kg bw/day (nominal)
- System:
- other: blood
- Organ:
- blood
- Conclusions:
- The NOAEL for S/P MDT in male rats was 3240 mg/kg bw/day (5% of diet), and the NOAEL for female rats was 3430 mg/kg bw/day (5% of diet).
- Executive summary:
The oral toxicity of S/P MDT was determined in a 13-week feed study. The substance was added to the diet at 0, 1, 3, and 5%. Groups of 20 male and 20 female rats were tested at each dose level. After 13 weeks, the animals were sacrificed and necropsied. A slight mean increase in GPT activity of the medium and high dose males, and high dose females was noted. As all the observed values were within the control range, a longer term test would be needed to determine if this was treatment related. As there were no definitive treatment related effects, the NOAEL for both males and females was the highest dose, 5% of feed. For males, this was the equivalent of 3240 mg/kg bw/day, and for females 3430 mg/kg bw/day. The NOAEL for LMD is therefore expected to be 3240 mg/kg bw/day for males, and for females 3430 mg/kg bw/day.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 991
- Report date:
- 1991
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: Toxicological Principles for the Safety Assessment of Direct Food Aditives and Color Additives used in Food (FDA, USA, 1982)
- Deviations:
- yes
- Remarks:
- Stability testing was performed on feed mixes containing 1 and 5% of test substane after 18 weeks, rather than feed containing 0.1 and 10% of feed after 10 weeks storage in refrigeration.
- GLP compliance:
- yes
- Limit test:
- no
Test material
Constituent 1
- Specific details on test material used for the study:
- TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Final preparation of a solid: Mixed with basal diet feed.
Test animals
- Species:
- rat
- Strain:
- Fischer 344/DuCrj
- Details on species / strain selection:
- Strain chosen as it has been used extensively in long-term toxicity study, and therefore sufficient background data is available on it.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Japan, Inc.
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 5 weeks
- Weight at study initiation: 73-88 g males, 74-89 g females
- Fasting period before study: No
- Housing: 2 animals in polycarbonate cages with hardwood chip bedding
- Diet: CRF-1, Oriental Yeast Co., radition-sterilized, ad libitum
- Water: filtered, UV sterilized tap water ad libitum
- Acclimation period: 5-8 days
DETAILS OF FOOD AND WATER QUALITY: Food was analyzed by a third party to ensure contaminants were below acceptable levels. Drinking water is tested biannually.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25
- Humidity (%): 40-70
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: January 14, 1991 To: April 26, 1991
Administration / exposure
- Route of administration:
- oral: feed
- Details on route of administration:
- Since the test substance will be taken orally during actual use, it was decided to perform an oral toxicity study in feed.
- Vehicle:
- other: feed
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): radiation sterilized powdered feed for rats and mice
VEHICLE
- Justification for use and choice of vehicle (if other than water): appropriate feed for species selected
- Concentration in vehicle: 1, 3, and 5% - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples were taken from the top, middle, and bottom of the first batch of feed prepared. All lots of feed mix were analyzed. The stability of the test substance with checked after 18 weeks at 5-10 °C storage for the 1 and 5% mixtures. Analysis was done using gas chromatography.
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Animals were given feed containing the test substance ad libitum throughout the study period.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Control group
- Dose / conc.:
- 636 mg/kg bw/day (nominal)
- Remarks:
- 1% of diet male
- Dose / conc.:
- 666 mg/kg bw/day (nominal)
- Remarks:
- 1% of diet female
- Dose / conc.:
- 1 900 mg/kg bw/day (nominal)
- Remarks:
- 3% of diet male
- Dose / conc.:
- 1 950 mg/kg bw/day (nominal)
- Remarks:
- 3% of diet female
- Dose / conc.:
- 3 240 mg/kg bw/day (nominal)
- Remarks:
- 5% of diet male
- Dose / conc.:
- 3 430 mg/kg bw/day (nominal)
- Remarks:
- 5% of diet female
- No. of animals per sex per dose:
- 20
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: 5% was the maximum dose recommended in the guideline.
- Rationale for animal assignment (if not random): random sampling based on body weight stratification
- Section schedule rationale (if not random):
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: weekly
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: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
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: 3-1 days before study start, and 5-2 days before end of study
- Dose groups that were examined: control, high dose
HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to sacrifice at end of study
- Anaesthetic used for blood collection: Yes (sodium pentobarbital)
- Animals fasted: Yes
- How many animals: all
- Parameters checked: erythrocyte count, leucocyte count, platelet count, hemoglobin concentration, hematocrit, differential leucocyte count, reticulocyte count, prothrombin time, activated partial thromboplastin time, mean corpuscular volume, and mean corpuscular hemoglobin
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to sacrifice
- Animals fasted: Yes
- How many animals: all
- Parameters checked: total protein, glucose, triglycerides, total cholesterol, phospholipids, free fatty acids, urea nitrogen, creatinine, calcium, inorganic phosphorous, GOT, GPT, gamma-GTP, ALP, albumin, A/G ratio, sodium, potassium, and chlorine
URINALYSIS: Yes
- Time schedule for collection of urine: 4-3 days before end of study
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked: pH, occult blood, protein, glucose, ketone bodies, bilirubin, urobilirubin
NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
General examination, weights of liver, kidneys, adrenals, testes, ovaries, brain, heart, lung, and spleen
HISTOPATHOLOGY: Yes
brain, pituitary, thyroid/parathyroids, 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 gland, muscle, sciatic nerve, femur, sternum, eyes, spinal cord, any other organs with macroscopic changes - Statistics:
- Bartlett's equal variance, ANOVA for homogenous variance, Dunnett's method was used to compare mean values between groups with the same number of animals, Scheffe's method was used to compare mean values between groups with different numbers of animals, heterogeneous variance was analyzed using the Kruskal-Wallis H-test, Data from the urinalysis was analyzed using the Armitage chi-squared test
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Bilateral alopecia of the forelimbs was noted in one female in the low dose group at 10 weeks. As this was not seen in any other group, it was not considered to be related to treatment.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Suppression of weight gain was noted in the medium dose male group in the early to mid-part of the study period. As this effect was not dose dependent, it was not considered treatment related.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Males in the high dose group showed increased food consumption. The increase was not consistent, and the difference was slight. When the weight of test substance was subtracted from the total food weight, the actual consumption in this group was identical.
- Food efficiency:
- effects observed, non-treatment-related
- Description (incidence and severity):
- A decrease in food efficiency was observed in some males animals, but this effect was short-term.
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Females in the high dose group showed prolonger activated partial thromboplastin times. As the value was still within the normal range of background data, this effect was concluded to be non-treatment related.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- A significant increase in albumin, and elevation in GPT in the medium and high dose male groups. The high dose males also showed a significant increase in potassium. The increase in albumin and potassium was not considered treatment related. The female high dose group also showed significant elevation of GPT. The increase in GPT values was dose-dependent, but within the range of the control group. Since no changes were seen in the livers, this effect, though treatment related, was considered to be of minor importance. A longer term study would be needed to determine the full significance of this increase. Males in the medium dose group and females in the low dose group showed decreased levels of sodium. As this decrease was not dose-dependent, it was not considered treatment related.
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- A decrease of ketone bodies was observed in males in the high dose group. However, this effect is not considered to be toxicologically significant.
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- High and medium dose males showed a significant decrease in absolute kidney weights. A significant decrease in relative kidney weights was seen in all male treatment groups. A decrease in relative liver weight was seen in the high dose male group. These differences were 5% or less, and no other changes relating to the decrease were observed. Thus, these effects were not attributed to treatment. A significant decrease in absolute adrenal weight was seen in the medium dose male group. This decrease was attributed to the decrease in average body weight of the treatment groups, and so the effect was not considered significant.
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- One female in the medium dose group showed a unilateral ovarian cyst. Ovarian bursa cysts were also in one female in the low dose group, and two in the medium dose group. Hydrometra was seen in one female in the control, medium, and high dose groups. Partial alopecia was seen in one female in the low dose groups. As none of theses changes was dose-related, they were not considered to be treatment related.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Hyaline droplets in the epithelium of the renal uriniferous tubules were frequently found in the control and high dose male. Since there was no significant difference between the groups, this change was not considered to be treatment related. Other changes noted in various groups were focal myocardial degeneration, dilation of the tracheal glands, calcinosis of the reanal cortico-medullary junction, and regeneration fo the uriniferous tubules. These changes were not dose dependent, and therefore not considered to be treatment related. Changes noted in less than 5 males or females, and therefore not considered to be treatment related, were increased extramedullary hematopoiesis in the spleen, lymphocytic infiltration of the tracheal submucosa, cellular infiltration in Glisson's sheath and focal necrosis in the liver, interstitial ductal proliferation and lymphocytic infiltration in the pancreas, lymphocytic infiltration of the hyaline casts and interstitial tissue in the kidney, interstitial lymphocytic infiltration of the thyroid gland, and interstitial lymphocytic infiltration of the Harderian glands. Cysts formed by the dilation of the lymphatic vessels of the ovaries, hydrometra, and hair loss were also observed. These did not occur often enough to be considered treatment related.
- Histopathological findings: neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Focal osseous metaplasia of the alveolar wall was seen in less than 5 males or females.
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 3 240 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Remarks on result:
- other: No adverse effects observed up to the highest dose tested.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 3 430 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Remarks on result:
- other: No adverse effects observed up to the highest dose tested.
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
- Lowest effective dose / conc.:
- 3 240 mg/kg bw/day (nominal)
- System:
- other: blood
- Organ:
- blood
Applicant's summary and conclusion
- Conclusions:
- The NOAEL for male rats was 3240 mg/kg bw/day (5% of diet), and the NOAEL for female rats was 3430 mg/kg bw/day (5% of diet).
- Executive summary:
The oral toxicity of the test substance was determined in a 13-week feed study. The substance was added to the diet at 0, 1, 3, and 5%. Groups of 20 male and 20 female rats were tested at each dose level. After 13 weeks, the animals were sacrificed and necropsied. A slight mean increase in GPT activity of the medium and high dose males, and high dose females was noted. As all the observed values were within the control range, a longer term test would be needed to determine if this was treatment related. As there were no definitive treatment related effects, the NOAEL for both males and females was the highest dose, 5% of feed. For males, this was the equivalent of 3240 mg/kg bw/day, and for females 3430 mg/kg bw/day.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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