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EC number: 473-160-6 | 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
Endpoint summary
Administrative data
Description of key information
A study according OECD TG 407 performed in rats with the read-across substance Blue MGi 1037 is available. Here, 50 mg/kg body weight/day of Blue MGi 1037 was established as the no-observed-effect-level (NOEL) and the no-observed-adverse-effect- level (NOAEL).
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 5 June 2000 - 2 August 2000
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- 27 July 1995
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: Directive 69/54/EEC, B.7
- Version / remarks:
- 30 September 1996
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- other: HanRcc:WIST (SPF)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: RCC Ltd, Biotechnology & Animal Breeding Division, CH-4414 Füllinsdorf/Switzerland
- Age at study initiation: 6 weeks
- Weight at study initiation: males: 118-162 g; females: 104-143 g
- Fasting period before study: yes
- Housing: in groups of five in Makrolon type-4 cages
- Diet: ad libitum, pelleted standard Provimi Kliba 3433 rat maintenance diet
- Water: ad libitum), tap water
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3
- Humidity (%): 40-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- bi-distilled water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test item formulations were prepared weekly. BLUE MGi 1037 was weighed into a glass beaker on a tared Mettler balance and the vehicle added. The mixtures were prepared using a magnetic stirrer and stored at room temperature (17-23°C). Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer. - Analytical verification of doses or concentrations:
- yes
- Remarks:
- HPLC
- Details on analytical verification of doses or concentrations:
- Concentration, homogeneity and stability (after 2 hours and 7 days) of the dose formulations were determined in samples taken during acclimatization. Concentration and homogeneity of the dose formulations were determined in samples taken during week 3 of the treatment. The analyses were performed by RCC Ltd (Environmental Chemistry & Pharmanalytics Division) according to a HPLC method supplied by the Sponsor.
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- 7 days/week
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Dose / conc.:
- 200 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10 (groups 1 and 4 ) or 5 (groups 2 and 3)
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Based upon the results of a non-GLP 5 day dose-range finding study in which the substance was administered by gavage to 2 rats per group and sex. Other than dark feces at the highest dose level, animals treated with 200, 600 or 1000 mg/kg bw/day showed no reaction to treatment.
- Fasting period before blood sampling for clinical biochemistry: yes
- Post-exposure recovery period in satellite groups: 14 days - Positive control:
- none
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION
- recorded once during the pre-test period and weekly thereafter
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of exposure period (4 weeks)
- Anaesthetic used for blood collection: Yes
- Animals fasted: Yes
- How many animals: all
- Parameters checked: Erythrocyte count, Hemoglobin, Hematocrit, Mean corpuscular volume, Mean corpuscular hemoglobin, Mean corpuscular hemoglobin concentration, Platelet count PLATELETS, Reticulocyte count, Reticulocyte fluorescence ratios Nucleated erythrocytes (normoblasts), Heinz bodies, Methemoglobin, Total leukocyte count, Differential leukocyte count, Red blood cell morphology, thromboplastin time, activated partial thromboplastin time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of exposure period (4 weeks)
- Animals fasted: Yes
- How many animals: all
- Parameters checked: Glucose, Urea, Creatinine, Uric Acid, Bilirubin, total, Cholesterol, total, Triglycerides, Phospholipids, Aspartate aminotransferase, Alanine aminotransferase, Lactate dehydrogenase, Creatine, Alkaline phosphatase, Gamma-glutamyl transferase, Calcium, Phosphorus, Sodium, Potassium, Chloride, Albumin, Protein, total, Globulin, Albumin/Globulin ratio
URINALYSIS: Yes
- Time schedule for collection of urine: after 4 weeks and after 6 weeks
- Metabolism cages used for collection of urine: No
- Animals fasted: Yes
- Parameters checked: osmolarity, pH, protein, glucose, ketone, bilirubin, blood and urobilinogen, volume, specific gravity, color appearance, ketone, bilirubin, blood nitrite, sediment, red blood cells, white blood cells, crystals
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: during week 4
- Dose groups that were examined: all animals
- Battery of functions tested: grip strength / locomotor activity
IMMUNOLOGY: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
Adrenal glands, Aorta, Bone (sternum, femur including joint), Bone marrow (femur), Brain (telecephalon, cerebellum, pons), Cecum, Colon, Duodenum, Epididymides (fixed in Bouin's solution), Esophagus, Eyes with optic nerve (fixed in Davidson's solution), Harderian gland (fixed in Davidson's solution), Heart, Ileum, with Peyer's patches, Jejunum with Peyer's patches, Kidneys, Larynx, Lacrimal gland (exorbital), Liver, Lungs (infused with formalin at necropsy), Lymph nodes (mesenteric, mandibular), Mammary gland area, Nasal cavity, Ovaries, Pancreas, Pituitary gland, Prostate gland, Rectum, Salivary glands (mandibular, sublingual), Sciatic nerve, Seminal vesicles, skeletal muscle, Skin, Spinal cord (cervical, midthoracic, lumbar), Spleen, Stomach, Testes (fixed in Bouin's solution), Thymus, Thyroid (incl. parathyroid gland), Tongue, Trachea, Urinary bladder (infused with formalin at necropsy), Uterus, Vagina
HISTOPATHOLOGY: Yes
Bone marrow (femur), brain, cecum, colon, duodenum, epididymes, heart, ileum, jejunum, kidneys, liver, lungs, lymph nodes, ovaries, prostate gland, rectum sciatic nerve, seminal vesicles, spindal cord, spleen, stomach, testes, thymus, thyroid, trachea, urinary bladder, uterus, vagina, gross lesions
Slides of these organs were collected at scheduled sacrifice from the animals of control and high-dose groups were examined by a pathologist. As test item-related morphologic changes were detected in the kidney and stomach of animals treated with 1000 mg/kg/day, these organs from animals of the mid- and low-dose groups were examined. - Statistics:
- The following statistical methods were used to analyze grip strength, locomotor activity, body weights, organ weights and all ratios, as well as clinical laboratory data :
• The Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
• The Steel-test (many-one rank test) was applied instead of the Dunnett-test when the data could not be assumed to follow a normal distribution.
• Student's T-Test was applied to locomotor activity and grip strength.
• Fisher's exact-test was applied to macroscopic findings.
• Armitage/Cochran Trend Test for non-neoplastic lesions. - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- No clinical signs of toxicity were noted at any dose level. Dark feces were noted during daily observations in males and females treated with 200 mg/kg bw/day and 1000 mg/kg bw/day. These findings were considered to be passive test item-related findings which commonly occur following oral administration of a dyestuff, rather than an indication of toxicity.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Significantly lower red blood cell count (p<0.05), hemoglobin levels (p<0.01) and hematocrit (p<0.01) were noted in males treated with 1000 mg/kg/day for four weeks. Significantly higher absolute and relative reticulocyte counts (p<0.01) were also recorded in the males treated with 1000 mg/kg/day. Although these differences were within the 95% tolerance limits of the historical control data, they were close to the lower or upper limits of the ranges. These changes were considered to be evidence of very slight anemia with compensatory reticulocytosis, but these findings were reversible after two weeks' recovery.
Males treated with 50 mg/kg/day or 200 mg/kg/day for four weeks were not affected.
Females treated with 50 mg/kg/day, 200 mg/kg/day or 1000 mg/kg/day for four weeks had slightly lower mean cell hemoglobin when compared with the controls. Although these differences attained statistical significance at 50 mg/kg/day (p<0.01) and 1000 mg/kg/day (p<0.05), they were not dose-dependant and therefore considered to be incidental changes. The mean prothrombin time of the test item-treated females was abbreviated when compared with the controls, and the differences attained statistical significance at 50 mg/kg/day (p<0.01) and 1000 mg/kg/day (p<0.05). These differences were well within the 95% tolerance limits of the historical control data and therefore considered to be incidental. - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Test item-related changes included significantly lower total protein levels (p<0.01) and significantly lower globulin levels (p<0.01) in males and females treated with 1000 mg/kg/day when compared with the control values. The albumin levels were significantly lower in females treated with 1000 mg/kg/day when compared with the control values, whereas the males were unaffected. These findings were largely reverted after the two-week recovery period, although some differences remained. The remaining differences from the control values (higher glucose levels in males treated with 50 mg/kg/day or 1000 mg/kg/day; higher uric acid levels in males and females at 1000 mg/kg/day; lower levels of total bilirubin in females treated at 1000 mg/kg/day, higher levels of total cholesterol in males treated with 1000 mg/kg/day; higher phospholipids in males at 1000 mg/kg/day; lower gamma glutamyl transferase activity in males treated at 1000 mg/kg/day; higher phosphorus levels in males treated with 1000 mg/kg/day; lower chloride levels in males treated with 1000 mg/kg/day) were either well within the 95% tolerance limits of the historical control data, not supported by concomitant differences in related parameters or not observed in the opposite sex and therefore considered to be fortuitous.
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- After four weeks' treatment, males treated with 1000 mg/kg/day had significantly higher specific gravity (p<0.05), higher osmolality (p<0.05) and higher pH (p<0.05) when compared with the controls. These changes were considered to be test item-related effects upon the ability of the kidney to concentrate urine. In females treated with 1000 mg/kg/day, a slight but statistically significant increase in the urinary pH was noted, when compared with controls. Ketone, considered likely to be a metabolic byproduct, was also present in the urine of males treated with 1000 mg/kg/day. All other differences from the control values noted after four week's treatment were considered to be fortuitous. All values compared favorably after two weeks' recovery.
- Behaviour (functional findings):
- effects observed, treatment-related
- Description (incidence and severity):
- The mean locomotor activity of the males and females treated with 1000 mg/kg bw/day was reduced when compared with the control animals. The difference from the controls attained statistical significance in males during the first two measurement intervals (p<0.01: 0-15 minutes; p<0.05: 15-30 minutes), and in females during the first measurement interval (p<0.01, 0-15 minutes). The overall mean locomotor activity of the males was reduced significantly (p<0.01) when compared with the controls. These differences were considered to be test item related. The animals treated with 50 mg/kg bw/day or 200 mg/kg bw/day were unaffected.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Changes in the kidney weights of males treated with 200 mg/kg/day and 1000 mg/kg/day for four weeks were considered to be test item-related. All weights and ratios exceeded those of the control males, and in several cases, attained statistical significance (absolute kidney weights at 200 mg/kg/day, p<0.01; kidney-to-body weight ratio at 200 mg/kg/day and 1000 mg/kg/day, p<0.05), and were considered to be indications of slight toxicity. After the two-week recovery period, the differences in absolute and relative kidney weights were partly reversible in the males previously treated with 1000 mg/kg/day when compared with the controls. The absolute and relative kidney weights of the females treated with 1000 mg/kg/day were generally similar to those of the control females after four weeks' treatment and two weeks' recovery. Females treated with 200 mg/kg/day had slightly elevated kidney weights and ratios (absolute kidney weight was statistically significant, p<0.05) when compared with the controls. This finding was considered to be incidental, as similar differences were not seen at the higher dose level. The remaining statistically significant changes noted in males (higher absolute spleen weight at 50 mg/kg/day, p<0.05; higher absolute brain and liver weights at 200 mg/kg/day, p<0.05) and females (higher absolute heart weight at 200 mg/kg/day, p<0.05; higher absolute and relative spleen weights at 200 mg/kg/day, p<0.05) after four week's treatment were considered to be incidental. After the two-week recovery period, the absolute and relative liver weights of females previously treated with 1000 mg/kg/day were lower than those of the control females. This finding was considered to be incidental.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In animals treated for four weeks, discolored kidneys were deemed to be test item-related findings.
The remaining findings were considered to be within the range of background lesions which may be recorded in animals of this strain and age. They consisted of renal pelvic dilation, seminal vesicles and thyroid glands reduced in size, uterus horn dilation, and discoloration or discolored foci in various organs. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- In the kidneys of animals treated for four weeks, tubular basophilia and lymphoid cell focus/foci increased slightly in incidence in animals treated with 1000 mg/kg/day. These findings were accompanied by minor degrees of tubular cell swelling consisting of small vacuolated tubular cells in some females. Such findings were not recorded in recovery animals.
Hyaline droplets were recorded in the glandular mucosa of one male and one female treated with 50 mg/kg/day, five males and four females treated with 200 mg/kg/day and all rats treated with 1000 mg/kg/day. This finding was also noted after recovery in two control females, as well as in two males and three females previously treated with 1000 mg/kg/day. Vacuolation of the squamous epithelium at the limiting ridge was recorded after four weeks' treatment in one control male and one control female, in four males and four females treated with 200 mg/kg/day, as well as four males and five females treated with 1000 mg/kg/day, and persisted after two weeks' recovery in one control female and two females previously treated with 1000 mg/kg/day.
The severity of these findings was increased slightly after the four week treatment period with dose dependence. Furthermore, increased inflammatory cell focus/foci in the glandular submucosa was recorded after four weeks treatment in all animals treated with 1000 mg/kg/day and after two weeks' recovery in one animal previously treated with 1000 mg/kg/day. - Histopathological findings: neoplastic:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 50 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: non-neoplastic
- Key result
- Critical effects observed:
- no
- Lowest effective dose / conc.:
- 200 mg/kg bw/day (nominal)
- System:
- gastrointestinal tract
- Organ:
- stomach
- Conclusions:
- Based on the results of this study, 50 mg/kg body weight/day of BLUE MGi 1037 was established as the NOEL and NOAEL.
- Executive summary:
Oral administration of BLUE MGi 1037 to Wistar rats at doses of 50, 200 and 1000 mg/kg/day, for 28 days resulted no toxic effects upon mortality, daily or weekly clinical signs, functional observational battery, grip strength, food consumption or body weights. Treatment-related findings were generally restricted to males and females treated with 1000 mg/kg/day, manifested by transient reductions of locomotor activity, changes in hematology parameters (indicative of very slight anemia with compensatory reticulocytosis, males only), changes in clinical biochemistry parameters (lower total protein and lower globulin levels in both sexes, and lower albumin levels in females only), and increased absolute and relative kidney weights (males only). These findings were noted after four week's treatment, but were reversible after two weeks' recovery.
Test item-related discoloration was noted macroscopically in the kidneys of animals treated with 1000 mg/kg/day after four weeks. Histologically, the incidence of lymphoid cell focus/foci increased slightly in animals treated with 1000 mg/kg/day after four weeks' treatment and two weeks' recovery. These findings were accompanied by minor degrees of tubular cell swelling, consisting of small vacuolated tubular cells in two females after four weeks of treatment.
In the stomach, the findings consisted of a higher incidence and severity of hyaline droplets in the glandular mucosa accompanied by an increased incidence and severity of epithelial vacuolation at the limiting ridge at 200 mg/kg/day and 1000 mg/kg/day, as well as increased inflammatory cell focus/foci at 1000 mg/kg/day. These findings are indicative of a minor irritant potential of the test article. These findings were mostly recovered after the two week recovery period.
Reference
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 50 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- OECD TG 407, GLP
- System:
- gastrointestinal tract
- Organ:
- stomach
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
In a subacute toxicity study, the read across substance BLUE MGi 1037 was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 50, 200 and 1000 mgykg body weight/day for a period of 28 days. A control group was treated similarly with the vehicle, bidistilled water, only. The groups comprised 5 animals per sex which were sacrificed after 28 days of treatment.
Additional 5 rats per sex and group were used at 0 and 1000 mg/kg. These animals were treated for 28 days and then allowed a 14-day treatment-free recovery period after which they were sacrificed. Clinical signs, outside cage observation, food consumption and body weights were recorded periodically during pretest, the treatment and recovery periods. Functional observational battery, locomotor activity and grip strength were performed during week 4. At the end of the dosing and the treatment-free recovery period, blood samples were withdrawn for hematology and plasma chemistry analyses. Urine samples were collected for urinalyses. All animals were killed, necropsied and examined post mortem. Histological examinations were performed on organs and tissues from all control and high dose animals, and all gross lesions from all animals. From the animals of the low and middle dose groups, the kidney and stomach were examined to establish a no-effect level.
All animals survived until scheduled necropsy.No clinical signs of toxicity were noted at any dose level during daily or weekly observations (weeks 1-3) or during the functional observational battery (week 4). Dark feces was noted during daily observations in males and females treated with 200 mg/kg/day and 1000 mg/kg/day. These findings were considered to be passive test item-related findings which commonly occur following oral administration of a dyestuff, rather than an indication of toxicity.
The fore- and hindlimb grip strength of the test item-treated animals was unaffected. A transient reduction of locomotor activity was noted in males and females treated with 1000 mg/kg/day when compared with the controls, most strongly in males during the first 30 minutes and in females during the first 15 minutes of the 60-minute measurement interval. These differences were considered to be related to the treatment with the test item.
Food consumption and body weights were unaffected by treatment with the test item.
Test item-related findings, generally indicative of very slight anemia with compensatory reticulocytosis, were noted in males treated with 1000 mg/kg/day for four weeks. These changes were seen neither in males treated with 50 mg/kg/day or 200 mg/kg/day, nor in any females treated with the test item. The findings noted in the males treated with 1000 mg/kg/day were no longer present after the two week recovery period.
Lower total protein levels and lower globulin levels were noted in males and females treated with 1000 mg/kg/day when compared with the controls. Albumin levels were lower in females treated with 1000 mg/kg/day when compared with the control values, whereas the males were unaffected. Although these findings were largely reversible after the two-week recovery period, some differences remained. All other parameters were considered to be unaffected by the treatment with the test item after four weeks' treatment and two weeks' recovery.
Changes in the urinalysis parameters (higher specific gravity, osmolality and pH) noted in males and females treated with 1000 mg/kg/day for four weeks were generally commensurate with effects upon the ability of the kidney to concentrate urine. In males treated with 1000 mg/kg/day for four weeks, ketone was present in the urine. The latter finding was not seen in females treated with 1000 mg/kg/day. These findings were reversible after two weeks' recovery. The urinalysis parameters of animals treated with 50 mg/kg/day or 200 mg/kg/day were unaffected after four weeks' treatment and two weeks' recovery.
Test item-related increases in kidney weights (accompanied with changes in urinalysis parameters and morphology) were restricted to the males treated with 1000 mg/kg/day for four weeks. The absolute and relative kidney weights of the females treated with 1000 mg/kg/day compared favorably with those of the controls. Although minor differences were noted in the some absolute and relative organ weights of males and females at 50 mg/kg/day or 200 mg/kg/day, these were not accompanied by corroborating evidence in related parameters and therefore considered to be incidental. All organ weights and ratios compared favorably after two weeks' recovery.
In the kidneys of animals treated for four weeks, discolored kidneys were recorded at necropsy. There was no histological correlate to the discoloration, and therefore, it may be considered that this finding was due to passive coloration form the test item or a metabolite thereof. However, the relative and absolute kidney weights increased significantly in males after four weeks' treatment. Tubular basophilia and lymphoid cell focus/foci increased in incidence in animals treated with 1000 mg/kg/day. These findings were accompanied by minor degrees of tubular cell swelling consisting of small vacuolated tubular cells in some females. The latter finding is deemed to be contributive to higher kidney weights, although this finding was not recorded in males. It is considered, that the test item led to a slightly osmotic tubular nephrosis. This is supported by minor increased uric acid and minor decreased bilirubin, albumin and protein levels at the high dose group after the treatment period. Moreover, urine osmolality increased significantly in males after the treatment period.
In the stomach, the findings consisted of a higher incidence of hyaline droplets in the glandular mucosa after four weeks' treatment and two weeks' recovery. This finding was accompanied by an increased incidence and severity of limiting ridge vacuolation in animals treated with 1000 mg/kg/day after four weeks. Furthermore, increased inflammatory cell focus/foci in the glandular submucosa was recorded in all animals after four weeks and on one recovery animal treated with 1000 mg/kg/day. These findings are indicative for a minor irritative potential of the test item.
ASSESSMENT
Oral administration of BLUE MGi 1037 to Wistar rats at doses of 50, 200 and 1000 mg/kg/day, for 28 days resulted no toxic effects upon mortality, daily or weekly clinical signs, functional observational battery, grip strength, food consumption or body weights. Treatment-related findings were generally restricted to males and females treated with 1000 mg/kg/day, manifested by transient reductions of locomotor activity, changes in hematology parameters (indicative of very slight anemia with compensatory reticulocytosis, males only), changes in clinical biochemistry parameters (lower total protein and lower globulin levels in both sexes, and lower albumin levels in females only), and increased absolute and relative kidney weights (males only). These findings were noted after four week's treatment, but were reversible after two weeks' recovery.
Test item-related discoloration was noted macroscopically in the kidneys of animals treated with 1000 mg/kg/day after four weeks. Histologically, the incidence of lymphoid cell focus/foci increased slightly in animals treated with 1000 mg/kg/day after four weeks' treatment and two weeks' recovery. These findings were accompanied by minor degrees of tubular cell swelling, consisting of small vacuolated tubular cells in two females after four weeks of treatment.
In the stomach, the findings consisted of a higher incidence and severity of hyaline droplets in the glandular mucosa accompanied by an increased incidence and severity of epithelial vacuolation at the limiting ridge at 200 mg/kg/day and 1000 mg/kg/day, as well as increased inflammatory cell focus/foci at 1000 mg/kg/day. These findings are indicative of a minor irritant potential of the test article. These findings were mostly recovered after the two week recovery period.
Based on the results of this study, 50 mg/kg body weight/day of BLUE MGi 1037 was established as the no-observed-effect-level (NOEL) and the no-observed-adverse-effect- level (NOAEL).
Justification for classification or non-classification
Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. The substance is not considered to be classified for repeated dose toxicity according to Regulation (EC) No 1272/2008 (CLP), as amended for the twelfth time in Regulation (EU) 2019/521.
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.
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