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EC number: 424-650-3 | 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
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- 21 September 1998
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.26 (Sub-Chronic Oral Toxicity Test: Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- 21.08.2001
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Details on species / strain selection:
- Considered suitable for type of study and usually required by regulatory agencies.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 6 weeks old
- Weight at study initiation: females: 153 - 177g; males 117 - 150g
- Housing: Macrolon cages with wood shavings as bedding material and shredded paper. Animals housed in groups of five, separated by sex
- Diet (e.g. ad libitum): ad libitum, commercial rodent diet (RM3)
- Water (e.g. ad libitum): ad libitum tap water for human comsumption
- Acclimation period: approx. 12 days
DETAILS OF FOOD AND WATER QUALITY:
Each batch of RM3 diet is analysed by the supplier for nutrients and contaminants
Routine microbiological, physical and chemical analysis of water made by supplier
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/-3°C
- Humidity (%): 30-70%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 hours dark; 12 hours light - Route of administration:
- oral: feed
- Details on route of administration:
- Test item extracted from diet using acetonitrile. Extracts examined using HPLC and Fluorescence detection. Quantitation of test item was obtained by comparing peak areas of the samples with reference solutions containing a known amount of the test substance.
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
- DIET PREPARATION
- Rate of preparation of diet (frequency): Once at start of study
- Mixing appropriate amounts with : Homogeneity was obtained by mixing in a mechanical blender. Feed in feeder was replaced by fresh portions once a week and topped up once weekly in between
- Storage temperature of food: Directly after preparation the feed was stored in a freezer (<-10C) until use. - Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Continuous - dietary
- Dose / conc.:
- 0.12 other: % (w/w)
- Remarks:
- low-dose
- Dose / conc.:
- 0.4 other: % (w/w)
- Remarks:
- mid-dose
- Dose / conc.:
- 1.2 other: % (w/w)
- Remarks:
- high-dose
- No. of animals per sex per dose:
- 10 males per dose
10 females per dose - Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale:
- Rationale for animal assignment (if not random): 7 days before start of the treatment, the rats were weighed. On starting day of the treatment (Day 0), they were weighed , checked for normal growth and correct weight variation. The rats were then allocated to groups proportionately by weight class by a computer randomisation program - Positive control:
- None
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: weekdays - twice per day; weekends - once per day
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: all rats prior to exposure, once weekly during treatment up to and including Week 12
BODY WEIGHT: Yes
- Time schedule for examinations: Day 0 and once per week thereafter. Final (fasted) body weights were determined on the day of the scheduled necropsy (Day 91 for males and Day 92 for females) in order to calculate the correct organ to body weight ratios
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: 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
WATER CONSUMPTION: Yes
- Time schedule for examinations: Weighing bottles daily over a four day period in Week 1, 6 and 12 of the study.
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Prior to start of study (Day -3)
- Dose groups that were examined: All groups
- Time schedule for examinations: Last week of treatment (Day 89)
- Dose groups that were examined: Control and high dose group
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at necropsy
- Anaesthetic used for blood collection: Yes (CO2/O2)
- Animals fasted: Yes
- How many animals: All groups
- Parameters checked in table 1 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at necrospy
- Animals fasted: Yes
- How many animals: All groups
- Parameters checked in table 2 were examined.
URINALYSIS: Yes (renal concentration test)
- Time schedule for collection of urine: Day 88-89 of study
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes (deprived of water for 24 hours, food in last 16 hours)
- Parameters checked in table 3 were examined.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Day 82-25 of the study
- Dose groups that were examined: All groups
- Battery of functions tested: see table 4
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table 5)
All rats from each treatment group were subjected to a complete macroscopic examination. Organs in table 5 were weighed (Paried organs together) as soon as possible after dissection to avoid drying
HISTOPATHOLOGY: Yes (see table 6)
Histopathological examination was performed on all tissues and organs in table 6 on all animal of the control and high dose groups
Liver, kidneys and all gross lesions were examined microscopically in all rats of all groups. - Statistics:
- -Body weight: one-way analysis of covariance using pre-exposure (Day 0) weights as the covariate. When group means were significantly different (p<0.005), individual pair wise comparisons were made using Dunnett's multiple comparison method.
-Food intake, food conversion efficiency, water intake, red blood cell and clotting potential variable, total white blood cell counts, absolute differential white blood cell counts, clinical chemistry values, volume and density of the urine and organ weights and terminal body weights: ANOVA followed by Dunnett's multiple comparison tests or the least significant difference (LSD) test, Independent from the results of anova, the homogeneity of variances was tested by means of Bartlett's test. Parameters for which the variances differed significantly (p<0.001), were re-evaluated with Kruskal-Wallis non-parametric Anova followed by Mann-Whitney U-tests.
Reticulocytes and relative differential white blood cell counts, semi-quantitative urinary determinations and microscopy of the urinary sediment: Kruskal-Wallis non-parametric anova. When this analysis yielded a signifcant difference, pair wise comparisons between the control- and treatment groups were made by means of Mann-Whitney U-tests.
- Functional observational battery and motor activity results: anova followed followed multiple comparison tests (continuous data), Kruskal-Wallis non-parametric anova followed by multiple comparisaon tests (rank order data) or Paerson chi-square test (categorical data)
- Histopathological changes: Fisher's exact probability test
All analyses were two-sided. Group mean differences with an assciated probability of less thatn 0.05 were considered to be statistically significant. - Clinical signs:
- effects observed, non-treatment-related
- 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:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Food conversion efficiency was comparable between the groups; a statistically significant decrease in high-dose males in Week 9 was considered an incidental finding.
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Increased haemoglobin concentration was noted in females of the low dose group.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Cholesterol concentration in the plasma was statistically significantly increased in females of the high-dose group.
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Presence of ketones in the urine in almost all males of the mid- and high-dose groups. Ketones were not detected in females in any group.
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- The relative weight of the liver was increased in males and females of the high-dose group
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Findings observed were common for rats of this strain and age, and occurred only incidental.
- Neuropathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Findings observed were common for rats of this strain and age, and occurred only incidentally.
Incidence of focal mineralisation in the overies was statistically significantly lower in the high-dose females that in the control. This is considered fortuitous because mineralization in the ovaries is frequently observed in Wistar rats at variable incidences - Histopathological findings: neoplastic:
- not examined
- Other effects:
- not specified
- Details on results:
- Decrease in feed intake per kg bw due to increasing age of the rats, intake of the test substance per kg bw gradually decreased. Overall mean intake of test substance in the low- mid- and high-dose groups was 74, 244 and 750 mg/kg bw/day for males and 74, 251 and 767 mg/kg bw/day for females
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 74 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- urinalysis
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 250 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- clinical biochemistry
- organ weights and organ / body weight ratios
- Critical effects observed:
- no
- Conclusions:
- It was concluded that the test substance NOAEL in this 13 week dietary study is placed at 0.12% in the diet (overall intake ca. 74 mg/kg bw/day) as the worst case value in males.
Reference
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 74 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
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
Justification for classification or non-classification
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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