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EC number: 414-310-2 | CAS number: 191358-81-3
- 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:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2007-09-28 to 2008-03-11
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline Study (OECD 407 adopted 1995), GLP compliant. Acceptable deviations fromOECD Guideline 407 adopted 2008: less organs weighed and mircoscopically examined.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 008
- Report date:
- 2008
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- adopted 1995
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: Japanese Guidelines for Screening Toxicity Testing of Chemicals: Testing Methods for New Substances, enacted July 13, 1974, amended December 5, 1986
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: RCC Ltd Laboratory Animal Services; Wölferstrasse 4; 4414 Füllinsdorf / Switzerland
- Total Number of Animals Used: 30 males and 30 females
- Age (at Delivery): 7 weeks
- Body Weight Range: Males: 158.3 to 170.2 g (mean 164.0 g) ; Females: 128.1 to 145.0 g (mean 135.1 g)
- Acclimation: 7 days under test conditions after health examination. Only animals without any visible signs of illness were used for the study.
- Housing: In groups of five in Makrolon type-4 cages with wire mesh tops and standard softwood bedding
- Diet: Pelleted standard Kliba Nafag 3433 (batch no. 40/07) rat maintenance diet was available ad libitum.
- Water: Community tap-water from Itingen was available ad libitum in water bottles
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12 with music during the light period
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): microgranulated feed; an appropriate amount of water was added to aid pelleting; the pellets were dried with air for approximately 48 hours before storage.
- Storage temperature of food: room temperature (20 ± 5 °C) - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- After experimental start, samples of the control group as well as three samples (top, middle and bottom) of each concentration were taken prior to dosing for analysis of homogeneity, concentration and stability. Samples of each concentration were taken during weeks 2 to 4 after each adjustment of feed preparations (based on previously measured body weight gain and feed consumption) to confirm homogeneity and concentration. Analysis done by High Performance Liquid Chromatographic demonstrated a stability of 12 days and confirmed homogeneity and concentrations.
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- continuous
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
0, 50, 200, 1000 mg/kg bw/day
Basis:
nominal in diet
- Remarks:
- Doses / Concentrations:
0, 52, 215, 1063 (males) and 0, 52, 207, 1020 (females) mg/kg bw/d
Basis:
actual ingested
- No. of animals per sex per dose:
- Main test: 5 males / 5 females per dose;
Reccovery: additional 5 animals/sex at 0 and at 1000 mg/kg bw/day - Control animals:
- yes, plain diet
- Details on study design:
- - Post-exposure recovery period in satellite groups: 14 days
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Viability/Mortility: twice daily
- General clinical observations: once daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once weekly
BODY WEIGHT: Yes
- Time schedule for examinations: Twice weekly during week 1, once weekly during week 2 to 4
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Time schedule: Twice weekly during week 1, once weekly during week 2 to 4
- Food 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
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 4 and 6 weeks
- Anaesthetic used for blood collection: Yes (light isoflurane anesthesia)
- Animals fasted: Yes, 18 hours fasting period
- How many animals: all
- Parameters examined: Erythrocyte count
Hemoglobin, Hematocrit, Mean corpuscular volume, Red cell volume distribution width, Mean corpuscular hemoglobin, Mean corpuscular hemoglobin concentration, Hemoglobin concentration distribution width, Reticulocyte count, Reticulocyte maturity index (low, medium,high fluorescence), Leukocyte count, total, Differential leukocyte count: Neutrophils, Eosinophils, Basophils, Lymphocytes, Monocytes, Large unstained cells, Platelet count
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after 4 and 6 weeks
- Animals fasted: Yes, 18 hours fasting period
- How many animals: all
- Parameters examined: Glucose, Urea, Creatinine, Bilirubin, total, Cholesterol, total, Triglycerides, Aspartate aminotransferase, Alanine aminotransferase, Lactate dehydrogenase, Glutamate dehydrogenase, Alkaline phosphatase, Gamma-glutamyl-ransferase, Creatine kinase, Sodium Potassium, Chloride, Calcium, Phosphorus, Protein, total, Albumin, Globulin, Albumin/Globulin ratio, Prothrombin time (= Thromoplastin time), Activated partial Thromoplastin time, Methemoglobin
URINALYSIS: Yes
- Time schedule for collection of urine: after 4 and 6 weeks
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes (urine collected during 18 hours fasting period)
- Parameters examined: Urine volume (18 hour), Specific gravity (relative density), Color, Appearance, pH value, Nitrite, Protein, Glucose, Ketones, Urobilinogen, Bilirubin, Erythrocytes, Leukocytes
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: During week 4
- Dose groups that were examined: all
- Battery of functions tested: modified Irwin screen incl. sensory activity / grip strength / motor activity - Sacrifice and pathology:
- - Sacrifice:
After 4 Weeks: Main test
After 6 Weeks: Recovery
GROSS PATHOLOGY: Yes
- All animals were weighed and necropsied. Descriptions of all macroscopic abnormalities were recorded.
- Organ weights dertemined: Adrenal glands, Brain, Epididymides, Heart, Kidneys, Liver, Ovaries, Spleen, Testes, Thymus, Thyroid / parathyroid, Uterus
HISTOPATHOLOGY: Yes
- Tissues examined: Adrenal glands; Bone marrow (femur); Brain - including section of medulla/pons, cerebral and cerebellar cortex; Cecum; Colon; Duodenum; Epididymides (fixed in Bouin's solution); Heart including auricles; Ileum, with Peyer's patches; Jejunum with Peyer's patches; Kidneys; Liver; Lungs, filled w/formalin at necropsy; Lymph nodes - mesenteric and mandibular; Ovaries; Prostate gland incl. coagulating glands; Rectum; Sciatic nerve; Seminal vesicles; Spinal cord - cervical, midthoracic, lumbar; Spleen; Stomach; Testes (fixed in Bouin's solution); Thymus; Thyroid (incl. parathyroid gland, if possible); Trachea; Urinary bladder, filled w/formalin at necropsy; Uterus; Vagina; Gross lesions; - Statistics:
- The following statistical methods were used to analyze the grip strength, locomotor activity, food consumption, body weight, clinical laboratory data, organ weights and ratios as well as macroscopic findings:
• 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 Dunnetttest when the data could not be assumed to follow a normal distribution.
• Fisher's exact-test.
Results and discussion
Results of examinations
- Details on results:
- CLINICAL SIGNS AND MORTALITY
All animals survived until scheduled necropsy. No test item-related clinical signs were noted.
BODY WEIGHT AND WEIGHT GAIN
No test item-related effects on the absolute or relative body weights were noted at any dose level tested.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
No test item-related effects on the absolute and relative food consumption was noted. The mean of means of the test item intake over treatment period was close to all target doses. It ranged from 103.8% to 107.7% in males and 102.0% to 103.4% in females.
HAEMATOLOGY
No test item-related changes were noted in the hematology parameters of either sex after treatment and revovery period at any dose level tested.
CLINICAL CHEMISTRY
Test item-related adaptive changes were noted in males and females treated with 1000 mg/kg body weight/day and in females treated with 200 mg/kg body weight/day.
In animals treated with 1000 mg/kg body weight/day elevated sodium, albumin and protein was noted and additionally elevated cholesterol, calcium and decreased phoshorus in females, only. Females treated with 200 mg/kg body weight/day showed elevated sodium, only.
No changes were noted in enzymes indicating liver or kidney damage.
No test item-related changes were noted after recovery period.
URINALYSIS
No test item-related changes were noted.
NEUROBEHAVIOUR
- Functional observation battery and grip strength: No test item-related findings were noted.
- Locomotor activity: Initial elevation of the locomotor activity was noted at the first two timepoints of measurement in animals treated with 1000 mg/kg body weight/day. Nevertheless, during the detailed behavioral observations, no clinical signs were noted which would have been indicative of possible neurotoxicity. Therefore this finding was considered to be non-adverse.
ORGAN WEIGHTS
No test item-related changes were noted in the mean absolute or relative organ weights at the end of treatment or recovery period.
GROSS PATHOLOGY / HISTOPATHOLOGY
No test item-related macroscopic or microscopic findings were noted at the end of treatment or recovery period at any dose level tested.
Effect levels
open allclose all
- Dose descriptor:
- NOEL
- Effect level:
- 50 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Increased albumin, protein, cholesterol and calcium levels and decreased phosphorous levels at 1000 mg/kg bw/day
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Effects seen in lower doses are considered to be adaptive processes or were not noted after recovery period anymore, and therefore non-adverse
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Dietary administration of the test item at target dose levels of 50, 200 and 1000 mg/kg body weight/day had no effects on survival rate, clinical signs, grip strength, food consumption, body weights, hematology, urinalysis parameters, organ weights and macroscopic or microscopic changes in pathology.
In clinical biochemistry, slight increased sodium levels in both sexes treated with 1000 mg/kg body weight/day and in females treated with 200 mg/kg body weight/day were noted but not accompanied by changes in hematocrit, urinalysis parameters such as volume or density or changes of the adrenal gland in histopathology. The changes stayed within ranges of historical reference data and were not noted after recovery period. Increased sodium levels were considered to be test item-related but non-adverse.
In animals treated with 1000 mg/kg body weight/day increased levels of albumin and protein were above ranges of historical reference data in females. These changes in albumin and protein levels were not accompanied by increased hematocrit indicating dehydration and therefore considered to be an adaptive process of the liver. In absence of microscopic findings, changes in liver specific enzymes and findings after recovery period, the findings of elevated albumin and protein were considered to be test item-related but non-adverse. An interference of a possible coloring effect of the test item with the colorimetric method of measuring albumin and protein in plasma could not be outruled.
Elevated cholesterol, calcium and decreased phosphorus in high dose females were not noted after recovery period anymore and also considered to be test item-related but non-adverse.
Initially elevated locomotor activity in males and females treated with 1000 mg/kg body weight/day was not accompanied by any test item-related clinical signs and was therefore considered to be non-adverse.
Based on the results of this study, 1000 mg/kg/day of the test item was established as the no-observed-adverse-effect-level (NOAEL) and 50 mg/kg body weight/day as the no-observed-effect-level (NOEL).
Applicant's summary and conclusion
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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