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EC number: 480-420-2 | CAS number: 144702-27-2
- 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:
- 26 July - 22 August 2012
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: The study was conducted in GLP compliance and in accordance with several internationally established guidelines (OECD, EEC guidelines, see below).
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 007
- Report date:
- 2008
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- not specified
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Deviations:
- not specified
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- yes
Test material
- Reference substance name:
- -
- EC Number:
- 480-420-2
- EC Name:
- -
- Cas Number:
- 144702-27-2
- Molecular formula:
- C33 H29 N5
- IUPAC Name:
- 4'-{[4-methyl-6-(1-methyl-1H-1,3-benzodiazol-2-yl)-2-propyl-1H-1,3-benzodiazol-1-yl]methyl}-[1,1'-biphenyl]-2-carbonitrile
- Test material form:
- other: solid
- Details on test material:
- - Name of test material (as cited in study report): BIBR 277 Nitril
- Physical state: Solid
- Analytical purity: 99.7%
- Purity test date: 20 March 2007
- Lot/batch No.: 80A
- Expiration date of the lot/batch: 08 March 2008
- Stability under test conditions: yes
- Storage condition of test material: At room temperature, dark and dry
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Budapest, Hungary
- Age at study initiation: 8 weeks
- Weight at study initiation: 180-272 g
- Housing: groupa caging (5 animals per cage)
- Diet (e.g. ad libitum): ssniff (R) ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 8 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3°C
- Humidity (%): 36 - 69%
- Air changes (per hr): 8-12
- Photoperiod (hrs dark / hrs light): 12 hrs light daily from 6am - 6pm
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- polyethylene glycol
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test substance was prepared in PEG400 (50% of the final volume) and diluted with distilled water to the final volume at constant dosing volume of 10 mL/kg b.w.
VEHICLE
- Amount of vehicle (if gavage): 10 mL/kg b.w. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analytical control of dosing preparations was performed during the 1st and 4th dosing weeks. The measured concentrationa ranged from 93% - 100% of the nominal concentrations.
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- once daily
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
25 mg/kg b.w.
Basis:
nominal in water
- Remarks:
- Doses / Concentrations:
100 mg/kg b.w.
Basis:
nominal in water
- Remarks:
- Doses / Concentrations:
300 mg/kg b.w.
Basis:
nominal in water
- No. of animals per sex per dose:
- each 5 per sex and dose,
5 per sex and control - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: doses were determined during a preliminary study
- Positive control:
- none
Examinations
- Observations and examinations performed and frequency:
- DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:twice daily
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 / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data
FOOD EFFICIENCY:
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: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: 1 day after the last treatment
- Anaesthetic used for blood collection: Yes (euthanyl)
- Animals fasted: Yes
- How many animals: all
- Parameters checked in table were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 1 day after the last treatment
- Anaesthetic used for blood collection: Yes (euthanyl)
- Animals fasted: Yes
- How many animals: all
- Parameters checked in table were examined.
URINALYSIS: NO
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: at the end of the 4th exposure week
- Dose groups that were examined: all
- Battery of functions tested: sensory activity / grip strength / motor activity - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: Yes (see table) - Other examinations:
- weight of selected organs was checked
- Statistics:
- Statistic were performed using SPSS PC+ software for the following data:
bodyweight
clinical chemistry
haematology
organ weight data
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- no mortality occured in any of the animals. The general physical state of all testes animals was considered regular throughout the test. High dose animals (f/m) displayed thin faeces.
- Mortality:
- no mortality observed
- Description (incidence):
- no mortality occured in any of the animals. The general physical state of all testes animals was considered regular throughout the test. High dose animals (f/m) displayed thin faeces.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- minor variations were observed, however, these were not related to treatment due to the lack of dosage-relationship and the inconsistency between sexes.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- no siginificant changes in food intake compared to that of the control animals were noted.
- 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):
- Aenemia was observed in both f/m at the 300 mg/kg b.w. dosage level. In high dose females, RBC count and HGB content was slightly lower than in historical data. In correlation, significantly higher RDW value was observed in the high dose females.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- No siginificant observations were made in males. In females, there was a dose-dependant increase in cholesterol. Differences in total biliruin at the 300 mg/kg b.w. /d level correlated with haematological findings indicated a haemolytic origin of aenemia.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- Slight variations were noted, however, these were consideres as regular biological variations in the animal behaviour patterns.
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- liver weights were increased in high-dosed males and females. Spleen weight was increased in high-dosed females.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- no macroscopic findings were noted in any male animals. In females, pinprick-sized haemmorraghes
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- There were no consistent microscopic changes observed.
- Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- There were no consistent microscopic changes observed.
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: overall effects
- Dose descriptor:
- NOEL
- Effect level:
- 25 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: overall effects
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- It is concluded that administration of BIBR 277 Nitril to Wistar Rats at dpsages of 25, 100 and 300 mg/kg bodyweight for 28 days was generelly well tolerated. The marked clinical pathology and organ weight changes seen in females at the highest dose indicated slight aenemia and functional hepatic changes without any associated histopathological changes. Trends observed in 300 mg/kg b.w. dosed male rats were comparable. Similarly, satistical slight differences in females given 100 mg/kg b.w. were all within the respective historic control ranges and were not considered to represent adverse effects. The NOAEL was determined to be 100 mg/kg bw/day and the NOEL was determined to be 25 mg/kg bw/day.
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