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EC number: 922-049-5 | CAS number: 656247-17-5
- 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:
- supporting study
- Study period:
- 26 July - 9 August 2001
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Remarks:
- non-GLP
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 002
- Report date:
- 2002
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- The study was conducted by a well experienced laboratory and was very well performed and described and is therefore regarded reliable.
- GLP compliance:
- no
Test material
- Reference substance name:
- methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate
- EC Number:
- 922-049-5
- Cas Number:
- 656247-17-5
- Molecular formula:
- C31H33N5O4
- IUPAC Name:
- methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate
- Test material form:
- not specified
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Germany, Sulzfeld
- Age at study initiation: approximately 7 weeks
- Weight at study initiation: approximately 185 g
- Diet (e.g. ad libitum): Standard chow
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 0.5% hydroxyethylcellulose (Natrosol)
- Duration of treatment / exposure:
- 14 days
- Frequency of treatment:
- Number of applications: 14 (12 at the high dose level)
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 5 per dose
- Control animals:
- yes, concurrent vehicle
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Hematological changes observed in the high-dose group are considered directly related to the pharmacological action of BIBF 1120 BS on hematopoietic stem cells (see H-P Gerber et al., VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism, Nature 417, 954-958 (2002)).
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- There was no spontaneous mortality in the course of the study. However, the high-dose group had to be prematurely sacrificed two days before the scheduled necropsy for animal welfare reasons. These animals showed unspecific clinical signs like piloerection, apathy and emaciation. No clinical signs were noted in the mid and low-dose group.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- BIBF 1120 BS caused a substantial dose-dependent reduction in body-weight gain. At the high-dose level a severe drop in actual body weight was noted. Impaired body weight development appeared to be directly related to concomitantly reduced food consumption.
Effect levels
- Dose descriptor:
- NOEL
- Effect level:
- < 100 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- organ weights and organ / body weight ratios
Applicant's summary and conclusion
- Conclusions:
- Repeated oral application of 100, 300 and 1000 mg/kg/day BIBF 1120 BS to 5 male rats per
dose-level lead to substantial but highly variable test compound plasma levels. The highest
dose level was not tolerated for the scheduled duration of 14 days. There were no substantial,
life-threatening changes noted in the Clinical pathology parameters. Adrenal glands, bone
marrow, bone, kidney, heart, salivary glands, thyroids and parathyroids, brain, pancreas,
spleen, adrenals, liver and thymus were identified as toxicological relevant target organs of
which panmyelophthisis in the bone marrow and the kidney findings are among the most
serious. The first one is ultimately not compatible with survival, the latter has to be considered
a potentially irreversible lesion.
The No Observable Adverse Effect level for this study is <100 mg/kg/don the basis of the
kidney findings.
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