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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:
2002
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

Constituent 1
Chemical structure
Reference substance name:
3-[1-(4-{Methyl-[2-(4-methyl-piperazin-1-yl)-acetyl]-amino}-phenylamino)-1-phenyl-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indole-6-ca
EC Number:
922-049-5
Cas Number:
656247-17-5
Molecular formula:
C31H33N5O4
IUPAC Name:
3-[1-(4-{Methyl-[2-(4-methyl-piperazin-1-yl)-acetyl]-amino}-phenylamino)-1-phenyl-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indole-6-ca
Test material form:
not specified

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.