Registration Dossier

Administrative data

Endpoint:
in vivo mammalian somatic cell study: cytogenicity / bone marrow chromosome aberration
Remarks:
Type of genotoxicity: chromosome aberration
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
9 March - 11 March 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted in GLP compliance and in accordance with an internationally established guideline (OECD, see below). BIBR 277 CL is the hydrochloride of BIBR 277 SE (Telmisartan, free acid).

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report date:
1992

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 475 (Mammalian Bone Marrow Chromosome Aberration Test)
Deviations:
not specified
Qualifier:
according to guideline
Guideline:
JAPAN: Guidelines for Screening Mutagenicity Testing Of Chemicals
Deviations:
not specified
Qualifier:
according to guideline
Guideline:
other: EEC L251; 1984 and 75/318, 1989
Deviations:
not specified
GLP compliance:
yes
Type of assay:
micronucleus assay

Test material

Constituent 1
Reference substance name:
Automatically generated during migration to IUCLID 6, no data available
IUPAC Name:
Automatically generated during migration to IUCLID 6, no data available
Test material form:
solid - liquid: suspension
Details on test material:
- Name of test material (as cited in study report): BIBR 0277 SE
- Substance type: slight yellowish powder
- Physical state: powder
- Analytical purity: 99.8 %
- Impurities (identity and concentrations): 0.07 5 ethanol, 0.1 % glacial acetic acid, 0.01 % ethylmethylketone, 0.12 % ethylaccetate, heavy metals less than 10 ppm
- Composition of test material, percentage of components: BIBR 277 SE suspended in 0.5% hydroxyethylcellulose (solution of natrosol), daily preprared
- Purity test date: October 31, 1991
- Lot/batch No.: 81 101 10
- Expiration date of the lot/batch: March 11, 1992
- Stability under test conditions: at least over 4 hours stable
- Storage condition of test material: At room temperature (dark) , ambient humidity

Solubility: in water practically insoluble
ph: 5.6

Test animals

Species:
mouse
Strain:
other: Chbb: NMRI/SPF quality
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Dr. Karl Thomae GmbH, Biberach
- Age at study initiation: 6 to 8 weeks old
- Weight at study initiation: 23- 32 g
- Assigned to test groups randomly: yes
- Housing: individually in Macroln cages, type 2, floor area 400 cm²
- Diet (e.g. ad libitum): NAFAG 8577 /batch 2550 (Nafag company, in Grossau/Switzerland)
- Water (e.g. ad libitum): tape water ad libitum
- Acclimation period:no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): environmentally regulated
- Humidity (%):environmentally regulated
- Photoperiod (hrs dark / hrs light): 9/15 hours light -dark cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
- Vehicle(s)/solvent(s) used: hydroxyethylcellulose (type Natrosol R 250 HX)
- Concentration of test material in vehicle: 25 /50/ 100 mg/ml suspension
- Amount of vehicle (if gavage or dermal): 0.5% solution
Duration of treatment / exposure:
24 h treated at a concentration of 250 mg/kg, 500 mg/kg and 1000 mg/kg and 48 hours treated at a concetration of 1000 mg/kg
Frequency of treatment:
single oral treatment
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
250 mg/kg /conc: 25 mg/ml
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
500 mg/kg and 50 mg/ml
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
1000 mg/kg and 100 mg/ml
Basis:
analytical conc.
No. of animals per sex per dose:
5 males per group at a dose of 250 mg/kg and 500 mg/kg
5 female and 5 males per group at a dose of 1000 mg/kg
Control animals:
yes, concurrent vehicle
Positive control(s):
cyclophosphamide:
- Route of administration: oral
- Doses / concentrations: 30 mg/ kg

Examinations

Tissues and cell types examined:
examined for signs of toxicity, morbundity and mortality; the onset, intensity and duration of adverse effects were recorded. particular attention was paid to the six hours period following dosing
Bone marrow cells are obtained from the femurs
Details of tissue and slide preparation:
CRITERIA FOR DOSE SELECTION: given no acute toxicity data in mice were available, a pretest using 500 and 100 mg/kg was conducted in one male and one female mouse . the animals shoed piloerection after oral treatment. At the high dose level additionally sedation was observed.

DETAILS OF SLIDE PREPARATION: Bone marrow cells were obtained from the femurs, prepared (flushed with fetal calf serum; centrifugated)and the slides were stained (with May-Grünwald/Giemsa) and overlipped with Entellan mounting medium (Merck Darmstadt).

METHOD OF ANALYSIS: 1000 polychromatic erythrocytes per animal were analized for incidence of micronuclei; the portion of poly- to normochromatic erythrocytes was determined ( NCE/PCE).


Evaluation criteria:
A positive result is a statistically significant , dose dependent increase in the freaquenecy of micronucleated polychromatic erythrocytes in treated animals as compared with controls.
Statistics:
The Fisher -Pitman permutation tests and the algorithms given by Edgington were used to verify the results , taking into account the characteristics of the micronucleus assay . A probability of P < 5% (cells with micronuclei in any dose group) was considered statisticlly significant.

Results and discussion

Test results
Sex:
male/female
Genotoxicity:
negative
Toxicity:
yes
Vehicle controls validity:
valid
Negative controls validity:
valid
Positive controls validity:
valid

Any other information on results incl. tables

see attached table: micronuclei (MN) in PCE and ratio of PCE/NCE in mice after a single oral treatment with BIBR 0277 SE

 
 
   

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative
In conclusion, the test demostrated, the test item BIBR 0277 SE did not damage the chromosome complement (structural and numerical) of mice in vivo, when given at maximum administrable doses clearly exceeding the anticipated therapeutic dose in man.

Executive summary:

According to the guidelines (OECD 474, 1983 and EEC L251, 1984, 75/318, 1989), a maximum tolerated dose or a dose producing some indication of cytotoxicity of 1000 mg/kg BIBR 0277 SE was applied orally to 5 males and females per group. In agreement to Japanese guidelines (1989), two lower dose groups (500 and 250 mg/kg, 5 males per group) were treated for the 24 hour harvesting time. The applied dose exceeded the anticipated therapeutical dosage 2500 to 50000 fold. A vehicle (NatrosolR 250HX) and a positive control group (cyclophosphamide 30 mg/kg) were investigated. 24 and 48 hours after the treatment bone marrow smears were prepared and analyzed for the incidence of micronuclei.

Clinical signs: After treament with increasing doses of BIBR 0277 SE the animals in all dose groups showed no drug -dependent clinical signs. However, due to the limited suspensibility no higher dose levels could be investigated adequately.

Toxicokinetecs: Plasma level measurements in 2 animals of the 1000 mg/kg BIBR 2077 SE 2 hours post dosing revealed concentrations between 40.8 and 71.4 µg/ml exceeding the anticipated therapeutic levels 1000 fold.

No significant increase in the number of polychromatic erythrocytes containing micronuclei (0.06 -0.3%) was observed after dosing up to 1000 mg/kg BIBR 0277 SE compared with the corresponding negative control (0.14 -0.10 %) As indicated by the frequency for individual animals, there were no significant differences within or between the sexes and various sampling times (24 and 48 hours port treatment).

Bone Marrow toxicity : There was no clear shift in the typical ratio of poly-to normochromatic erythrocytes of vehicle control and BIBR 0277 SE treated animals. Over all, there was no signs of a treatment related inhibition of cell proliferation.