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Toxicological information

Genetic toxicity: in vitro

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Administrative data

Endpoint:
in vitro cytogenicity / chromosome aberration study in mammalian cells
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:
25 February 1992 - 25 April 1994
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:
1994
Report date:
1994

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 473 (In Vitro Mammalian Chromosome Aberration Test)
GLP compliance:
yes (incl. QA statement)
Type of assay:
in vitro mammalian chromosome aberration test

Test material

Constituent 1
Reference substance name:
BIBR0277SE
IUPAC Name:
BIBR0277SE
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): BIBR 277 CL
- Molecular formula (if other than submission substance): C33H30N4O2*HCl
- Molecular weight (if other than submission substance): 514.6 g/mol
- Structural formula attached as image file (if other than submission substance): see reference substance
- Physical state: solid; slight yellowish white powder
- Purity test date: 23. October 1991 and 6. April 1993
- Lot/batch No.: WE8110110 and 8350071
- Expiration date of the lot/batch: 31. October 1992 and 30. April 1994
- Storage condition of test material: at room temperature, dark and dry

Method

Target gene:
not specified
Species / strain
Species / strain / cell type:
other: human lymphocytes
Additional strain / cell type characteristics:
not specified
Metabolic activation:
with and without
Metabolic activation system:
S9
Test concentrations with justification for top dose:
10, 50, 75, 100, 125, 150, 200, 250, 500 µg/ml; without activation
10, 50, 125, 150, 200; with activation
Vehicle / solvent:
- Vehicle(s)/solvent(s) used: DMSO
Controls
Untreated negative controls:
no
Negative solvent / vehicle controls:
yes
Remarks:
DMSO
True negative controls:
no
Positive controls:
yes
Positive control substance:
cyclophosphamide
other: adriamycin/ADR
Remarks:
cyclophosphamide with S9;
Details on test system and experimental conditions:
METHOD OF APPLICATION: in medium; preincubation; in suspension;

DURATION
- Exposure duration: 4 hours with S9 and 24 hours without S9
- Expression time (cells in growth medium): 72 hours
- Fixation time (start of exposure up to fixation or harvest of cells): after 70 hours; delayed harvest 94 hours

SPINDLE INHIBITOR (cytogenetic assays): Colcemid
STAIN (for cytogenetic assays): Giemsa stain

NUMBER OF REPLICATIONS: 2 per concentration

NUMBER OF CELLS EVALUATED: 200/concentration

DETERMINATION OF CYTOTOXICITY
- Method: mitotic index

OTHER EXAMINATIONS:
- Determination of polyploidy: yes
- Determination of endoreplication: yes



Evaluation criteria:
The clastogenic potential of the test compound was evaluated by an increase in the percentage of cells showing structural chromosomal aberrations excluding gaps. A positive response is defined, if there is a reproducible and concentration dependent increase in the aberration frequency in the exposed cultures. Comparisons are made with the negative control values (vehicle) in the respective test. Additionally, historical control frequencies obtained in similar lymphocyte experiments are also taken into consideration. Historical data may prove useful in deciding wheter effects not observed or observed at a low incidence in the particular culture resulted by chance or were treatment-related. In order to exclude donor-specific effects, the aberration analysis was repeated with blood from another healthy donor.
Generally, an assay will be considered acceptable for evaluation if the vehicle control data were within historical ranges and if positive controls showed significant increases in cells with chromosomal aberrations.
Statistics:
The statistical calculations were carried out by the Biometrics Group. The percentage of aberrant cells of the treated cultures were compared with the concurrent control means using the 2-sided Fishers Exact Test without an adjustment for multiple comparisons. If there were no qualitative differences between the replicates, data of individual cultures were pooled. A probability of p < 5 % was considered statistically significant.

Results and discussion

Test results
Species / strain:
other: human whole blood lymphocytes
Metabolic activation:
with and without
Genotoxicity:
negative
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Additional information on results:
COMPARISON WITH HISTORICAL CONTROL DATA: control results were within the range of historical control values


Remarks on result:
other: all strains/cell types tested
Remarks:
Migrated from field 'Test system'.

Any other information on results incl. tables

Summary structural chromosome aberrations; % aberrant cells excl. gaps; without metabolic activation

 Dose µG/ML  Cult.  Exp. 1; 72 Hr  Exp. 2; 72 hr  Exp. 3; 72 hr**  Exp. 2; 96 hr
 Controls          
 Negative DMSO  A+B  0  0.5  0  1.5
 Positive: ADR 0.05  A  34.0*    8.0*  28.0*
 ADR 0.075  A    29.3*    
 Test substance          
 10  A+B  0  0  0  
 50  A+B  0  0  Toxic  
 75  A      Toxic  
 100  A+B    1.0  Toxic  
 125  A+B  5.0*    Toxic  
 150  A+B    2.3  Toxic 0.5 
 200  A+B    Toxic    Toxic
 250  A+B  Toxic      
 500P  A+B  Toxic    Toxic  

where P = Precipitation; * significantly different from the vehicle control (p < 5.00); ** = only one culture

Historical negative control values calculated on the basis of the most recent experiments (2306 Metaphases))

% Aberrant cells excl. gaps: 0.22 (range 0 - 1.8)

Summary structural chromosome aberrations; % aberrant cells excl. gaps; metabolic activation S9 rat

 Dose µG/ML  Cult.  Exp.1; 72 hr  Exp.2; 72 hr  Exp.2; 96 hr
 Controls        
 Negative: DMSO  A+B  0.5  0.5  0
 Positive; CP28  A  4.0*    
 CP42  A    12.0*  10.0*
 Test substance        
 10  A+B  0.5  0.5  
 50  A+B  0  1.0  
 125  A+B  2.5    
 150  A+B    0  
 200  A+B    0.5  0.5
 250  A+B  Toxic    
 500 P  A+B  Toxic    

where P = Precipitation; * = significantly different from the vehicle control (p < 5.00)

Historical negative control values calculated on the basis of the most recent experiments (2200 Metaphases)

% aberrant cells excl. gaps: 0.36 (range 0 -2)

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information):
negative

In summary, these results showed, that the test substance, when tested with and without liver enzymes up to concentration levels of 100 and 200 µg/ml, respectively, did not induce chromosomal aberrations in human peripheral lymphocytess in vitro.