Trimetazidine

Genetic toxicity: in vitro

Administrative data

Endpoint:

in vitro gene mutation study in bacteria

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

8 june 2004 to 4 August 2004

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2004

Report date:

2004

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 471 (Bacterial Reverse Mutation Assay)

Deviations:

no

GLP compliance:

yes

Type of assay:

bacterial reverse mutation assay

Test material

Test material information

Constituent 1

Reference substance name:

Trimetazidine

EC Number:

225-690-2

EC Name:

Trimetazidine

Cas Number:

5011-34-7

Molecular formula:

C14H22N2O3

IUPAC Name:

1-[(2,3,4-trimethoxyphenyl)methyl]piperazine

Test material form:

liquid

Details on test material:

No details are provided in the study report

Method

Target gene:

His D, His C, His G, Tryp E.

Species / strain

Species / strain / cell type:

S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and E. coli WP2

Additional strain / cell type characteristics:

not specified

Metabolic activation:

with and without

Metabolic activation system:

2-Anthramine Sigma A1381. Microsomal fraction of Rat Sprague Dawley liver homogenate

Test concentrations with justification for top dose:

Higest concentration tested is 5000µg/dish

Vehicle / solvent:

A stock solution of the product at 50 mg/ml in ultrapure water is prepared.

Controls

Untreated negative controls:

yes

Negative solvent / vehicle controls:

yes

True negative controls:

yes

Positive controls:

yes

Positive control substance:

7,12-dimethylbenzanthracene

9-aminoacridine

2-nitrofluorene

sodium azide

other: β-Propiolactone, 2-Anthramine, cis•Platinum (II) Diammine Dichloride

Results and discussion

Test results

Test results 1

Species / strain:

S. typhimurium TA 1535

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not determined

Vehicle controls validity:

not specified

Untreated negative controls validity:

valid

Positive controls validity:

valid

Test results 2

Species / strain:

S. typhimurium TA 1537

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not determined

Vehicle controls validity:

not specified

Untreated negative controls validity:

valid

Positive controls validity:

valid

Test results 3

Species / strain:

S. typhimurium TA 98

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not determined

Vehicle controls validity:

not specified

Untreated negative controls validity:

valid

Positive controls validity:

valid

Test results 4

Species / strain:

S. typhimurium TA 100

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not determined

Vehicle controls validity:

not specified

Untreated negative controls validity:

valid

Positive controls validity:

valid

Test results 5

Species / strain:

E. coli WP2 uvr A pKM 101

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not determined

Vehicle controls validity:

not specified

Untreated negative controls validity:

valid

Positive controls validity:

valid

Applicant's summary and conclusion

Conclusions:

The test item (TMZ), does not exhibit mutagenic activity with respect to the four Salmonella typhimurium strains (TA 1535, TA 1537 , TA 98, TA 100) and an Escherichia coli strain WP2 (uvr A) (PKM 101), with and without metabolic activation.

Executive summary:

The comparison between the values obtained for spontaneous reversals and for the positive controls, without and with metabolic activation does not reveal any significant differences.

No increase in the number of revertants was observed in the presence of the different concentrations of the product (5000, 1500, 500, 150, 50μg / dish), in the absence or in the presence of metabolic activation, for strains Salmonella typhimurium TA 1535, TA 1537, TA 98, TA 100 and Escherichia coli strain WP2 (uvr A) (PKM 101).

For the dose of 5000 µg / dish a significant decrease in the level of revertants was observed for the strains TA 1535 (assay 1), TA 1537 and TA 98 and Escherichia coti WP2fuvr A) (PKM 101) in agreement with the bacteriostatic activity measured at this concentration.