2-Pyridinecarboxamide, 4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-

Genetic toxicity: in vitro

Administrative data

Endpoint:

in vitro gene mutation study in bacteria

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Oct 1998

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1998

Report date:

1998

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 471 (Bacterial Reverse Mutation Assay)

Version / remarks:

1997

Deviations:

yes

Remarks:

- screening version (only one plate per dose and strain investigated, purity of test item not specified)

GLP compliance:

no

Type of assay:

bacterial reverse mutation assay

Test material

Test material information

Constituent 1

Reference substance name:

4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide

EC Number:

608-209-4

Cas Number:

284461-73-0

Molecular formula:

C21 H16 Cl F3 N4 O3

IUPAC Name:

4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide

Constituent 2

Reference substance name:

2-Pyridinecarboxamide, 4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-

IUPAC Name:

2-Pyridinecarboxamide, 4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-

Constituent 3

Reference substance name:

4-{ 4-[( {[ 4-chloro-3-(trifluoromethyl)phenyl]amino }carbonyl)amino ]phenoxy }-Nmethyl-2-pyridinecarboxamide

IUPAC Name:

4-{ 4-[( {[ 4-chloro-3-(trifluoromethyl)phenyl]amino }carbonyl)amino ]phenoxy }-Nmethyl-2-pyridinecarboxamide

Details on test material:

- Purity not specified

Method

Target gene:

Histidine gene locus

Species / strain

Species / strain / cell type:

S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102

Additional strain / cell type characteristics:

not applicable

Metabolic activation:

with and without

Metabolic activation system:

Aroclor 1254 induced male rat liver S9 mix

Test concentrations with justification for top dose:

Plate incorporation test: 0, 16, 50, 160, 500, 1600, 5000 µg/plate
Independent preincubation test: 0, 1, 2, 4, 8, 16, 32 µg/plate

Vehicle / solvent:

DMSO

Controls

Untreated negative controls:

no

Negative solvent / vehicle controls:

yes

True negative controls:

no

Positive controls:

yes

Positive control substance:

other: sodium azide (only TA 1535), nitrofurantoin (only TA 100), 4-nitro-1,2-phenylene diamine (TA 1537 and TA 98), cumene hydroperoxide (only TA 102), 2-aminoanthracene.

Remarks:

The positive controls sodium azide, nitrofurantoin, 4-nitro-1,2-phenylene diamine and cumene hydroperoxide were only used without S9 mix; the positive control 2-aminoanthracene was only used with S9 mix.

Details on test system and experimental conditions:

METHOD: Standard plate test and preincubation test; only one plate per dose and strain investigated

Evaluation criteria:

A reproducible and dose-related increase in mutant counts of at least one strain is considered to be a positive result. For TA 1535, TA 100 and TA 98 this increase should be about twice that of negative controls, whereas for TA 1537 at least a threefold increase should be reached. For TA 102 an increase of about 150 mutants should be reached. Otherwise, the result is evaluated as negative. However, these criteria may be overruled by good scientific judgment. In case of questionable results, investigations should continue, possibly with modifications, until a final evaluation is possible.

Statistics:

not specified

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:

cytotoxicity

Remarks:

bacteriotoxic effects at all tested doses

Vehicle controls validity:

valid

Untreated negative controls validity:

not applicable

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:

cytotoxicity

Remarks:

bacteriotoxic effects at all tested doses

Vehicle controls validity:

valid

Untreated negative controls validity:

not applicable

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:

cytotoxicity

Remarks:

bacteriotoxic effects at all tested doses

Vehicle controls validity:

valid

Untreated negative controls validity:

not applicable

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:

cytotoxicity

Remarks:

bacteriotoxic effects at all tested doses

Vehicle controls validity:

valid

Untreated negative controls validity:

not applicable

Positive controls validity:

valid

Test results 5

Key result

Species / strain:

S. typhimurium TA 102

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

cytotoxicity

Remarks:

bacteriotoxic effects at all tested doses

Vehicle controls validity:

valid

Untreated negative controls validity:

not applicable

Positive controls validity:

valid

Any other information on results incl. tables

The Ames test screening, employing doses of up to 5000 µg per plate, showed BAY 43-9006 to produce bacteriotoxic effects with all tested doses. Therefore, 32 µg per plate and above could not be used for assessment. Substance precipitation started at 1600 µg per plate.

Evaluation of individual dose groups, with respect to relevant assessment parameters (dose effect, reproducibility), revealed no biologically relevant variations from the respective negative controls. In spite of the low doses used, positive controls increased the mutant counts to well over those of the negative controls, and thus demonstrated the system's high sensitivity. Despite this sensitivity, no indications of mutagenic effects of BAY 43-9006 could be found at assessable doses of up to 16 µg per plate in any of the Salmonella typhimurium strains used.

Due to these results BAY 43-9006 has to be regarded as non-mutagenic.

Applicant's summary and conclusion

Conclusions:

Interpretation of results: negative

Executive summary:

BAY 43-9006 was initially screened with one plate per dose using the Salmonella/microsome plate incorporation test for point mutagenic effects in assessable doses of up to and including 16 µg per plate on the Salmonella typhimurium strains TA 98, TA 100, TA 102, TA 1535 and TA 1537 (similar to OECD TG 471). The independent repeat was performed as preincubation for 20 minutes at 37°C. Other conditions remained unchanged. All tested doses caused bacteriotoxic effects. Total bacteria counts were reduced and inhibition of growth was observed. Therefore, the used dose range could only be used to a limited extent up to and including 16 µg per plate for assessment purposes. Substance precipitation occurred at the dose 1600 µg per plate and above. Evidence of mutagenic activity of BAY 43-9006 was not seen. No biologically relevant increase in the mutant count, in comparison with the negative controls, was observed.

 

Therefore, BAY 43-9006 was considered to be non-mutagenic without and with S9 mix in the plate incorporation as well as in the preincubation modification of the Salmonella/microsome test.