4-Quinazolinamine, N-(3-chloro-4-fluorophenyl)-6-nitro-7-(phenylsulfonyl)-

Genetic toxicity: in vitro

Administrative data

Endpoint:

in vitro gene mutation study in bacteria

Remarks:

Type of genotoxicity: gene mutation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted in GLP compliance and according to an OECD guideline.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 471 (Bacterial Reverse Mutation Assay)

Deviations:

yes

Principles of method if other than guideline:

There were 6 plates for the negative control according to the SOP.
This deviation did neither alter the outcome nor the conclusion of the study.

GLP compliance:

yes

Type of assay:

bacterial reverse mutation assay

Test material

Test material information

Constituent 1

Reference substance name:

PD 281

IUPAC Name:

PD 281

Test material form:

other: solid

Details on test material:

Test substance: PD 281 (BIBW 2992 Sulfon, impurity of BIBW 2992)
Batch no.: 1034234
Appearance: beige to yellow solid substance
Purity: 99.4 %
Certificate of analysis: 05 March 2009
To be retested: January 2010
Storage conditions: At room temperature in the dark (ambient humidity)
Manufacturer: Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach (Germany)

Method

Species / strain

Species / strain 1

Species / strain / cell type:

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

Species / strain 2

Species / strain / cell type:

S. typhimurium TA 102

Metabolic activation:

with and without

Metabolic activation system:

S9

Test concentrations with justification for top dose:

5 concentrations 10, 30, 100, 300 and 1000 μg/plate
highest concentration: 1000 μg/plate was investigated as the highest concentration due to solubility

Vehicle / solvent:

DMSO

Controls

Controls 1

Untreated negative controls:

yes

Remarks:

DMSO

Negative solvent / vehicle controls:

yes

Remarks:

DMSO

Positive controls:

yes

Positive control substance:

9-aminoacridine

2-nitrofluorene

sodium azide

mitomycin C

Remarks:

without activation

Controls 2

Untreated negative controls:

yes

Remarks:

DMSO

Negative solvent / vehicle controls:

yes

Remarks:

DMSO

Positive controls:

yes

Positive control substance:

other: 2-Aminoanthracene

Remarks:

with activation

Details on test system and experimental conditions:

METHOD OF APPLICATION: plate incorporation
DURATION
- Preincubation period: 6 h
- Exposure duration: 48 h (TA102: 72 h) at 37°C

NUMBER OF REPLICATIONS: 3 per concentration

Data recording: colonies were counted using an automatic colony counter IPI Analyzer 982 B

Evaluation criteria:

A reproducible, concentration-dependent increase in the number of revertants of at least one tester strain over the vehicle control value
and/or outside the historical control range is indicative of genotoxic activity.

Results and discussion

Test results

Test results 1

Species / strain:

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

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity

Vehicle controls validity:

valid

Untreated negative controls validity:

valid

Positive controls validity:

valid

Test results 2

Species / strain:

S. typhimurium TA 102

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity

Vehicle controls validity:

valid

Untreated negative controls validity:

valid

Positive controls validity:

valid

Remarks on result:

other: all strains/cell types tested

Remarks:

Migrated from field 'Test system'.

Any other information on results incl. tables

No recognizable incidents that might have affected the quality or integrity of the experimental outcome were noted during the study.

PD 281 (BIBW 2992 Sulfon) precipitated at concentrations ≥ 300 μg/plate and no bacteriotoxicity was observed up to the highest concentration of 1000 μg/plate.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information):
negative with metabolic activation
negative without metabolic activation

PD 281 (BIBW 2992 Sulfon) caused neither base-pair substitutions nor frameshift mutations in different strains of S. typhimurium in the presence and absence of metabolic activation when tested up to insoluble concentrations. Based on these results it was concluded, that the test substance is
"Ames negative".