Phosphonic acid, P-[2-[[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]amino]-2-oxoethyl]-, diethyl ester

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:

May 5 - 15, 2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Report date:

2009

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:

diethyl [({4-[(3-chloro-4-fluorophenyl)amino]-7-[(3S)-oxolan-3-yloxy]quinazolin-6-yl}carbamoyl)methyl]phosphonate

EC Number:

928-634-1

Cas Number:

618061-76-0

Molecular formula:

C24 H27 Cl F N4 O6 P

IUPAC Name:

diethyl [({4-[(3-chloro-4-fluorophenyl)amino]-7-[(3S)-oxolan-3-yloxy]quinazolin-6-yl}carbamoyl)methyl]phosphonate

Method

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 specified

Metabolic activation:

with and without

Metabolic activation system:

S9 mix

Test concentrations with justification for top dose:

A maximum concentration of 5000 µg/plate should be investigated according to relevant
guidelines. CDBB 250 precipitated at concentrations higher than 1250 µg/plate in a non-GLP
solubility test. Therefore, 1000 µg/plate was investigated as the highest concentration.

Vehicle / solvent:

DMSO

Controls

Negative solvent / vehicle controls:

yes

Positive controls:

yes

Positive control substance:

9-aminoacridine

2-nitrofluorene

sodium azide

mitomycin C

other: 2-Aminoanthracene

Rationale for test conditions:

The assay was considered valid since the following criteria were met:
All tester strains exhibit a characteristic number of spontaneous revertants per plate. The
addition of the metabolic activation system did not alter significantly the number of
spontaneous revertants per plate and therefore the numbers were combined and given as
ranges (see below). These ranges were taken from about 168 experiments conducted in our
laboratory with Merck plates.
TA 1535: 5 - 22
TA 1537: 3 - 29
TA 98: 16 - 68
TA 100: 57 - 192
TA 102: 252 - 531
The validation studies have shown that the source of the plates do not influence the outcome
of the study (Maron and Ames [4]). Therefore, the same historical control data range obtained
with Merck plates can be used for the interpretation of the results in this study.
In addition, the reference mutagens induced a distinct increase in the number of revertants,
reflecting also the activity of the metabolizing system.

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

Species / strain:

other: S.typhimurium TA 1537, TA 98, TA 100

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

cytotoxicity

Vehicle controls validity:

valid

Untreated negative controls validity:

not examined

True negative controls validity:

not examined

Positive controls validity:

valid

Applicant's summary and conclusion

Conclusions:

CDBB 250 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
bacteriotoxic or insoluble concentrations. Based on these results it was concluded, that the
test substance is "Ames negative".