7-But-2-ynyl-8-[(R)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-piperidin-1-yl]-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2004

Report date:

2004

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The chemical intermediate CD 749 BS was investigated in a
modified bacterial reverse mutation test as described by Ames et al. (1975). The traditional
Salmonella microsome mutation assay (Ames test) is used extensively as a routine test for
mutagenicity for more than 25 years. The high throughput microtitre-based version, called
Ames II, is based on the same genetic principle (base-pair substitution and frameshift
mutations in the his operon of S. typhimurium) as the traditional Ames test but combined
with the fluctuation method (Gee et al., 1998). Because of its high concordance (80%)
compared with the standard assay, the Ames II procedure seems an effective screen for
identifying bacterial mutagens (Flueckiger et al., 2004).

GLP compliance:

no

Type of assay:

bacterial reverse mutation assay

Test material

Test material information

Constituent 1

Reference substance name:

7-But-2-ynyl-8-[(R)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-piperidin-1-yl]-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro- purine-2,6-dione

EC Number:

937-756-4

Cas Number:

886588-63-2

Molecular formula:

C33 H30 N8 O4

IUPAC Name:

7-But-2-ynyl-8-[(R)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-piperidin-1-yl]-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro- purine-2,6-dione

Method

Species / strain

Species / strain / cell type:

other: TA 7001, TA 7002, TA 7003, TA 7004, TA 7005, TA 7006 and TA 98

Test concentrations with justification for top dose:

1 to 2500 μg/mL.
The highest test concentration 5000 μg/mL was not soluble in DMSO

Vehicle / solvent:

DMSO

Controls

Untreated negative controls:

not specified

Negative solvent / vehicle controls:

yes

True negative controls:

not specified

Positive controls:

yes

Positive control substance:

4-nitroquinoline-N-oxide

2-nitrofluorene

other: 2-aminoanthracene

Results and discussion

Test results

Species / strain:

other: TA Mix (TA 7001, TA 7002, TA 7003, TA 7004, TA 7005 and TA 7006) and TA 98

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity

Remarks:

No bacteriotoxicity was seen up to the highest soluble concentration of 2500 μg/mL.

Vehicle controls validity:

valid

Untreated negative controls validity:

not examined

Positive controls validity:

valid

Additional information on results:

CD 749 BS showed precipitation at concentrations ≥100 μg/mL.

Applicant's summary and conclusion

Conclusions:

Based on the described results it is concluded, that CD 749 BS, when tested up to
insoluble concentrations, caused neither base-pair substitutions nor frameshift
mutations in bacteria. No evidence of genotoxic activity was observed in a series of
S. typhimurium tester strains (TA Mix and TA 98) in the absence and presence of
metabolic activation. The test article is, therefore, classified as "Ames II negative".