Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
in vitro gene mutation study in bacteria
Type of information:
experimental study
Adequacy of study:
other information
Study period:
14 July 2009 - 20 July 2009
Reliability:
1 (reliable without restriction)

Data source

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: ICH. Topic S2A Genotoxicity: Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals; CPMP/ICH/141/95 Step 5 Guideline (Into Operation April 1996)
Qualifier:
according to guideline
Guideline:
other: ICH. Topic S2B Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals; CPMP/ICH/174/95 Step 5 Guideline (Into Operation March 1998).
GLP compliance:
yes
Type of assay:
bacterial reverse mutation assay

Test material

Constituent 1
Chemical structure
Reference substance name:
2-(3-chloropropoxy)-1-methoxy-4-nitrobenzene
EC Number:
618-883-1
Cas Number:
92878-95-0
Molecular formula:
C10H12ClNO4
IUPAC Name:
2-(3-chloropropoxy)-1-methoxy-4-nitrobenzene
Details on test material:
Molecular formula C10H12ClNO4
Molecular weight 245.66
CAS Number 92878-95-0
Description Slightly yellow powder
Batch 18238702
Purity 99.8%
Test substance storage At room temperature protected from light
Stability under storage conditions Stable

Method

Target gene:
At least five different doses (increasing with approximately half-log steps) of the test substance were tested in triplicate in each strain. In the mutation experiment WAY-188471 was tested both in the absence and presence of S9-mix in tester strains TA1535, TA1537, TA98 and TA100.
Species / strainopen allclose all
Species / strain / cell type:
S. typhimurium TA 100
Details on mammalian cell type (if applicable):
Histidine mutation: hisG46/R-factor* ; Mutation type:Base-pair substitutions
received on 14-06-2006, used batch: TA100.111208
Trinova Biochem GmbH, Germany (Master culture from Dr. Bruce N. Ames)
Additional strain / cell type characteristics:
not specified
Species / strain / cell type:
S. typhimurium TA 98
Details on mammalian cell type (if applicable):
Histidine mutation: hisD3052/R-factor* ; Mutation type:Frameshift
received on 14-06-2006, used batch: TA98.111208
Trinova Biochem GmbH, Germany (Master culture from Dr. Bruce N. Ames)

*: R-factor = plasmid pKM101 (increases error-prone DNA repair)
Additional strain / cell type characteristics:
not specified
Species / strain / cell type:
S. typhimurium TA 1537
Details on mammalian cell type (if applicable):
Histidine mutation: hisC3076; Mutation type:Frameshift
received on 14-06-2006, used batch: TA1537.120609
Trinova Biochem GmbH, Germany (Master culture from Dr. Bruce N. Ames)
Additional strain / cell type characteristics:
not specified
Species / strain / cell type:
S. typhimurium TA 1535
Details on mammalian cell type (if applicable):
Histidine mutation: hisG46; Mutation type: Base-pair substitutions
received on 14-06-2006, used batch: TA1535.120609
Trinova Biochem GmbH, Germany (Master culture from Dr. Bruce N. Ames)
Additional strain / cell type characteristics:
not specified
Species / strain / cell type:
E. coli WP2 uvr A
Details on mammalian cell type (if applicable):
received on 06-02-2008, used batch: EC.100209.
Trinova Biochem GmbH, Germany (Master culture from The National Collections of Industrial and Marine Bacteria, Aberdeen, UK)
Additional strain / cell type characteristics:
not specified
Metabolic activation:
with and without
Metabolic activation system:
Rat liver microsomal enzymes were routinely prepared from adult male Wistar rats, which were obtained from Charles River, Sulzfeld, Germany.
Test concentrations with justification for top dose:
concentrations of 3, 10,33, 100, 333, 1000, 3330 and 5000 μg/plate in the absence and presence of S9-mix.
Controlsopen allclose all
Untreated negative controls:
yes
Remarks:
The vehicle of the test article, being dimethyl sulfoxide.
Negative solvent / vehicle controls:
yes
True negative controls:
yes
Positive controls:
yes
Positive control substance:
methylmethanesulfonate
Remarks:
TA100

Migrated to IUCLID6: Sigma; Concentration:650μg; solvent:DMSO
Positive controls:
yes
Positive control substance:
sodium azide
Remarks:
TA1535

Migrated to IUCLID6: Sigma, Zwijndrecht, The Netherlands; Concentration:5 μg; Solvent: Saline
Positive controls:
yes
Positive control substance:
9-aminoacridine
Remarks:
TA1537

Migrated to IUCLID6: Acros Organics, Geel, Belgium; Concentration: 60 μg; Solvent: Milli-Q water
Positive controls:
yes
Positive control substance:
2-nitrofluorene
Remarks:
TA98

Migrated to IUCLID6: Merck; Concentration: 10 μg; Solvent:DMSO
Positive controls:
yes
Positive control substance:
4-nitroquinoline-N-oxide
Remarks:
WP2uvrA

Migrated to IUCLID6: Sigma; Concentration:10 μg; Solvent:DMSO

Results and discussion

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information):
positive

Based on the results of this study it is concluded that WAY-188471 is mutagenic in the Salmonella typhimurium reverse mutation assay and in the Escherichia coli reverse mutation assay.