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EC number: 807-342-7 | CAS number: 1009119-83-8
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
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:
- January 31st, 2007 to February 20th, 2007
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study conducted according to OECD method and in accordance with GLP. Study material is well characterized.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 007
- Report date:
- 2007
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.13/14 (Mutagenicity - Reverse Mutation Test Using Bacteria)
- GLP compliance:
- yes
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- 2-[(2S)-pyrrolidin-2-yl]-5-(4'-{2-[(2S)-pyrrolidin-2-yl]-1H-imidazol-5-yl}-[1,1'-biphenyl]-4-yl)-1H-imidazole tetrahydrochloride
- EC Number:
- 807-342-7
- Cas Number:
- 1009119-83-8
- Molecular formula:
- C26H32Cl4N6
- IUPAC Name:
- 2-[(2S)-pyrrolidin-2-yl]-5-(4'-{2-[(2S)-pyrrolidin-2-yl]-1H-imidazol-5-yl}-[1,1'-biphenyl]-4-yl)-1H-imidazole tetrahydrochloride
- Test material form:
- solid: particulate/powder
- Remarks:
- migrated information: powder
- Details on test material:
- Powder stored at room temperature, in the dark, under nitrogen.
Constituent 1
Method
- Target gene:
- five histidine-requiring strains
Species / strain
- Species / strain / cell type:
- other: Salmonella typhimurium: TA1535, TA1537, TA98, TA100, Escherichia coli: WP2 uvrA (pKM101)
- Metabolic activation:
- with and without
- Metabolic activation system:
- S-9 mix
- Test concentrations with justification for top dose:
- For genotoxicity experiment concentrations (with & without metabolic activation) used:
First test: 5, 15, 50, 150, 500, 1500, 5000 ug/plate
Second test: 1.5, 5, 15, 50, 150, 500 ug/plate - Vehicle / solvent:
- Vehichle: water
Solvent: DMSO (A.C.S. spectrophotometric grade)
Controlsopen allclose all
- Untreated negative controls:
- yes
- Remarks:
- water
- Positive controls:
- yes
- Remarks:
- In the absence of S9 mix
- Positive control substance:
- sodium azide
- Remarks:
- 2 µg/plate for strains TA100 and TA1535
- Positive controls:
- yes
- Remarks:
- In the absence of S9 mix
- Positive control substance:
- 9-aminoacridine
- Remarks:
- 50 µg/plate for strain TA1537
- Positive controls:
- yes
- Remarks:
- In the absence of S9 mix
- Positive control substance:
- 2-nitrofluorene
- Remarks:
- 2 µg/plate for strain TA98
- Positive controls:
- yes
- Remarks:
- In the absence of S9 mix
- Positive control substance:
- 4-nitroquinoline-N-oxide
- Remarks:
- 2 µg/plate for strain WP2 uvrA (pKM101)
- Positive controls:
- yes
- Remarks:
- In the presence of S9 mix
- Positive control substance:
- other: 2-Aminoanthracene
- Remarks:
- 5 µg/plate for strains TA100 and TA1535 10 µg/plate for strain WP2 uvrA (pKM101)
- Positive controls:
- yes
- Remarks:
- In the presence of S9 mix
- Positive control substance:
- benzo(a)pyrene
- Remarks:
- 5 µg/plate for strains TA98 and TA1537
- Details on test system and experimental conditions:
- MUTATION TEST PROCEDURE
First test
Aliquots of 0.1 mL of the test substance solutions (seven concentrations up to 5000 µg/plate),
positive control or negative control were placed in glass vessels. The negative control was the
chosen vehicle, water. S9 mix (0.5 mL) or 0.1 M pH 7.4 phosphate buffer (0.5 mL) was added,
followed by 0.1 mL of a 10-hour bacterial culture and 2 mL of agar containing histidine (0.05 mM),
biotin (0.05 mM) and tryptophan (0.05 mM). The mixture was thoroughly shaken and overlaid
onto previously prepared Petri dishes containing 25 mL minimal agar. Each Petri dish was
individually labelled with a unique code, identifying the contents of the dish. Three Petri dishes
were used for each treatment. Plates were also prepared without the addition of bacteria in order to
assess the sterility of the test substance, S9 mix and sodium phosphate buffer. All plates were
incubated at approximately 37°C for ca 72 hours. After this period, the appearance of the
background bacterial lawn was examined and revertant colonies counted using an automated colony
counter (Perceptive Instruments Sorcerer). Some plates in the first were scored manually because
of the presence of precipitate.
Any toxic effects of the test substance would be detected by a substantial reduction in mean
revertant colony counts or by a sparse or absent background bacterial lawn. In the absence of any
toxic effects, the maximum concentration selected for use in the second test would be the same as
that used in the first. If toxic effects were observed, a lower concentration might be chosen,
ensuring that signs of bacterial inhibition were present at this maximum concentration. Ideally a
minimum of four non-toxic concentrations should be obtained. If precipitate were observed on the
plates at the end of the incubation period, at least four non-precipitating concentrations should be
obtained, unless otherwise justified by the Study Director.
Second test
As a clear negative response was obtained in the first test, a variation to the test procedure was used
for the second test. The variation used was the pre-incubation assay in which the tubes, which
contained mixtures of bacteria, buffer or S9 mix and test dilution, were incubated at 37°C for 30
minutes with shaking before the addition of the agar overlay. Because of toxicity observed in the
first test, the maximum concentration chosen for the Salmonella strains was 500 µg/plate, and the
maximum concentration chosen for the E. coli strain was 1500 µg/plate, and only six
concentrations were used - Evaluation criteria:
- If exposure to a test substance produces a reproducible increase in revertant colony numbers of at
least twice (three times in the case of strains TA1535 and TA1537) the concurrent vehicle controls,
with some evidence of a positive dose-response relationship, it is considered to exhibit mutagenic
activity in this test system. No statistical analysis is performed. - Statistics:
- If exposure to a test substance does not produce a reproducible increase in revertant colony
numbers, it is considered to show no evidence of mutagenic activity in this test system. No
statistical analysis is performed.
If the results obtained fail to satisfy the criteria for a clear “positive” or “negative” response, even
after additional testing, the test data may be subjected to analysis to determine the statistical
significance of any increases in revertant colony numbers. The statistical procedures used are those
described by Mahon et al (1989) and are usually Dunnett’s test followed, if appropriate, by trend
analysis. Biological importance should always be considered along with statistical significance. In
general, treatment-associated increases in revertant colony numbers below two or three times the
vehicle controls (as described above) are not considered biologically important. It should be noted
that it is acceptable to conclude an equivocal response if no clear results can be obtained.
Results and discussion
Test results
- Species / strain:
- other: all strains/cell types tested
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- 500 ug upwards
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- The absence of colonies on sterility check plates confirmed the absence of microbial contamination
of the S9 mix, buffer and test substance formulation.
The total colony counts on nutrient agar plates confirmed the viability and high
cell density of the cultures of the individual organisms.
The mean revertant colony counts for the vehicle controls were within or close to the 99%
confidence limits of the current historical control range of the laboratory. Appropriate
positive control chemicals (with S9 mix where required) induced substantial increases in revertant
colony numbers with all strains in all reported tests, confirming sensitivity of the cultures and
activity of the S9 mix. - Remarks on result:
- other: all strains/cell types tested
- Remarks:
- Migrated from field 'Test system'.
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information):
negative
It is concluded that BMS-749445-02 showed no evidence of mutagenic activity in this bacterial
system under the test conditions employed.
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