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EC number: 810-753-4 | CAS number: 1374639-78-7
- 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
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:
- Feb - May 2014
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 014
- Report date:
- 2018
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:
- tert-Butyl 4-({6-[7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}pyridin-3-yl)piperazine-1-carboxylate
- EC Number:
- 810-753-4
- Cas Number:
- 1374639-78-7
- Molecular formula:
- C28H38N8O3
- IUPAC Name:
- tert-Butyl 4-({6-[7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}pyridin-3-yl)piperazine-1-carboxylate
- Test material form:
- solid: bulk
Constituent 1
Method
- Target gene:
- reverse mutations in a gene of histidine-requiring Salmonella typhimurium bacterial strains resulting in histidineindependent strains.
Species / strain
- Species / strain / cell type:
- S. typhimurium, other: Escherichia coli
- Remarks:
- TA1535, TA97, TA98, TA100 and TA102
- Additional strain / cell type characteristics:
- not specified
- Metabolic activation:
- with and without
- Metabolic activation system:
- Rat liver microsomal enzymes (S9 homogenate)
- Test concentrations with justification for top dose:
- Selection of an adequate range of doses was based on a dose range finding test with strain TA100 with and without 5% (v/v) S9-mix.
Eight concentrations, 3, 10, 33, 100, 333, 1000, 3330 and 5000 μg/plate were tested in triplicate. Due to precipitate of the test substance on the plates, the highest concentration of LEE011-A3 used in the subsequent mutation assay was 333 μg/plate. - Vehicle / solvent:
- dimethyl sulfoxide (DMSO, SeccoSolv, Merck, Darmstadt, Germany)
Controls
- Untreated negative controls:
- yes
- Positive controls:
- yes
- Positive control substance:
- 2-nitrofluorene
- sodium azide
- cumene hydroperoxide
- methylmethanesulfonate
- other: ICR-191
- Details on test system and experimental conditions:
- The characteristics of the different Salmonella typhimurium strains were as follows:
Strain Histidine mutation Mutation type
TA97 hisD6610/ R-factor* Frameshift
TA102 hisG428/ R-factor** Transitions/transversions
TA98 hisD3052/R-factor* Frameshift
TA1535 hisG46 Base-pair substitutions
TA100 hisG46/R-factor* Base-pair substitutions
*: R-factor = plasmid pKM101 (increases error-prone DNA repair)
**: R-factor = pKM101 and pAQ1
Each tester strain contained the following additional mutations:
rfa : deep rough (defective lipopolysaccharide cellcoat)
gal : mutation in the galactose metabolism
chl : mutation in nitrate reductase
bio : defective biotin synthesis
uvrB : loss of the excision repair system (deletion of the ultraviolet-repair B gene)
The Salmonella typhimurium strains were regularly checked to confirm their histidine-requirement, crystal violet sensitivity, ampicillin resistance (TA97, TA98, TA100 and TA102), tetracycline resistance (TA102), UV-sensitivity and the number of spontaneous revertants. Stock cultures of the five strains were stored in liquid nitrogen (-196°C).
Environmental conditions
All incubations were carried out in a controlled environment at a temperature of 37.0 ± 1.0°C (actual range 36.3 – 39.0°C) in the dark. Temporary deviations of maximally 2 hours (in the range of 38.0 – 39.0°C) occurred due to addition of plates (which were at room temperature) to the incubator or
due to opening and closing the incubator door. Based on laboratory historical data these deviations are considered not to affect the study integrity - Rationale for test conditions:
- The Salmonella typhimurium reverse mutation assay has been shown to be rapid and adequate indicators for the mutagenic activity of a wide range of chemical compounds.
The assay was conducted in the absence and presence of a metabolizing system (S9-mix).
The Salmonella typhimurium strains used in this study were TA1535, TA97, TA98, TA100 and TA102.
The strains TA97 and TA98 are capable of detecting frameshift mutagens; strains TA100 and TA1535 are capable of detecting base-pair substitution mutagens, and strain TA102 is capable of detecting transitions/transversions - Evaluation criteria:
- No formal hypothesis testing was done.
A test substance is considered negative (not mutagenic) in the test if:
a) The total number of revertants in the tester strain TA100, TA97 and TA102 is not greater than two
(2) times the concurrent control, and the total number of revertants in tester strains TA1535 and TA98 is not greater than three (3) times the concurrent vehicle control.
b) The negative response should be reproducible in at least one independently repeated experiment.
A test substance is considered positive (mutagenic) in the test if:
a) The total number of revertants in tester strain TA100, TA97 and TA102 is greater than two (2) times the concurrent control, or the total number of revertants in tester strains TA1535 and TA98 is greater than three (3) times the concurrent vehicle control.
b) In case a repeat experiment is performed when a positive response is observed in one of the tester strains, the positive response should be reproducible in at least one independently repeated experiment.
The preceding criteria were not absolute and other modifying factors might enter into the final evaluation decision.
Results and discussion
Test results
- Key result
- Species / strain:
- S. typhimurium, other: TA1535, TA97, TA98, TA100 and TA102
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity, but tested up to precipitating concentrations
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- The solvent control of tester strain TA97 (second experiment, absence of S9-mix) showed a response (mean plate count) which was not within the laboratory historical range.
Evaluation: The value (175) was above the limit of the range (169). The mean plate count was just outside the limit of the range and clear negative results are observed in all experiments, therefore this deviation in the mean plate count of the solvent control had no effect on the results of the study.
2. The mean plate counts of the positive control substance of tester strain TA102 did not reach a two-fold increase compared to the concurrent vehicle control group mean in some experiments.
Evaluation: Although the response of the positive control substance in the second experiment was just outside the laboratory historical range, the responses showed 1.5 and 1.8-fold increases compared to the concurrent vehicle controls and clear negative results were obtained in this tester strain, therefore, this deviation in the mean plate counts of the positive control had no effect on the results of the study The study integrity was not adversely affected by the deviations.
Any other information on results incl. tables
LEE011-A3 was tested in tester strain TA100 with concentrations of 3, 10, 33, 100, 333, 1000, 3330 and 5000 μg/plate in the absence and presence of S9-mix. Based on the results of the dose range finding test, the following dose range was selected for the mutation assay with the tester strains, TA1535, TA98, TA102 and TA97 in the absence and presence of S9-mix: 3, 10, 33, 100 and 333 μg/plate.
Precipitate
No precipitation of LEE011-A3 on the plates was observed at the start of the incubation period however at the end of the incubation period precipitate was observed at the concentration of 333 μg/plate.
Toxicity
There was no reduction of the bacterial background lawn and no biologically relevant decrease in the number of revertants at any of the concentrations tested in all tester strains in the absence and presence of S9-mix.
Mutagenicity
No increase in the number of revertants was observed upon treatment with LEE011-A3 under all conditions tested.
Applicant's summary and conclusion
- Conclusions:
- All bacterial strains showed negative responses over the entire dose range, i.e. no significant doserelated increase in the number of revertants in two independently repeated experiments.
Based on the results of this study it is concluded that LEE011-A3 is not mutagenic in the Salmonella typhimurium reverse mutation assay.
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