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EC number: 807-111-0 | CAS number: 1211441-98-3
- 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:
- March - July 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:
- 2014
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)
- Qualifier:
- according to guideline
- Guideline:
- other: ICH. S2(R1): Guidance on Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use; ICH Consensus Guideline, Step 4 of the Process, November 2011
- GLP compliance:
- yes
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide
- EC Number:
- 807-111-0
- Cas Number:
- 1211441-98-3
- Molecular formula:
- C23H30N8O
- IUPAC Name:
- 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide
- Test material form:
- solid: bulk
Constituent 1
Method
- Target gene:
- The objective of this study was to evaluate the test substance for its ability to induce reverse mutations in a gene of histidine-requiring Salmonella typhimurium bacterial strains resulting in histidineindependent strains.
Species / strain
- Species / strain / cell type:
- other: TA1535, TA97, TA98, TA100 and TA102
- Metabolic activation:
- with and without
- Metabolic activation system:
- In the presence and absence of S9-mix (rat liver S9-mix induced by a combination of phenobarbital and ß-naphthoflavone).
- Test concentrations with justification for top dose:
- concentrations of 3, 10, 33, 100, 333, 1000, 3330 and 5000 μg/plate
In the dose range finding test, LEE011-A4 was tested up to concentrations of 5000 μg/plate in the absence and presence of S9-mix in tester strain TA100. LEE011-A4 precipitated only on the plates at the top dose of 5000 μg/plate in the presence of S9-mix.
Based on the results of the dose range finding test, LEE011-A4 was tested in the first mutation assay at a concentration range of 33 to 5000 μg/plate in the absence and presence of 5% (v/v) S9-mix in tester strains TA1535, TA97, TA98 and TA102. LEE011-A4 did not precipitate on the plates at the top dose of 5000 μg/plate. - Vehicle / solvent:
- dimethyl sulfoxide
Controls
- Untreated negative controls:
- yes
- Remarks:
- The vehicle of the test substance, which was DMSO
- Positive controls:
- yes
- Positive control substance:
- sodium azide
- methylmethanesulfonate
- other: ICR-191, 2-nitrofluorene, tert-butyl hydroxide, 2-aminoanthracene
- Details on test system and experimental conditions:
- Salmonella typhimurium bacteria and Escherichia coli bacteria.
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). - Rationale for test conditions:
- 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:
- A Salmonella typhimurium reverse mutation assay is considered acceptable if it meets the following criteria:
a) The negative control data (number of spontaneous revertants per plate) should be within the laboratory historical range for each tester strain.
b) The positive control chemicals should produce responses in all tester strains, which are within the laboratory historical range documented for each positive control substance. Furthermore, the mean plate count should be at least two times (TA102) and three times (TA100, TA97, TA1537 and TA98) the concurrent vehicle control group mean.
c) The selected dose range should include a clearly toxic concentration or should exhibit limited solubility as demonstrated by the preliminary toxicity range-finding test or should extend to 5 mg/plate. - Statistics:
- 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:
- other: TA1535, TA97, TA98, TA100 and TA102
- Remarks:
- Salmonella typhimurium strains
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- In tester strain TA98, LEE011-A4 induced up to 3.5- and 3.2-fold increases in the number of revertant colonies compared to the solvent control in the absence and presence of S9-mix, respectively in the first experiment. However since these increases were not seen in the second and third experiment, no dose related response was observed and there was a large difference in the number of revertant colonies in the three replicate plates of the dose level which showed an increase in the number of revertant colonies, these increases are considered to be not biologically relevant and LEE011-A4 is considered not mutagenic.
The mean plate counts of the positive control of TA102, in the presence of S9-mix did not reach a two-fold increase compared to the concurrent vehicle control group mean.
Evaluation: Although the responses showed 1.6 to 1.7-fold increases compared to the concurrent vehicle controls, the responses were within the laboratory historical range 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. - Remarks on result:
- other: not mutagenic
Applicant's summary and conclusion
- Conclusions:
- Based on the results of this study it is concluded that LEE011-A4 is not mutagenic in the Salmonella typhimurium reverse mutation assay.
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