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EC number: 944-343-2 | CAS number: 2050038-81-6
- 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:
- 27th March 2017 to 6th June 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 017
- Report date:
- 2017
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- GLP compliance:
- yes
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- benzyl (3R,4S)-3-{2-[(ethoxycarbonyl)[5-(4-methylbenzenesulfonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]amino]acetyl}-4-ethylpyrrolidine-1-carboxylate
- EC Number:
- 944-343-2
- Cas Number:
- 2050038-81-6
- Molecular formula:
- C32H35N5O7S
- IUPAC Name:
- benzyl (3R,4S)-3-{2-[(ethoxycarbonyl)[5-(4-methylbenzenesulfonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]amino]acetyl}-4-ethylpyrrolidine-1-carboxylate
- Test material form:
- solid: particulate/powder
Constituent 1
Method
- Target gene:
- The histidine locus in several strains of Salmonella typhimurium (Salmonella; TA98, TA100, TA1535, and TA1537) and the tryptophan locus of Escherichia coli strain WP2uvrApKM101
Species / strainopen allclose all
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
- Species / strain / cell type:
- E. coli WP2 uvr A pKM 101
- Metabolic activation:
- with and without
- Metabolic activation system:
- Aroclor™ 1254-induced rat liver homogenate (S9) was purchased commercially and used with co-factors (S9 mix). S9 mix was prepared by standard procedures on the day of use and kept on ice until needed
- Test concentrations with justification for top dose:
- The limit dose of 5000 μg/well, suggested by OECD 471, was reduced to 1000 μg/well based on the surface area of the well compared to that of a Petri plate.
The test article was evaluated in the mutagenicity assay at concentrations 0.3, 0.8, 2, 7, 22, 67, 200, 600 and 1000 μg/well. - Vehicle / solvent:
- N,N-Dimethylformamide (DMF)
Controlsopen allclose all
- Negative solvent / vehicle controls:
- yes
- Remarks:
- N,N-Dimethylformamide (DMF)
- Positive controls:
- yes
- Remarks:
- E.coli WP2uvrApKM101
- Positive control substance:
- 4-nitroquinoline-N-oxide
- other:
- Negative solvent / vehicle controls:
- yes
- Remarks:
- N,N-Dimethylformamide (DMF)
- Positive controls:
- yes
- Remarks:
- TA1537
- Positive control substance:
- 9-aminoacridine
- other:
- Negative solvent / vehicle controls:
- yes
- Remarks:
- N,N-Dimethylformamide (DMF)
- Positive controls:
- yes
- Remarks:
- TA1535
- Positive control substance:
- sodium azide
- other: 2-aminoanthracene with metabolic action
- Negative solvent / vehicle controls:
- yes
- Remarks:
- N,N-Dimethylformamide (DMF)
- Positive controls:
- yes
- Remarks:
- TA100
- Positive control substance:
- other:
- Negative solvent / vehicle controls:
- yes
- Remarks:
- N,N-Dimethylformamide (DMF)
- Positive controls:
- yes
- Remarks:
- TA98
- Positive control substance:
- 2-nitrofluorene
- benzo(a)pyrene
- Details on test system and experimental conditions:
- Tester strains were exposed to the test article via the plate incorporation methodology. In the plate incorporation methodology, the tester strain, test article, and S9 mix (where appropriate) were combined in molten supplemented top agar, which was then overlaid on minimal bottom agar in a well of a 6-well plate. Following incubation, revertant colonies were counted.
Each 6-well plate was labeled with the study number, date, test article, tester strain, activation condition, and concentrations.
Treatments in the absence of S9 were performed by adding 20 μL test or control articles, 100 μL of phosphate buffered saline (PBS) and 25 μL tester strain to sterile tubes containing 0.5 mL molten supplemented top agar (maintained at 46 ± 2°C). The mixture was overlaid onto the surface of bottom agar wells and gently spread with swirling of the plate. The plates were kept at room temperature until the top agar solidified. After the top agar solidified, the 6-well plates were inverted and incubated for two days at 37 ± 2C. When S9 was required, 100 μL S9 mix was used instead of PBS.
The condition of the background lawn was evaluated for evidence of cytotoxicity and test article precipitate. Evidence of cytotoxicity was scored relative to the vehicle control. Revertant colonies were counted by hand or automated colony counter.
Results and discussion
Test resultsopen allclose all
- Key result
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 100
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 1535
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 1537
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- E. coli WP2 uvr A pKM 101
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- other: These results indicate A-1634356.0 is negative (non-mutagenic)
Applicant's summary and conclusion
- Conclusions:
- These results indicate A-1634356.0 is negative (non-mutagenic) in the 6-well 5-strain bacterial reverse mutation assay under the conditions, and according to the criteria, of the study plan.
- Executive summary:
The objective of this study was to evaluate A-1634356.0, a component of the synthetic route of ABT-494, and/or metabolites for the ability to induce reverse mutations at the histidine locus in several strains of Salmonella typhimurium (Salmonella; TA98, TA100, TA1535, and TA1537), and at the tryptophan locus of Escherichia coli (E. coli) strain WP2uvrApKM101 in the presence or absence of an Aroclor™ 1254-induced exogenous rat liver metabolic activation system (S9).
A-1634356.0 was evaluated in the mutagenicity assay using the plate incorporation treatment method at concentrations ranging from 0.3-1000 μg/well both with and without S9. A-1634356.0 was formulated in N,N-Dimethylformamide and formed a colorless solution at the highest concentration of 50 mg/mL. After the incubation period there was no toxicity present under either metabolic condition. Precipitate was present beginning at 200 μg/well both with and without metabolic activation. The criteria for a positive response were not met for any condition tested in the assay.
All vehicle control values were within acceptable ranges and the positive controls demonstrated the tester strains were capable of detecting mutagens. Therefore, the study was considered valid.These results indicate A-1634356.0 is negative (non-mutagenic) in the 6-well 5-strain bacterial reverse mutation assay under the conditions, and according to the criteria, of the study plan.
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