Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 618-844-9 | CAS number: 923604-58-4
- 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
- Remarks:
- Type of genotoxicity: gene mutation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From 2011-08-01 to 2011-08-08
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 011
- Report date:
- 2011
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: the OECD principles of Good Laboratory Practice (1998) and the Application of the Principles of GLP to In Vitro Studies (2004)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: FDA Toxicological Principles for the Safety Assessment of Direct Food Ingredients. Section IV.C1.a:Bacterial Reverse Mutation Test. “Redbook 2000”. U.S. FDA Washington DC 2000
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: Ministry of Health and Welfare (MHW), Japanese Guidelines for Nonclinical Studies of Drugs Manual (1995), Section 5. Reverse Mutation Test in Bacteria.
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human use
- Version / remarks:
- Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals. S2A document recommended for adoption at step 4 of the ICH process on July 19, 1995. Federal Register 61:18198-18202, April 24, 1996.
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human use.
- Version / remarks:
- Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals. S2B document recommended for adoption at step 4 of the ICH process on July 16, 1997. Federal Register 62:16026-16030, November 21, 1997
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- (1R,4R,6S,7Z,15R,17R)-17-({7-methoxy-8-methyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0^{4,6}]octadec-7-ene-4-carboxylic acid
- EC Number:
- 618-844-9
- Cas Number:
- 923604-58-4
- Molecular formula:
- C35H42N4O6S
- IUPAC Name:
- (1R,4R,6S,7Z,15R,17R)-17-({7-methoxy-8-methyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0^{4,6}]octadec-7-ene-4-carboxylic acid
- Test material form:
- solid: particulate/powder
- Details on test material:
- - Name of test material (as cited in study report): JNJ-38940642-AAA (T003010)
- Physical state: solid
- Appearance: white powder
Constituent 1
- Specific details on test material used for the study:
- Batch number: RT003010PFA121
Conversion factor: 1.04
Purity: 96%
Storage conditions: At room temperature in a closed and labelled container
Retest date: 2012-12-01
Method
- Target gene:
- histidine locus
Species / strain
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102
- Metabolic activation:
- with and without
- Metabolic activation system:
- Aroclor 1254-induced S9-mix from male Sprague-Dawley rat liver
- Test concentrations with justification for top dose:
- Based on the solubility findings, 5000 μg/plate was selected as the maximum final concentration.
First mutation experiment: 0, 78.13, 156.25, 312.5, 625, 1250, 2500, 5000 μg/plate (with and without S9)
Second mutation experiment: 0, 6.86, 20.58, 61.73, 185.19, 555.56, 1666.67, 5000 µg/plate (with and without S9) - Vehicle / solvent:
- According to the solubility determination step of the study, the test substance was found to be soluble in DMSO, and then was used as the concurrent vehicle control for the test item.
Controlsopen allclose all
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- 2-nitrofluorene
- Remarks:
- without S9, at 5 µg/plate for TA98
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- sodium azide
- Remarks:
- without S9, at 1 µg/plate for TA1535 and TA 100
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- 9-aminoacridine
- Remarks:
- without S9, at 50 µg/plate for TA1537
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- 4-nitroquinoline-N-oxide
- Remarks:
- without S9, at 5 µg/plate for TA102
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: 2-aminoanthracene
- Remarks:
- with S9, at 2.5 µg/plate for TA98, TA100, TA1535 and TA1537 and at 7.5 µg/plate for TA102
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in agar (plate incorporation)
EXPERIMENTAL PERFORMANCE:
The following solutions were added to 2 ml histidine-biotin supplemented top agar:
- 0.1 ml of an overnight bacterial culture of the tester strain
- 0.1 ml of a dilution of the test item, vehicle control or positive control
- 0.5 ml of S9-mix for the activation portion or 0.5 ml phosphate buffer for the non-activation portion.
The content of the tube was then mixed and poured onto minimal glucose agar plates. The plates were incubated in the dark at 37°C for 48 to 72 hours.
DURATION
- Exposure duration: 48-72 hours
- Selection time: 48-72h (simultaneous with exposure)
SELECTION AGENT: histidine
NUMBER OF REPLICATIONS: All concentration levels of JNJ- 38970191-AAA, vehicle controls and positive controls were plated in triplicate.
Approximate No. of Bacteria Assayed/Dose: 10^9
DETERMINATION OF CYTOTOXICITY:
reduced number of revertants and/or thinning of the bacterial background lawn - Rationale for test conditions:
- The Ames reverse mutation test has been shown to be a sensitive, rapid and accurate indicator of the mutagenic activity of a wide range of chemical classes (Ames et al., 1973a, 1973b; McCann et al., 1975a, 1975b).
- Evaluation criteria:
- CRITERIA FOR A POSITIVE RESPONSE:
According to Brusick (1980), a test item is considered positive (mutagenic) if all of the following criteria are met:
- The test substance produces at least a two-fold increase in the mean number of revertants with one of the strains TA98, TA102 or TA100, or a three-fold increase in the mean number of revertants with one of the strains TA1535 or TA1537 at one or more concentration levels in comparison to the mean concurrent vehicle control value;
- a concentration-related effect is observed;
- these effects can be reproduced in an additional experiment.
CRITERIA FOR A NEGATIVE RESPONSE:
If the test item does not produce (1) a concentration-dependent increase in the number of revertant colonies and (2) a two-fold increase in the mean number of revertants with one of the strains TA98, TA102 or TA100, or a three-fold increase in the mean number of revertants with one of the strains TA1535 and TA1537 in comparison to the mean concurrent vehicle control value, it will be considered as negative (non-mutagenic) in this test system under the current test conditions. Furthermore, the negative response should be reproducible.
CRITERIA FOR AN EQUIVOCAL RESPONSE
When criteria for a clear positive or a clear negative are not satisfied (e.g., concentration-dependent increase that fails to reach two-fold in the mean number of revertants for the strains TA98, TA102 or TA100, or three-fold in the mean number of revertants for the strains TA1535 and TA1537; or biological significant increase in the reversion rate that does not appear to be concentration-dependent), more tests may be required, in order to evaluate the mutagenic potential of the test item. If the test item produces a positive response in a single test that cannot be reproduced in additional testing, the initial positive data will be discounted. If still the test item cannot be judged to be positive or negative, the results may be classified as equivocal. - Statistics:
- No data
Results and discussion
Test results
- Species / strain:
- S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Evaporation from medium: no data
- Water solubility: no data
- Precipitation:
RANGE-FINDING/SCREENING STUDIES: No dose range finding study.
HISTORICAL CONTROL DATA:
- Positive historical control data: The positive controls induced a biologically significant increase in th e mean number of revertant colonies in comparison to the mean concurrent vehicle control value, indicating the capacity of the test system to identify mutagens.
- Negative (solvent/vehicle) historical control data: The mean number of spontaneous and vehicle control revertant colonies in the absence and in the presence of S9-mix fell within the range of the laboratory historical data
ADDITIONAL INFORMATION ON CYTOTXICITY:
First mutation experiment: Bacteriotoxic effects, visualised by a reduction in the number of revertant colonies were observed with the strain TA1537 in the absence of S9-mix from 1250 μg/plate onwards. From 625 μg/plate onwards at the start and from 2500 μg/plate onwards at the end of treatment, a concentration-related increase in milky suspension was observed with the five strains in the absence and/or in the presence of S9-mix.
Second mutation experiment: Bacteriotoxic effects, visualised by a reduction in the number of revertant colonies were observed with the strain TA98 in the absence of S9-mix and with the strain TA1537 in the absence and in the presence of S9-mix from 1666.67 μg/plate onwards. From 555.56 μg/plate onwards at the start and from 1666.67 μg/plate onwards at the end of treatment, a concentration-related increase in milky suspension was observed with the five strains in the absence and/or in the presence of S9-mix.
OTHERS:
Sterility checks and bacterial titre of the five strains were according to the criteria. - Remarks on result:
- other: all strains/cell types tested
Any other information on results incl. tables
Solubility determination
The test substance was found to be insoluble in water at 50 mg/ml. In DMSO, the test item was soluble at 50 mg/ml (= 5000 μg/plate) after 10 minutes at 37ºC, but a strong milky suspension was obtained upon mixing with water. Sequential dilutions from this maximum concentration resulted in moderate to slight milky suspension upon mixing with water, until at 3.125 mg/ml (= 312.5 μg/plate) a clear solution was obtained upon mixing with water. Based on these solubility findings, DMSO was selected as vehicle and 5000 μg/plate was selected as the maximum final concentration for the first mutation experiment (plate incorporation method).
Concentration analysis
Concentration analysis of the vehicle control (DMSO) revealed that there were no traces of the test substance present and that the concentration of test item in the stock formulation fell within the predefined acceptance criteria (85% - 115%). This stock formulation was used to prepare further dilutions.
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results:
negative with metabolic activation
negative without metabolic activation
Based on this study, it is concluded that the test substance has no mutagenic properties towards the various Salmonella typhimurium strains in the absence and in the presence of S9-mix under the test conditions described in this report, up to the maximum test concentration of 5000 μg/plate.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.