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EC number: 607-384-4 | CAS number: 244768-32-9
- 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:
- 2004-06-10 to 2004-09-10
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study without detailed documentation
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 004
- Report date:
- 2004
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: Ministry of Health and Welfare (MHW), Japanese Guidelines for Nonclinical Studies of Drugs Manual, Section 5. Reverse Mutation Test in Bacteria (1995).
- 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: International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use. Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals.
- Version / remarks:
- 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. Genotoxicity : A Standard Battery for Genotoxicity Testing of Pharmaceuticals.
- Version / remarks:
- S2B document recommended for adoption at step 4 of the ICH process on July 16, 1997. Federal Register 61;16026-16030, November 21, 1997.
- Deviations:
- no
- GLP compliance:
- no
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- 4-[(4-CHLOROPYRIMIDIN-2-YL)AMINO]BENZONITRILE
- EC Number:
- 607-384-4
- Cas Number:
- 244768-32-9
- Molecular formula:
- C11H7ClN4
- IUPAC Name:
- 4-[(4-CHLOROPYRIMIDIN-2-YL)AMINO]BENZONITRILE
- Test material form:
- solid: particulate/powder
- Details on test material:
- - Name of test material (as cited in study reports): JNJ-4754724-AAA (T002488)
- Physical state: solid
- Appearance: light brown powder
Constituent 1
- Specific details on test material used for the study:
- Batch-no.: RT002488PFA021 - conversion factor = 1.0000
Purity: 100.3%
Acceptance date: 2004-06-07
Retest date: 2006-05-25
Method
- Target gene:
- histidine locus
Species / strain
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102
- Details on mammalian cell type (if applicable):
- not applicable
- Additional strain / cell type characteristics:
- other: See below for additional strain characteristics.
- Remarks:
- The genotypes and viability of the bacteria were checked when a new set of frozen permanent cultures was prepared. Overnight cultures for the plate incorporation tests were checked for their genotypes and viability.
- Metabolic activation:
- with and without
- Metabolic activation system:
- Aroclor 1254 induced rat liver S9
- Test concentrations with justification for top dose:
- Range finding study: 0.64, 1.22, 2.44, 4.88, 9.77, 19.53, 39.07, 78.13, 156.25, and 312.5 μg/plate.
As in the range finding study, no bacteriotoxicity was observed, and the revertants could still be scored at the dose level of 321.5 μg/plate, it was decided to select 625 µg/plate as top dose for the first study.
First, second and third study: 9.77, 19.53, 39.07, 78.13, 156.25, 312.5 and 625 µg/plate - Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: DMSO
- Justification for choice of solvent/vehicle: The test substance was found to be not soluble in water at the concentration of 50 mg/mL. In DMSO, the test substance was found soluble at the concentration of 50 mg/mL (5000 µg/plate).
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 TA100
- 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:
- other: 2-aminoanthracene
- Remarks:
- with S9; at 1 µg/plate for TA98, TA100 and TA1535; at 2.5 µg/plate for TA1537 and TA102
- 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
- Details on test system and experimental conditions:
- METHOD OF APPLICATION:
in agar (plate incorporation)
EXPERIMENTAL PERFORMANCE:
The following solutions were successively added to 2 ml histidine-biotine supplemented top agar: 0.1 ml of an overnight bacterial culture of the tester strain, 0.1 ml of a dilution of T002488 and either 0.5 ml S9-mix containing 100 μl S9/ml 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 petri dishes.
The plates were incubated in the dark at 37°C for 48 to 72 hours.
DURATION
- Exposure duration: 48 to 72 hours
- Selection time: 48 to 72 hours (simultaneous with exposure)
SELECTION AGENT: histidine
NUMBER OF REPLICATIONS: All concentration levels of the test substance, vehicle controls and positive controls were plated in triplicate.
DETERMINATION OF CYTOTOXICITY
- Method: Toxic effects of the test substance were detected by a decrease in the number of revertant colonies, thinning of the bacterial background lawn or occurrence of pinpoints.
OTHER EXAMINATIONS:
- Agar, top agar, S9 mix and the highest concentration of the test substance were checked for sterility and were incubated at the same time and for the same length of time as the test plates. - Evaluation criteria:
- The mean number of the revertant colonies on the vehicle control plates was taken as the background level of the mutation test. The mean reversion values were considered as positive if:
- the test was valid;
- the test substance produced at least a two-fold increase in the mean number of revertants with one of the strains TA98, TA102 or TA100, or a threefold increase in the mean number of revertants with one of the strains TA1535, TA1537 at one or more concentration levels;
- a dose effect relationship was observed;
- these effects could be reproduced in an additional study.
When equivocal results were obtained, more tests may have been conducted. If the test substance produces a positive response in a single test that cannot be reproduced in additional runs, the initial positive test data will be discounted.
If the test substance produced a positive response in a single test that could not be reproduced in additional runs, the initial positive test data was discounted. - Statistics:
- No statistical analysis was used.
Results and discussion
Test results
- Species / strain:
- S. typhimurium, other: TA1535, TA1537, TA102, TA98 and TA100
- 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
- Water solubility: The test substance was found to be not soluble in water at the concentration of 50 mg/mL. In DMSO, the test substance was found soluble at the concentration of 50 µg/mL. However, precipitation was observed upon mixing with water down to the concentration of 156.25 µg/plate. At the concentration of 78.13 µg/plate, a colourless solution was obtained upon mixing the test substance with water. The concentration of 312.5 µg/plate was considered to be the highest applicable concentration for the range finding study
- Precipitation: In study 1, at the concentration of 39.07 or 156.25 µg/plate onwards in the absence of S9 mix and at 78.13 or 156.25 µg/plate onwards in the presence of S9 mix, a dose related increase in precipitation was observed. At the top dose of 625 µg/plate, no bacterial background could be observed due to the heavy precipitation. In study 3, at the concentration of 78.13 µg/plate onwards in the absence and in the presence of S9, a dose related increase in precipitation was observed. At the top dose of 625 µg/plate, no bacterial background could be observed due to the heavy precipitation.
RANGE-FINDING/SCREENING STUDIES:
A range finding study was performed with strain T100 in the absence and presence of S9-mix at concentrations ranging from 0.64-312.5 µg/plate using the plate incorporation assay. At concentrations up to 312.5
µg/plate the test substance did not reveal a biologically significant increase in the number of revertant colonies in the absence and in the presence (50 µL S9 homogenate) of S9-mix. No bacteriotoxic effects visualized by a decrease in the number of revertant colonies, thinning of the background lawn or occurrence of pinpoints were observed.
At concentrations of 78.13 µg/plate onwards in the absence and in the presence of rat liver S9-mix a dose related increase in precipitation was observed.
COMPARISON WITH HISTORICAL CONTROL DATA:
The number of spontaneous and vehicle control revertant colonies for the strains in the absence and in the presence of S9-mix fell within the range of the laboratory's historical data. The positive controls showed a significant increase in the number of revertant colonies indicating their mutagenic activity.
ADDITIONAL INFORMATION ON CYTOTOXICITY:
With all the stains, no bacteriotoxic effects visualized by a decrease in the number of revertant colonies, thinning of the background law or occurrence of pinpoints were observed. - Remarks on result:
- other: all strains/cell types tested
Any other information on results incl. tables
First study
Sterility checks, genotypes of all the bacterial strains and bacterial titre of all the strains were according to the criteria. The tests with all strains were considered acceptable for the evaluation of the mutagenic potential of the test substance. At the concentrations up to 625 µg/plate, the test substance did not reveal a biologically significant increase in the number of revertant colonies in the absence and in the presence (20 µL S9 homogenate) of S9-mix.
Second study
The same concentrations were applied in the second study as were used in the first study. As a bad lot of prepared bottom agar was used in the second study which did not allow the growth of bacteria, the second study was completely invalidated.
Third Study
Sterility checks, genotypes of all the bacterial strains and bacterial titre of all the strains were according to the criteria. The tests with all strains were considered acceptable for the evaluation of the mutagenic potential of the test substance. At concentrations up to 625 µg/plate, the test substance did not reveal a biologically significant increase in the number of revertant colonies in the absence of and in the presence (50 µL S9 homogenate) of S9-mix.
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results:
negative with metabolic activation
negative without metabolic activation
The tests were performed at maximum concentrations of 625 µg of the test substance/plate, which was not bacteriotoxic to the strains but which strongly precipitated. Decreasing concentration levels from the highest acceptable concentration level provided adequate number of data points to ensure that any possible dose-response would have been detected. All the tests satisfied the criteria for a valid test.
Based on the lack of a biologically significant increase in the reversion rate, it can be concluded that the test substance in the presence and in the absence of a rat liver metabolic activation system, has no mutagenic properties towards the Salmonella typhimurium strains under the test conditions described in the report.
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