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EC number: 810-161-6 | CAS number: 1229654-66-3
- 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 vivo
Administrative data
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 16 Sep - 30 Oct 2013
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
- Report date:
- 2013
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Version / remarks:
- adopted in 1997
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.12 (Mutagenicity - In Vivo Mammalian Erythrocyte Micronucleus Test)
- Version / remarks:
- adopted in 2008
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.5395 (In Vivo Mammalian Cytogenetics Tests: Erythrocyte Micronucleus Assay)
- Version / remarks:
- adopted in 1998
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- Hess. Ministerium für Umwelt, Energie, Landwirtschaft und Verbraucherschutz, Wiesbaden, Germany
- Type of assay:
- other: in vivo micronucleus test in mice
Test material
- Reference substance name:
- 1-(3-chloropyridin-2-yl)-N-[4-cyano-2-methyl-6-(methylcarbamoyl)phenyl]-3-{[5-(trifluoromethyl)-2H-1,2,3,4-tetrazol-2-yl]methyl}-1H-pyrazole-5-carboxamide
- EC Number:
- 810-161-6
- Cas Number:
- 1229654-66-3
- Molecular formula:
- C22 H16 Cl F3 N10 O2
- IUPAC Name:
- 1-(3-chloropyridin-2-yl)-N-[4-cyano-2-methyl-6-(methylcarbamoyl)phenyl]-3-{[5-(trifluoromethyl)-2H-1,2,3,4-tetrazol-2-yl]methyl}-1H-pyrazole-5-carboxamide
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- NMRI
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Sulzfeld, Germany
- Age at study initiation: 8 - 10 weeks
- Weight at study initiation: 35.0 ± 1.7 g (males), 28.5 ± 1.2 g (females)
- Assigned to test groups randomly: yes
- Housing: individual in Makrolon Type II (pre-test) / III (main study) cages with wire mesh top, granulated soft wood bedding
- Diet: certified standard diet, pelleted, ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 42.8 - 65
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- - Vehicle(s)/solvent(s) used: corn oil
- Justification for choice of solvent/vehicle: Corn oil was chosen due to its relative non-toxicity for the animals and as a smooth homogeneous suspension was attainable, which was not the case for several aqueous solvents/vehicles tested.
- Amount of vehicle: 10 mL/kg bw - Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: On the day of the experiment, the test item was suspended in corn oil. Grinding of the test item in a mortar was used to formulate the test item.
- Duration of treatment / exposure:
- not applicable
- Frequency of treatment:
- single treatment
- Post exposure period:
- 24 and 48 h after last treatment
Doses / concentrations
- Dose / conc.:
- 2 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 2 (pre-experiment on toxicity)
6 (main study) - Control animals:
- yes, concurrent vehicle
- Positive control(s):
- cyclophosphamide
- Route of administration: orally once
- Doses / concentrations: 40 mg/kg bw
Examinations
- Tissues and cell types examined:
- Cell type: bone marrow erythroblasts
- Details of tissue and slide preparation:
- CRITERIA FOR DOSE SELECTION: Since no signs of toxicity were observed in a pre-experiment on toxicity a limit test was performed in two sexes using the maximum dose of 2000 mg/kg b.w.
TREATMENT AND SAMPLING TIMES: The animals of all dose groups, except the positive control, were examined for acute toxic symptoms at intervals of around 0-1 h, 2-4 h, 5-6 h, 24 h, and/or 48 h after administration of the test item. Sampling of the bone marrow was done 24 and 48 h after treatment, respectively.
DETAILS OF SLIDE PREPARATION: Following sacrifice the femora were removed, the epiphyses were cut off and the marrow was flushed out with fetal bovine serum using a syringe. The cell suspension was centrifuged and a small drop of the re-suspended cell pellet was spread on a slide. The smear was airdried, stained with Giemsa and cover slips were mounted. One slide was made from each bone marrow sample.
METHOD OF ANALYSIS: Evaluation of the slides was performed using light microscopes with 100x oil immersion objectives. Per animal 2000 polychromatic erythrocytes were analysed for micronuclei. To describe a cytotoxic effect the ratio between polychromatic and normochromatic erythrocytes was determined in the same sample and expressed in polychromatic erythrocytes per 2000 erythrocytes. The analysis was performed with coded slides. - Evaluation criteria:
- A test item is classified as mutagenic if it induces either a dose-related increase or a clear increase in the number of micronucleated polychromatic erythrocytes in a single dose group above the laboratory’s historical solvent control data range. The primary point of consideration is the biological relevance of the results and statistical analysis was used as an aid in evaluating the results, if necessary. A test item that fails to produce a biological relevant increase in the number of micronucleated
polychromatic erythrocytes is considered non-mutagenic in this system. - Statistics:
- Statistical significance at the five per cent level (p < 0.05) was evaluated by means of the nonparametric Mann-Whitney test.
Results and discussion
Test results
- Key result
- Sex:
- male/female
- Genotoxicity:
- negative
- Toxicity:
- no effects
- Vehicle controls validity:
- valid
- Negative controls validity:
- not examined
- Positive controls validity:
- valid
- Additional information on results:
- RESULTS OF RANGE-FINDING STUDY
- Dose range: 2000 mg/kg bw
- Clinical signs of toxicity in test animals: The animals treated with the test item did not express any clinical symptoms.
RESULTS OF DEFINITIVE STUDY
- Induction of micronuclei (for Micronucleus assay): In comparison to the corresponding vehicle controls there was no statistically significant or biologically relevant enhancement in the frequency of the detected micronuclei at any preparation interval and gender after administration of the test item.
- Ratio of PCE/NCE (for Micronucleus assay): The mean number of polychromatic erythrocytes was not substantially decreased after treatment with the test item as compared to the mean value of polychromatic erythrocytes of the vehicle control.
Any other information on results incl. tables
Table 1: Results of the in vivo micronucleus assay in male animals
|
Mean PCEs / 2000 erythrocytes at sampling time
|
Total micronuclei per 1000 PCEs at sampling time (range) |
PCEs with micronuclei (%) |
|||||
Test group |
Number of animals |
Dose [mg/kg bw] |
24 h |
48 h |
24 h |
48 h |
24 h |
48 h |
Vehicle control (corn oil) |
6 |
0 |
1160 |
n.d. |
1 - 6 |
n.d. |
0.150 |
n.d. |
Positive control (cyclophosphamide) |
6 |
40 |
1163 |
n.d. |
12 – 60* |
n.d. |
1.900* |
n.d. |
Test substance |
6 |
2000 |
1173 |
1178 |
1 - 4 |
1 - 4 |
0.117 |
0.117 |
n.d. = not determined; *statistically significant (p<0.001); PCE = polychromatic erythrocytes
Table 2: Results of the in vivo micronucleus assay in female animals
|
Mean PCEs / 2000 erythrocytes at sampling time
|
Total micronuclei per 1000 PCEs at sampling time (range) |
PCEs with micronuclei (%) |
|||||
Test group |
Number of animals |
Dose [mg/kg bw] |
24 h |
48 h |
24 h |
48 h |
24 h |
48 h |
Vehicle control (corn oil) |
6 |
0 |
1149 |
n.d. |
0 - 5 |
n.d. |
0.083 |
n.d. |
Positive control (cyclophosphamide) |
6 |
40 |
1163 |
n.d. |
33 – 89* |
n.d. |
2.625* |
n.d. |
Test substance |
6 |
2000 |
1271 |
1212 |
0 - 3 |
0 - 4 |
0.108 |
0.083 |
n.d. = not determined; *statistically significant (p<0.001); PCE = polychromatic erythrocytes
Applicant's summary and conclusion
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.
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