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EC number: - | CAS number: -
- 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 cytogenicity / chromosome aberration study in mammalian cells
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 03 May 2017 - 09 July 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 018
- Report date:
- 2018
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 473 (In Vitro Mammalian Chromosome Aberration Test)
- Version / remarks:
- 29 July 2016
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- other: in vitro mammalian chromosome aberration test (migrated information)
Test material
- Test material form:
- liquid
- Details on test material:
- - Physical appearance: pale yellow liquid
- Storage conditions: at room temperature
Constituent 1
Method
Species / strain
- Species / strain / cell type:
- lymphocytes: cultured peripheral human lymphocytes
- Details on mammalian cell type (if applicable):
- CELLS USED
- Source of cells: whole blood treated with heparin, after being collected from healthy, adult, non-smoking volunteers
- Method of sampling: blood samples were collected by venepuncture using the Venoject multiple sample blood collecting system with a suitable size sterile vessel containing sodium heparin. Immediately after blood collection lymphocyte cultures were started.
- Suitability of cells: cells from healthy, adult, non smoking humans were used as recommended in international guidelines (e.g. OECD).
- Average Generation Time: 13.1 h (dose-range finding and first assay) and 13.2 (second assay)
- Sex, age and number of blood donors: 29 years old (dose-range finding and first assay) and 31 years old (second assay)
MEDIA USED
- Type and identity of media including CO2 concentration if applicable: RPMI 1640 medium supplemented with 20% (v/v) heat-inactivated (56°C; 30 min) foetal calf serum, L-glutamine (2 mM), penicillin/streptomycin (50 U/ml and 50 μg/ml respectively) and 30 U/ml heparin.
- Metabolic activation:
- with and without
- Metabolic activation system:
- Rat liver S9-mix induced by a combination of phenobarbital (80 mg/kg bw) and ß-naphthoflavone (100 mg/kg bw).
- Test concentrations with justification for top dose:
- The highest concentration analyzed was selected based on the solubility of the test item in the culture medium.
- Dose range finding study and first cytogenetic assay:
3 h exposure, with and without S9: 4.9, 9.8, 19.5 and 39 μg/mL
24 h exposure, 24 h fixation, without S9: 4.9, 9.8, 19.5, 39, 78 and 156 μg/mL
48 h exposure, 48 h fixation, without S9: 4.9, 9.8,19.5, 39, 78 and 156 μg/mL
- Second cytogenetic assay (24 h exposure, 24 h fixation and 48 h exposure, 48 h fixation; without S9): 5, 20 and 80 μg/mL - Vehicle / solvent:
- - Solvent used: ethanol
- Justification for choice of solvent: A solubility test was performed based on visual assessment. The test item was dissolved in ethanol, which is recommended by internation guidelines as solvent.
Controlsopen allclose all
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- mitomycin C
- Remarks:
- without S9
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- cyclophosphamide
- Remarks:
- with S9
- Details on test system and experimental conditions:
- Two independent cytogenetic assays were performed, preceeded by a dose-range finding assay.
METHOD OF APPLICATION: in medium
DURATION
- Preincubation period: 48 hr
- Exposure duration experiment 1: 3 h (with and without S9)
- Exposure duration experiment 2: 24, 48 h (without S9)
- Fixation time: 24 h (for 3 or 24 hour exposure period) and 48 h (for 48 hour exposure period)
ENVIRONMENTAL CONDITIONS:
- Humidity: 35-90%
- Temperature: 34.7-37.1 °C
SPINDLE INHIBITOR (cytogenetic assays): colchicine
STAIN (for cytogenetic assays): Giemsa
METHODS OF SLIDE PREPARATION AND STAINING TECHNIQUE USED: Fixed cells were dropped onto cleaned slides, which were immersed in a 1:1 mixture of 96% (v/v) ethanol (Merck)/ether (Merck) and cleaned with a tissue. At least two slides were prepared per culture. Slides were allowed to dry and thereafter stained for 10 - 30 min with 5% (v/v) Giemsa (Merck) solution in Sörensen buffer pH 6.8. Thereafter slides were rinsed in water and allowed to dry.
NUMBER OF REPLICATIONS: duplicates in two independent experiments
NUMBER OF CELLS EVALUATED: 1000
NUMBER OF METAPHASE SPREADS ANALYSED PER DOSE: 150 in each replicate
DETERMINATION OF CYTOTOXICITY
- Method: mitotic index (the highest concentration analyzed was determined by the solubility in the culture medium)
OTHER EXAMINATIONS:
- Determination of polyploidy: yes
- Determination of endoreplication: yes - Evaluation criteria:
- EVALUATION CRITERIA:
A test substance was considered positive (clastogenic) in the chromosome aberration test if:
a) At least one of the test concentrations exhibits a statistically significant (Fisher’s exact test, one-sided, p < 0.05) increase compared with the concurrent negative control.
b) The increase is dose related when evaluated with an Cochran Armitage trend test.
c) Any of the results are outside the 95% control limits of the historical control data range.
A test substance was considered negative (not clastogenic) in the chromosome aberration test if:
a) None of the test concentrations exhibits a statistically significant (Fisher’s exact test, one-sided, p < 0.05) increase compared with the concurrent negative control.
b) There is no concentration-related increase when evaluated with an Cochran Armitage trend test.
c) All results are inside the 95% control limits of the negative historical control data range.
ACCEPTABILITY CRITERIA:
a) The concurrent negative control data are considered acceptable when they are within the 95% control limits of the distribution of the historical negative control database.
b) The concurrent positive controls should induce responses that are compatible with those generated in the historical positive control database.
c) The positive control item induces a statistically significant increase in the number of cells with chromosome aberrations. The positive control data will be analysed by the Fisher’s exact test (one-sided, p < 0.05). - Statistics:
- Fisher's exact test, one-sided, was used to compare the incidence of abberant cells cells with the concurrent negative control. In case the Fisher’s exact test showed statistically significant differences between one or more of the test item groups and the vehicle control group, a Cochran Armitage trend test (p < 0.05) was performed to test whether there was a significant trend in the induction.
Graphpad Prism version 4.03 (Graphpad Software, San Diego, USA) was used for statistical analysis of the data.
Results and discussion
Test results
- Key result
- Species / strain:
- lymphocytes: cultured peripheral human lymphocytes
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Effects of pH: No
- Effects of osmolality: No
DOSE LEVELS SELECTED FOR SCORING:
- First cytogenetic assay: 9.8, 19.5 and 39 μg/mL
- Second cytogenetic assay: all dose levels tested were selected for scoring
RANGE-FINDING/SCREENING STUDIES:
- The test item precipitated in culture medium at a concentration of 39 μg/mL
- The test item did not induce a statistically significant or biologically relevant increase in the number of cells with chromosome aberrations
FIRST CYTOGENETIC ASSAY
- Precipitation in the main tests: In the first cytogenetic test, the test item precipitated in the culture medium from 250 µg/mL and upwards. In the second cytogenetic test, in the 24 h exposure time, the test item precipitated in the culture medium at 250 µg/mL. No precipitation was observed in the additional second test.
- The test item did not increase the number of polyploid cells and cells with endoreduplicated chromosomes.
SECOND CYTOGENETIC ASSAY
- The test item did not induce a statistically significant or biologically relevant increase in the number of cells with chromosome aberrations at the 48 h continuous exposure time
- At the 24 h exposure time, the test item induced a statistically significant increase in the number of cells with chromosome aberrations at the highest tested concentration of 80 μg/ml only. Although a significant trend was observed, the increase was within the 95% control limits of the negative control historical data range. Therefore this increase is not considered biologically relevant.
- The test item did not increase the number of polyploid cells and cells with endoreduplicated chromosomes
COMPARISON WITH HISTORICAL CONTROL DATA:
- The number of cells with chromosome aberrations and the number of polyploid cells and cells with endoreduplicated chromosomes found in the solvent control cultures was within the laboratory historical control data range. Positive control chemicals, mitomycin C and cyclophosphamide induced appropriate responses. In addition, the number of cells with chromosome aberrations found in the positive control cultures was within the 95% control limits of the distribution of the historical positive control database (see attached illustration for details).
Applicant's summary and conclusion
- Conclusions:
- A chromosome aberration study with X-19657 was performed according to OECD 473 guideline and GLP principles, in cultured peripheral human lymphocytes in two independent experiments. It is concluded that X-19657 is not clastogenic in human lymphocytes under the experimental conditions described in this report.
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