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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.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: 930-010-9 | CAS number: 461432-25-7
- 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
- Remarks:
- Type of genotoxicity: chromosome aberration
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 12 April 2016 - 23 October 2016
- 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 guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 473 (In Vitro Mammalian Chromosome Aberration Test)
- Version / remarks:
- 26-Sept-2014
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: International Conference on Harmonisation (ICH) guideline S2(R1)
- Version / remarks:
- 09-Nov-2011
- Deviations:
- no
- GLP compliance:
- yes
- Remarks:
- This study is conducted in compliance with U.S. Food and Drug Administration (FDA) Good Laboratory Practice (GLP) regulations; CFR Title 21, Part 58 with the following exception. Concentration analysis of the dose formulations will not be conducted.
- Type of assay:
- other: In vitro mammalian chromosome aberration test
Test material
- Reference substance name:
- [(2R,3R,4R,5S,6S)-3,4,5-tris(acetyloxy)-6-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}oxan-2-yl]methyl acetate
- EC Number:
- 930-010-9
- Cas Number:
- 461432-25-7
- Molecular formula:
- C29H33ClO10
- IUPAC Name:
- [(2R,3R,4R,5S,6S)-3,4,5-tris(acetyloxy)-6-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}oxan-2-yl]methyl acetate
- Test material form:
- solid: particulate/powder
- Details on test material:
- Appearance: White crystalline solid
Storage conditions: At room temperature protected from light
Constituent 1
Method
Species / strain
- Species / strain / cell type:
- Chinese hamster Ovary (CHO)
- Remarks:
- CHO-WBL
- Details on mammalian cell type (if applicable):
- CELLS USED
- Source of cells: Genetic Toxicology Laboratory at Pfizer,Inc.
- Number of passages if applicable: Cells were used at passage 22 for the range-finding assay, passage 7 for the aberration assay, passage 19 and 22 for the repeat aberration assay, passage 3 for the 2nd repeat aberration assay, passage 19, 22, and 5 for the 3rd repeat aberration assay
- Modal number of chromosomes: 21
- Normal (negative control) cell cycle time: 12 to 14 hours
MEDIA USED
- Type and identity of media including CO2 concentration if applicable: McCoy’s medium supplemented with a final concentration of 10% (v/v) heat-inactivated fetal bovine serum, 2mM L-glutamine, and 100 units/mL penicillin and 100 μg/mL streptomycin. All cultures were incubated in a humidified atmosphere of 4% to 6% CO2.
- Properly maintained: yes
- Periodically checked for Mycoplasma contamination: yes
- Periodically checked for karyotype stability: yes
- Metabolic activation:
- with and without
- Metabolic activation system:
- Rat liver S9-mix induced by Aroclor 1254.
- Test concentrations with justification for top dose:
- Dose range finding test:
With and without S9-mix, 3hr exposure; 20 hr fixation: 0.977, 1.95, 3.91, 7.81, 15.6, 31.3, 62.5, 125, 250, and 500 μg/mL.
Without S9-mix, 20 hour continuous exposure: 0.977, 1.95, 3.91, 7.81, 15.6, 31.3, 62.5, 125, 250, and 500 μg/mL.
The highest concentration chosen for evaluation of chromosome aberrations were from the lowest concentration tested at which precipitates were observed or a concentration at which 50% - 60% cytotoxicity was observed.
Repeat aberration assay:
Without S9-mix, 3 h exposure time, 20 h fixation time: 34.4, 57.4 and 87.5 μg/mL. (87.5 µg/ mL: lowest precipitating dose)
With S9-mix, 3 h exposure, 20 h fixation time: 70.9, 78.7 and 87.5 µg/ mL. (87.5 µg/ mL: lowest precipitating dose)
Without S9-mix, 20 h continuous exposure: 2.41, 9.62 and 34.4 μg/mL. (34.4 µg/ mL: 54% cytotoxicity) - Vehicle / solvent:
- - Vehicle used: DMSO
- Justification for choice of vehicle: A homogeneous suspension could be obtained in DMSO and DMSO is accepted and approved by authorities and international guidelines
Controlsopen allclose all
- Negative solvent / vehicle controls:
- yes
- Positive controls:
- yes
- Positive control substance:
- mitomycin C
- Remarks:
- without S9, in DMSO: 0.75 µg/mL for a 3 h exposure period and 0.10 µg/mL for a 24 h exposure period
- Negative solvent / vehicle controls:
- yes
- Positive controls:
- yes
- Positive control substance:
- cyclophosphamide
- Remarks:
- with S9 in DMSO: 7.5 µg/mL
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in medium
- Cell density at seeding (if applicable):
- Trail 1: 1.0-1.5 × 10^6 CHO cells per 75 cm^2 flask
- Trial 2, 3 and 4: 0.9 – 1.2 × 10^6 CHO cells per 75 cm^2 flask
DURATION
- Exposure duration: for short incubations 3 hours and for long incubations 20 hours for Trial 1 or 24 hours for Trial 2, 3 and 4
- Fixation time (start of exposure up to fixation or harvest of cells): 20 hours for Trail 1 or 24 hours for Trial 2,3 and 4
SPINDLE INHIBITOR (cytogenetic assays): Colcemid (approximately 2 hours prior to harvest)
STAIN (for cytogenetic assays): DiffQuik solution
NUMBER OF REPLICATIONS: duplicates in two independent experiments
METHODS OF SLIDE PREPARATION AND STAINING TECHNIQUE USED: Cells were trypsinized, centrifuged, resuspended in hypotonic solution (0.075 M KCL) and fixed twice using an approximately 3:1 methanol:glacial acetic acid mix. The final concentrated cell suspension was dropped on clean, cold wet glass slides, dried prior to staining with DiffQuik solution at room temperature, and coverslipped.
NUMBER OF METAPHASE SPREADS ANALYSED PER DOSE:
- 300 metaphase cells or ≥ 50 aberrant cells except for the 3-hour treatment with metabolic activation, for which 600 metaphase cells were scored
DETERMINATION OF CYTOTOXICITY
- Method: relative population doubling using cell counts
OTHER EXAMINATIONS:
- Determination of polyploidy: yes (from 400 cells)
- Determination of endoreplication: yes - Rationale for test conditions:
- Concentrations tested were based on the range-finding assay.
- Evaluation criteria:
- Acceptance criteria assay and controls
Each treatment condition (e.g., in the absence or in the presence of metabolic activation, short or long incubations) is considered independent with regard to assay acceptance. The positive control results for each treatment condition must be statistically significant (p ≤ 0.05) when compared with the relevant vehicle controls. The vehicle and positive control results should be comparable to relevant historical control data generated at Charles River Skokie. Additionally, a minimum population doubling of approximately 1.5 should be observed in the vehicle control cultures.
Criteria positive response
A test substance was considered positive (clastogenic) in the chromosome aberration test if a significant increase (p ≤ 0.05) in the mean percent of cells with chromosomal aberrations is observed at 1 or more dose levels. If a significant increase is seen at 1 or more dose levels, a dose-response should be observed. A response would be considered statistically significant for dose-response trend in the Cochran-Armitage test if p ≤ 0.05. At least 1 concentration should be associated with an increase that is outside the historical control range of previous vehicle control treated cultures.
Criteria negative response
A test substance was considered negative (not clastogenic) in the chromosome aberration test if no statistically significant increase (p ≤ 0.05) is observed in the mean percent of cells with chromosomal aberrations at any of the test concentrations and there is no concentration-related increase when evaluated in the Cochran-Armitage test. - Statistics:
- After completion of microscopic analyses, data were decoded and a One-tailed Fisher’s Exact test was performed on the total number of cells with structural aberrations and the total number of cells with more than one chromosome aberration comparing the treated cells to the results obtained from the relevant control group. The detection of dose-response trends was carried out using the Cochran-Armitage test. The same statistical analysis was performed for cells exhibiting polyploidy and/or endoreduplication.
Results and discussion
Test results
- Species / strain:
- Chinese hamster Ovary (CHO)
- Remarks:
- CHO-WBL
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- 3-Hour Treatment without Metabolic Activation 13% (lowest precipitating dose); 24-Hour Treatment without Metabolic Activation 54%; 3-Hour Treatment with Metabolic Activation 18% (lowest precipitating dose).
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Effects of pH: No
- Effects of osmolality: No
- Precipitation: Precipitation in the exposure medium was observed at the end of test article treatment at ≥ 87.5 μg/mL in the 3-hour treatments with and without metabolic activation, and at ≥ 57.4 μg/mL in the 24-hour treatment without metabolic activation.
RANGE-FINDING/SCREENING STUDIES:
- Cytotoxicity was observed at precipitating concentrations; at ≥ 250 μg/mL in the 3-hour treatments with and without metabolic activation and at ≥ 15.6 μg/mL in the 20-hour treatment without metabolic activation. Changes in cell morphology were noted at ≥ 125 μg/mL in the 3-hour treatment with metabolic activation.
COMPARISON WITH HISTORICAL CONTROL DATA:
Data from the vehicle and positive controls were comparable to expected historical control ranges and yielded expected results with the following exceptions. For the vehicle control for the 3-hour treatment without metabolic activation the percent of cells with aberrations was higher than the upper limit of the historical control range (5.3% versus a range of 0%-4%). This results was considere acceptable since there was only a limited historical control database, the response in all test article treated cultures were within the historical control range and the positive control treatment produced a statistically significant response. The positive control for the 24-hour treatment without metabolic activation induced a higher frequency of chromosomal aberrations that was not within the upper limit of the historical control range (71.4% versus a range of 4% to 65.2%). This response is considered acceptable as there was a longer exposure 24-hours in stead of 20-hours) and the scientific purpose of the positive control treatment was valid.
ADDITIONAL INFORMATION ON CYTOTOXICITY:
- Measurement of cytotoxicity used: RPD
- Changes in cell morphology were noted at ≥ 108 μg/mL in the 3-hour treatment with metabolic activation at harvest.
- In the 3-hour treatment with metabolic activation, three additional trials were conducted to determine reproducibility of the minor elevation in chromosomal aberrations at 87.5 μg/mL. Since optimal cytotoxicity was not achieved in these treatments, additional cells from the repeat aberration assay were scored, which provided enough data to make a definitive conclusion of the clastogenic potential of the substance.
Any other information on results incl. tables
Summary of structural aberrations
Exposure |
Concentration (μg/mL) |
Structural Aberrations (%) |
Polyploid cells (%) | Endoreplicated cells (%) |
3 hours -S9 |
0 |
5.3 |
8.5 | 0.0 |
|
34.4 |
3.7 |
8.3 | 0.0 |
|
57.4 |
1.3 |
6.0 | 0.0 |
|
87.5a |
2.3 |
7.0 | 0.0 |
|
MMC 0.75 |
68.5** |
6.0 | 0.0 |
3 hours +S9 |
0 |
3.0 |
6.5 | 0.5 |
|
70.9 |
3.7 |
6.8 | 0.0 |
|
78.7 |
2.7 |
5.8 | 0.5 |
|
87.5a |
4.8 |
9.0 | 0.0 |
|
CP 7.5 |
79.4** |
4.5 | 0.3 |
24 hours -S9 |
0 |
3.0 |
4.8 | 0.0 |
|
2.41 |
3.0 |
4.5 | 0.0 |
|
9.62 |
4.7 |
5.0 | 0.0 |
|
34.4 |
3.3 |
4.8 | 0.0 |
|
MMC 0.10 |
71.4** |
5.3 | 0.0 |
** p ≤ 0.01 using one-tailed Fisher’s Exact Test.
a Precipitates present at end of test article treatment
Applicant's summary and conclusion
- Conclusions:
- A chromosome aberration study with BMS-587172-01 was performed according to OECD 473 guideline and GLP principles, in cultured Chinese Hamster Ovary (CHO-WBL) cells in two independent experiments. It is concluded that BMS-587172-01 is not clastogenic in CHO-WBL cells.
- Executive summary:
In a chromosome aberration study, cultured Chinese Hamster Ovary (CHO-WBL) cells were exposed to different concentrations of BMS-587172-01 (dissolved in DMSO), in the presence and absence of S9-mix according to OECD 473/ICH S2(Rl) guidelines and GLP principles. In the range-finding assay, BMS-587172-01 was tested up to and including 500 μg/mL for a 3 hour exposure time in the presence or absence of metabolic activation with a 20 hour fixation time and for a 20 hour continuous exposure time without metabolic activation. In the repeat aberration assay, BMS-587172-01 was tested up to and including precipitating concentrations for a 3 hour exposure time in the presence or absence of metabolic activation with a 24 hour fixation time and for a 24 hour continuous exposure time without metabolic activation. BMS-587172-01 did not induce a statistically significant or biologically relevant increase in the number of cells with chromosome aberrations in the absence and presence of metabolic activation, in either of the two independently repeated experiments. No effects of BMS-587172-01 on the number of polyploid cells and cells with endoreduplicated chromosomes were observed both in the absence and presence of metabolic activation. Adequate positive and vehicle controls were included. Therefore it can be concluded that BMS-587172-01 does not disturb mitotic processes and cell cycle progression and does not induce numerical chromosome aberrations nor polyploidy when evaluated under conditions and at the maximum concentrations recommended by international guidelines for in vitro cytogenetic studies.
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.