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EC number: 424-110-7 | CAS number: 194602-23-8 UK-143,108
- 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
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
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:
- Between 23 October and 19 December 1996
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Done under GLP and OECD Methods
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 997
- Report date:
- 1997
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- other: Commission Directive 2000/32/EEC, Method B10.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 473 (In Vitro Mammalian Chromosome Aberration Test)
- Principles of method if other than guideline:
- In this study, blood taken from healthy male donors was pooled and diluted with tissue culture medium. The cultures were incubated in the presence of PHA before being treated with the test substance. Following treatment the cells were arrested at metaphase using the mitotic inhibitor, Colcemid•. Chromosomes in these metaphase cells were then examined for the presence of chromosome aberrations. The best estimate of the aberration frequency is at the first cell division after initiation of treatment since certain types of damage may be lost during subsequent cell divisions. In this laboratory the cell cycle time for human lymphocytes in whole blood culture is approximately 15 hours. On this basis the cells are examined after 21 hours. However, some test substances may delay the cell cycle and, for this reason, cells are also examined 45 hours after initiation of treatment, in the event of a negative or equivocal response at 21 hours. Additionally, the 21 hour part of the test is repeated.
Aberrations were scored according to the classification of the ISCN (1985). Traditionally gaps have been excluded from the quantitation of chromosome aberrations - GLP compliance:
- yes
- Type of assay:
- in vitro mammalian chromosome aberration test
Test material
- Test material form:
- solid: particulate/powder
- Remarks:
- migrated information: powder
- Details on test material:
- Intended use: Pharmaceutical intermediate
Appearance: White powder
Storage conditions: Room temperature
Expiry: Not supplied
Purity: 101.3%
Date received: 2 October 1996
Supplier: Pfizer Ltd
Constituent 1
Method
- Target gene:
- No data
Species / strain
- Species / strain / cell type:
- mammalian cell line, other: Human lymphocytes
- Details on mammalian cell type (if applicable):
- Human blood was collected aseptically from healthy male donors, pooled and diluted with RPMI 1640 tissue culture medium (Imperial Laboratories) containing 16.7% foetal calf serum (PAA). Aliquots (0.4m1 blood : 4.5m1 media : O. lml phytohaemagglutin (Wellcome)) of the cell suspension were placed in sterile universal containers and incubated at 37°C in a slanted position, for approximately 48 hours. The cultures were gently shaken once daily to resuspend the cells.
- Metabolic activation:
- with and without
- Metabolic activation system:
- Phenobarbital/Beta-Naphthoflavone induced rat-liver S9.
- Test concentrations with justification for top dose:
- Without S-9 mix, 21 hour harvest: 1250, 2500, 3750 and 5000 µg/ml.
With S-9 mix, 21 hour harvest: 1250, 2500, 3750 and 5000 µg/ml.
cultured medium
for each culture heparinsed whole blood was added to culture medium containing a mutagen (photohaemogglutinin) and incubated at 37C in a humidified atmosphere at 5% CO2/95% air for 48 hours
dose levels for positive controls
without S9 mix- mitomycin C 0.125 ug/ml ( 3 hour of treatment or 2 ug/ml ( continuous treatment)
with S9, cyclophosphamide: 12.5 ug/ml - Vehicle / solvent:
- Prior to commencing testing, the solubility of the test substance was assessed in solvents compatible with the test system. As UK-143,108 was found to be insoluble in all aqueous and organic solvents tested, it was formulated directly in tissue culture medium at a highest final concentration of 5000 µglml, from which halving dilutions were made. No precipitate was observed when UK-143,108 was dissolved directly in the culture medium at 5000 µg/ml.
Controlsopen allclose all
- Positive controls:
- yes
- Positive control substance:
- mitomycin C
- Remarks:
- without S9
- Positive controls:
- yes
- Positive control substance:
- cyclophosphamide
- Remarks:
- with S9
- Details on test system and experimental conditions:
- TREATMENT OF CELLS WITH TEST SUBSTANCE - FIRST TEST
After 48 hours, the cultures were centrifuged and the supernatant replaced by 5 ml culture medium which contained the appropriate treatment. To one set of cultures 1.25 ml S-9 mix was added to each culture. For cultures to be treated in the absence of S-9 mix, 1.25 ml of untreated culture medium was added. This diluted the various concentrations of UK-143,108 to give final concentrations of 39.1, 78.1, 156.3, 312.5, 625, 1250, 2500 and 5000 µg/ml. Three hours after dosing, the cultures containing the S-9 mix were centrifuged and the cell pellets resuspended in fresh medium. They were then incubated for a further 18 hours. The cultures treated in the absence of S-9 mix were incubated for 21 hours.
SECOND TEST
From the results obtained in the first test it was not deemed necessary to include a 45 hour harvest in the second test.
Cultures were initiated and maintained as previously described. Concentrations of UK-143,108 were as follows:
Without S-9 mix, 21 hour harvest: 1250, 2500, 3750 and 5000 µg/ml.
With S-9 mix, 21 hour harvest: 1250, 2500, 3750 and 5000 µg/ml.
Duplicate cultures were used for each treatment and four cultures in each set were untreated. Positive control cultures were treated as in the first test.
Three hours after dosing, the cultures containing S-9 mix were centrifuged and the cell pellets resuspended in fresh medium. They were then incubated for a further 18 hours. Cultures treated in the absence of S-9 mix were incubated for 21 hours.
All cultures were treated with Colcemid at a final concentration of 0.1 µg/ml two hours before the end of the incubation period. They were then harvested, fixed and the slides prepared as previously described. The slides were then examined microscopically. - Evaluation criteria:
- Chromosomes in these metaphase cells were then examined for the presence of chromosome aberrations. The best estimate of the aberration frequency is at the first cell division after initiation of treatment since certain types of damage may be lost during subsequent cell divisions
Cytotoxicity evaluated based on mitotic index which is number cells with mitosis indicating mitotic inhibition. 1000 cells with mitosis were evaluated with no blind scoring.
analysis of 200 metaphases/dose-level with 44 to 46 chromosome were made with 100 metaphases/culture whenever possible. Only 50 metaphases/culture were analyst when at least 10% with structural chromosome aberrations were observed. Blind scoring was done. - Statistics:
- No data
Results and discussion
Test results
- Species / strain:
- lymphocytes: Mitotic indices of cultured human lymphocytes
- Metabolic activation:
- with and without
- Genotoxicity:
- not determined
- Cytotoxicity / choice of top concentrations:
- not determined
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- In the absence of S-9 mix, UK-143, 108 caused no statistically significant increase in the proportion of aberrant cells compared to the untreated cultures at the lowest two concentration analysed, 2500 and 3750 µg/ml. There was a statistically significant increase (P<0.001) in the proportion of aberrant cells at the highest concentration analysed. This increase, to 8.5%, lies outside the historical control range and is therefore considered to be indicative of a clastogenic response.
In the presence of S-9 mix, UK-143, 108 did not cause any statistically significant increases in the proportion of metaphase figures containing chromosomal aberrations when compared to the untreated control at any dose level analysed.
Both positive control compounds, mitomycin C and cyclophosphamide, caused large, statistically significant increases (P <0.001) in the proportion of aberrant cells - Remarks on result:
- other: other: METAPHASE CHROMOSOME ANALYSIS OF HUMAN LYMPHOCYTES CULTURED IN VITRO
- Remarks:
- Migrated from field 'Test system'.
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information):
positive without metabolic activation
negative without metabolic activation
UK-143, 108 has shown evidence of clastogenic activity in the absence of S-9 mix, in this in vitro
cytogenetic test system, but not in its presence.
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.
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