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EC number: 414-310-2 | CAS number: 191358-81-3
- 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 cell study: DNA damage and/or repair
- Remarks:
- Type of genotoxicity: DNA damage and/or repair
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2003-01-07 to 2003-03-17
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline Study (OECD 486), GLP compliant
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 003
- Report date:
- 2003
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 486 (Unscheduled DNA Synthesis (UDS) Test with Mammalian Liver Cells in vivo)
- Version / remarks:
- adopted July 21, 1997
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- unscheduled DNA synthesis
Test material
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source:
Dose Range Finding: Charles River Laboratories, Raleigh, North Carolina, USA (males and females)
Main Study: Harlan, Dublin, Virginia, USA (males)
- Age at study initiation: approximately 8 weeks (dose range finding assay) or 10 weeks (UDS assay)
- Assigned to test groups randomly: yes
- Housing: up to 2 per cage (acclimation), singly after randomization in suspended stainless-steel cages
- Diet: PMI certified Rodent Diet® 5002, ad libitum
- Water: tap water ad libitum
- Acclimation period: at least 5 days prior to the initiation of dosing
ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 4°C, recorded at least once daily
- Humidity: 55 ± 15%, recorded at least once daily
- Photoperiod: 12-hour Iight - 12-hour
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- - Vehicle used: PEG 400
- Amount of vehicle: 10 mL/kg bw - Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Dosing suspensions were prepared for each treatment group by adding a weighed amount of test item to a measured volume PEG 400 and mixing well to obtain homogeneous suspensions. Suspensions were obtained over the entire target concentration range used of 25 to 200 mg/mL. The dosing suspensions were prepared no more than 3 hours prior to dosing and were held at room temperature. - Duration of treatment / exposure:
- not applicable (single oral gavage administration)
- Frequency of treatment:
- single administration
- Post exposure period:
- Two timepoints for UDS were employed, one at 2 to 4 hours after administration and another at 14 to 16 hours after administration.
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 500, 1000, 2000 mg/kg bw
Basis:
nominal conc.
- No. of animals per sex per dose:
- 4 males per dose
- Control animals:
- yes, concurrent vehicle
- Positive control(s):
- N-dimethylnitrosamine (DMN)
- Justification for choice of positive control(s): The positive control article, N-dimethylnitrosamine, is known to induce UDS in rat hepatocytes in vivo.
- Route of administration: gavage
- Doses / concentrations: administered at approximately 10 mg/kg and 15 mg/kg for the 2- to 4-hour and 14- to 16-hour timepoints, respectively (no control articles were used in the dose range finding assay).
Examinations
- Tissues and cell types examined:
- cultured rat liver hepatocytes
- Details of tissue and slide preparation:
- CRITERIA FOR DOSE SELECTION:
The highest dose selected for the UDS assay was 2000 mg/kg, based on the results of the dose range finding assay. Two additional dose levels were selected, using dilution steps of 50% and 25%.
TREATMENT AND SAMPLING TIMES:
Two timepoints for UDS were employed, one at 2 to 4 hours after administration of a single dose of the test article and another at 14 to 16 hours after administration. For the 2- to 4-hour timepoint, the animals ranged in weight from 201-219 grams. For the 14- to 16-hour timepoint, the weight range of the animals used was 203-226 grams.
DETAILS OF SLIDE PREPARATION:
All animals from each group were perfused for the collection of hepatocytes and establishment of cultures. However, cultures from only three animals per group were evaluated for UDS. After attachment of the cells, the cultures were labeled with 10 µCi/mL 3H-TdR for 4 hours. The cultures were prepared for analysis of nuclear labeling by autoradiography after washing out the unincorporated label.
METHOD OF ANALYSIS:
Three animals from the vehicle, positive control and test article dose groups were analyzed for nuclear labeling.
The cells were examined microscopically. Only normally-appearing nuclei were scored, and any occasional nuclei blackened by grains too numerous to count were excluded as cells in which replicative DNA synthesis occurred rather than repair synthesis. UDS was measured by counting nuclear grains and subtracting the average number of grains in three nuclear-sized areas adjacent to each nucleus (cytoplasmic count). This value is referred to as the net nuclear grain count.
The net nuclear grain count was routinely determined for 50 randomly selected cells on triplicate coverslips (150 total nuclei) for each animal. The average mean net nuclear grain count (± standard deviation) was determined from the triplicate coverslips (150 total nuclei) for each animal and averaged for each treatment condition. - Evaluation criteria:
- The test article is considered active in the UDS assay at applied concentrations that cause:
- An increase in the group average of the mean net nuclear grain count to at least three grains per nucleus above the concurrent vehicle control group average leading to a positive number, or;
- An increase in the group average of the percent of nuclei with five or more net grains such that the percentage of these nuclei in test cultures is 10% above the percentage observed in the group average of the concurrent vehicle controls.
Results and discussion
Test results
- Sex:
- male/female
- Genotoxicity:
- negative
- Toxicity:
- yes
- Vehicle controls validity:
- valid
- Negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Additional information on results:
- RESULTS OF RANGE-FINDING STUDY
- Dose range: 250-2000 mg/kg bw
- Clinical signs of toxicity in test animals:
All animals were normal (no signs of toxicity) within 1 hour of dosing. During the next two days of observations, toxic signs included soft feces, discolored (purple) urine, discolored (purple) feces, brown or purple stains of the anal/genital area, and purple stains on the tails and paws. No lethality occurred. Both sexes behaved very similarly, which justified the use of males only for the UDS assay.
RESULTS OF DEFINITIVE STUDY
- Clinical sings: Toxic signs were the same as those obtained in the dose range finding study. No deaths occurred.
- Mutagenicity results:
None of test article treatment groups yielded a positive mean net nuclear grain count (-1.22 and -0.28 for the early (2 to 4 hours after treatment) and late timpoint (14 to 16 hours after treatment), respectively, and the highest percent cells with >= 5 grains was only 4.00 % and 4.22 % for the early and late timpoint, respectively, well below the criterion for a positive response.
- Controls:
The vehicle and positive control results were well within the historical data ranges. The DMN positive control treatments induced large increases in nuclear labeling that clearly exceeded both criteria used to indicate UDS.
Since the positive control animals were responsive, the test results were considered to provide conclusive evidence for the lack of UDS induction by the test article.
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): negative
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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