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EC number: 946-565-5 | 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 vivo
Administrative data
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / bone marrow chromosome aberration
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 11 Sep 2017 - 19 Nov 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- In vivo testing was triggered by the positive outcome of an in vitro study. The in vivo study was initiated after final approval by ECHA.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 018
- Report date:
- 2018
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 475 (Mammalian Bone Marrow Chromosome Aberration Test)
- Version / remarks:
- 29 July 2016
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.11 (Mutagenicity - In Vivo Mammalian Bone-Marrow Chromosome Aberration Test)
- Version / remarks:
- 31 May 2008
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- mammalian bone marrow chromosome aberration test
Test material
- Reference substance name:
- Reaction products of 1H-Imidazole-1-ethanol, 4,5-dihydro-, 2-(C7-C17 odd-numbered, C17-unsatd. alkyl) derivs. and sodium hydroxide and chloroacetic acid
- EC Number:
- 931-291-0
- Molecular formula:
- Not applicable (a generic molecular formula cannot be provided for this specific UVCB substance)
- IUPAC Name:
- Reaction products of 1H-Imidazole-1-ethanol, 4,5-dihydro-, 2-(C7-C17 odd-numbered, C17-unsatd. alkyl) derivs. and sodium hydroxide and chloroacetic acid
- Test material form:
- liquid
- Details on test material:
- - Physical appearance: colourless to light yellow liquid
- Storage conditions: At 20 ± 5 °C, in the dark
Constituent 1
- Specific details on test material used for the study:
- Specific gravity / density: 1.1
A correction was made for the purity/composition of the test item. The correction factor was 2.554 based on the dry-content.
Solubility in vehicle Water: Soluble
Stability in vehicle: Stability for at least 6 hours at room temperature under normal laboratory light conditions is confirmed over the concentration range 1.0 to 200 mg/mL (Charles River Project 518378). Stability for at least 7 days in the refrigerator is confirmed over the concentration range 1.0 to 200 mg/mL (Charles River Project 518378).
Test animals
- Species:
- mouse
- Strain:
- NMRI
- Details on species / strain selection:
- NMRI mice (SPF) were used as test system. These mice are recommended by international guidelines (e.g. OECD, EC).
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: 6 weeks
- Weight at study initiation: 29 - 39 g
- Assigned to test groups randomly: yes
- Fasting period before study: yes, 3 - 4 hours prior to dosing until maximum 1 hour after administration
- Housing: animals were group housed (maximum 5 animals per sex per cage) in labelled polycarbonate cages containing sterilized sawdust as bedding material. Paper bedding was provided as cage enrichment.
- Diet: free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany), except prior to dosing
- Water: free access to tap-water
Diet, water, bedding and cage enrichment evaluation for contaminants and/or nutrients was performed according to facility standard procedures. There were no findings that could interfere with the study.
- Acclimation period: At least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 44-60
- Air changes (per hr): 10 or more
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 11 Sep 2017 To: 13 Oct 2017
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- Solvent used: water for injection
A solubility test was performed based on visual assessment. Miranol Ultra C32 was dissolved in water for injection. The dosing volume was 10 mL/kg body weight. - Details on exposure:
- Miranol Ultra C32 concentrations were dosed within 3 hours after preparation.
- Duration of treatment / exposure:
- 12 - 18 hours (three doses) and 36 - 44 hours (high dose only)
- Frequency of treatment:
- Single exposure
- Post exposure period:
- 12 - 18 hours (three doses) and 36 - 44 hours (high dose only)
Doses / concentrationsopen allclose all
- Dose / conc.:
- 500 mg/kg bw/day (actual dose received)
- Remarks:
- (based on dry weight)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- Remarks:
- (based on dry weight)
- Dose / conc.:
- 2 000 mg/kg bw/day (actual dose received)
- Remarks:
- (based on dry weight)
- No. of animals per sex per dose:
- 6 males (dose range finding study); 5 males (main study)
- Control animals:
- yes, concurrent vehicle
- Positive control(s):
- Cyclophosphamide, 40 mg/kg bw
Examinations
- Tissues and cell types examined:
- Bone marrow
- Details of tissue and slide preparation:
- Three to five hours prior to sacrifice, animals are treated with the metaphase-arresting chemical colchicine. 12 - 18 hours (1.5 x normal cell cycle length) and 36 - 44 hours (24 hours after the first sample time) after dosing the animals are sacrificed and bone marrow cells are collected. The cells are treated with a hypotonic solution and fixed. Finally, the cell material is spread on slides and stained. Metaphase cells are examined microscopically for the presence of structural chromosome aberrations such as breaks, gaps, minutes, dicentrics and exchange figures.
The mitotic index of bone marrow metaphase slides was determined by counting the number of metaphases from at least 1000 (with a maximum deviation of 5%) cells per animal. To prevent bias, all slides were randomly coded before examination of chromosome aberrations. One hundred twenty-five to two hundred metaphase chromosome spreads per animal were examined by light microscopy for chromosome aberrations. In case the number of aberrant cells, gaps excluded, was ≥ 50 in 100 metaphases no more metaphases were examined. Only metaphases containing 40 ± 2 centromeres (chromosomes) were analyzed. Type and number of aberrations were given separately for each animal, the total number of aberrations and the number of cells with aberrations per group was calculated. - Evaluation criteria:
- A bone marrow metaphase test is considered acceptable if it meets the following criteria:
a) The concurrent negative control data are considered acceptable when they are within 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 and produce a statistically significant increase compared to the negative control. If (one of) the acceptability criteria are not met and the Study Director decides that this has a critical effect on the study, the test will be rejected and repeated. - Statistics:
- Graphpad Prism version 4.03 (Graphpad Software, San Diego, USA) was used for statistical analysis of the data.
A test item is considered positive in the bone marrow metaphase test if all of the following criteria are met:
a) At least one of the treatment groups exhibits a statistically significant (one-sided, p < 0.05) increase in the frequency of cells with structural chromosome aberrations (excluding gaps) compared with the concurrent negative control
b) The increase is dose related when evaluated with a trend test.
c) Any of the results are outside the historical control data range.
A test item is considered negative in the bone marrow metaphase test if:
a) None of the treatment groups exhibits a statistically significant (one-sided, p < 0.05)
increase in the frequency of cells with structural chromosome aberrations (excluding
gaps) compared with the concurrent negative control.
b) There is no dose related increase when evaluated with a trend test.
c) All results are within the negative historical control data range.
Results and discussion
Test results
- Key result
- Sex:
- male
- Genotoxicity:
- negative
- Toxicity:
- no effects
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- RESULTS OF RANGE-FINDING STUDY
- In the dose range finding test, three males and three females were dosed with 2000 mg Miranol Ultra C32/kg body weight. The animals showed no clinical signs after dosing. Since there were no differences between sexes in toxicity only male animals were used in the main study, five male animals were used in each treatment group.
RESULTS OF DEFINITIVE STUDY
- The animals of the groups treated with 2000, 1000 and 500 mg Miranol Ultra C32/kg body weight and the animals of the negative and positive control groups showed no treatment related clinical signs or mortality.
- No biologically relevant decrease in the mitotic index was observed in animals treated with Miranol Ultra C32. The inhibition of the mitotic index of the positive control was 10%.
- The scores for the number of aberrant cells (gaps included and excluded) and the number of the various types of chromosome aberrations at the various concentrations of Miranol Ultra C32 are attached.
- The number of cells with chromosome aberrations found in the animals dosed with the vehicle control was within the laboratory historical control data range. The positive control chemical produced a statistically significant increase in the frequency of aberrant cells. It was therefore concluded that the test conditions were appropriate for the detection of a clastogenic response. Miranol Ultra C32 did not induce a statistically significant or biologically relevant increase in the number of cells with chromosome aberrations, at both sampling times. No effects of Miranol Ultra C32 on the number of polyploid cells and cells with endoreduplicated chromosomes were observed.
Applicant's summary and conclusion
- Conclusions:
- Based on the results of a mouse bone marrow cytogenetic assay was performed according to OECD/EC guidelines and GLP principles, it is concluded that Miranol Ultra C32 does not disturb mitotic processes and cell cycle progression and does not induce numerical chromosome aberrations in vivo.
- Executive summary:
A mouse bone marrow cytogenetic assay was performed with Miranol Ultra C32 according to OECD/EC guidelines and GLP principles. Male mice (5/group) were exposed to 500, 1000 or 2000 mg/kg bw/day and bone marrow was sampled 12-18 (all doses, vehicle control group and positive control group (treated with cyclophosphamide) or 36-44 (highest dose only) hours after dosing. No mortality occurred, no clinical signs were noted in any of the mice. The number of cells with chromosome aberrations found in the vehicle control animals was within the laboratory historical control data range. The positive control animals treated with cyclophosphamide induced a statistically significant increase in the number of cells with chromosome aberrations, indicating that the test conditions were adequate. Miranol Ultra C32 did not induce a statistically significant or biologically relevant increase in the number of cells with chromosome aberrations, at both sampling times.
Based on these results it is concluded that Miranol Ultra C32 does not disturb mitotic processes and cell cycle progression and does not induce numerical chromosome aberrations in vivo.
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