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EC number: 701-230-0 | 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 / erythrocyte micronucleus
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- April 2012 - April 2013
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Version / remarks:
- adopted 1997
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.12 (Mutagenicity - In Vivo Mammalian Erythrocyte Micronucleus Test)
- Version / remarks:
- adopted 2008
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.5395 (In Vivo Mammalian Cytogenetics Tests: Erythrocyte Micronucleus Assay)
- Version / remarks:
- adopted 1998
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- micronucleus assay
Test material
- Reference substance name:
- Reaction products of butane-1,4-diol and 1-chloro-2,3-epoxypropane, esters with acrylic acid
- EC Number:
- 701-230-0
- Cas Number:
- 52408-42-1
- Molecular formula:
- C16H26O8
- IUPAC Name:
- Reaction products of butane-1,4-diol and 1-chloro-2,3-epoxypropane, esters with acrylic acid
- Test material form:
- liquid
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- NMRI
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories Germany GmbH
- Age at study initiation: 5-8 weekds
- Weight at study initiation: on average 27.9g
- Assigned to test groups randomly: yes
- Housing: single in Makrolon type M II cages
- Diet (e.g. ad libitum): standardized pelleted feed ad lib.
- Water (e.g. ad libitum): ad lib.
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12h/12h
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- - Vehicle(s)/solvent(s) used: DMSO (4mL/kg b.w.) + corn oil
- Justification for choice of solvent/vehicle: solubility of the test substance, historic control data is available
- Concentration of test material in vehicle: 25 - 100mg/mL - Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The substance to be administered per kg body weight was dissolved by thourough shaking in DMSO (4 mL/kg) and than emulsified in corn oil (up to 10 mL/kg). All test substance formulations were prepared immediately before administration. - Duration of treatment / exposure:
- one admistration
- Frequency of treatment:
- one admistration
- Post exposure period:
- 24h , 48h (only high dose)
Doses / concentrationsopen allclose all
- Dose / conc.:
- 250 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 500 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
- Positive control(s):
- cyclophosphamide (CPP), Vincristine sulfate (VCR)
- Justification for choice of positive control(s): both substances are well-established reference clastogens and aneugens, respectively
- Route of administration: via gavage in deionized water
- Doses / concentrations: 20mg/kg (CPP), 0.15mg/kg (VCR)
Examinations
- Tissues and cell types examined:
- bone marrow
- Details of tissue and slide preparation:
- CRITERIA FOR DOSE SELECTION:
In a pretest to determine the acute oral toxicity in males and females, lethality was observed at the recommended highest dose of 2 000 mg/kg body weight. In addition, clear signs of toxicity were observed: piloerection, hunched posture and reduced general condition. However, there were no distinct differences in clinical observations between male and female animals. Thus, only male animals were used in the main experiment. Based on the data of the pretest a dose of 1 000 mg/kg body weight was defined as MTD (maximum tolerated dose) and was selected as the highest dose in the present cytogenetic study. 500 mg/kg and 250 mg/kg body weight were administered as further doses.
DETAILS OF SLIDE PREPARATION:
One drop of isolated bone marrow cells in FCS was dropped onto a clean microscopic slide, using a Pasteur pipette. Smears were prepared using slides with ground edges. The preparations were dried in the air and subsequently stained with eosin and methylene blue (modified May-Grünwald solution) for about 5 minutes. After briefly rinsing in deionized water, the preparations were soaked in deionized water for about 2 - 3 minutes. Subsequently, the slides were stained with Giemsa solution for about 15 minutes. After rinsing twice in deionized water and clarifying in xylene, the preparations were mounted in Corbit-Balsam.
METHOD OF ANALYSIS:
In general, 2 000 polychromatic erythrocytes (PCE) were evaluated for the occurrence of micronuclei from each animal of every test group, so in total 10 000 PCEs were scored per test group. The normochromatic erythrocytes (= normocytes / NCE) were also scored. The following parameters were recorded:
• Fraction of polychromatic erythrocytes containing micronuclei (index of clastogenic or aneugenic activity)
• Fraction of normochromatic erythrocytes containing micronuclei (24h value: control value for situation before test substance administration)
• Ratio of polychromatic to normochromatic erythrocytes (indicator that the test substance reached the bone marrow)
• Number of small micronuclei (d < D/4) and of large micronuclei (d = D/4) [d = diameter of micronucleus, D = cell diameter] (differentiation between a clastogenic and spindle poison effect, respectively) - Evaluation criteria:
- Acceptance criteria
• The quality of the slides must allow the evaluation of a sufficient number of analyzable cells; i. e. = 2 000 PCEs per animal and a clear differentiation between PCEs and NCEs.
• The ratio of PCEs/NCEs in the concurrent vehicle control animals has to be within the normal range for the animal strain selected.
• The number of cells containing micronuclei in vehicle control animals has to be within the range of the historical vehicle control data both for PCEs and for NCEs.
• The two positive control substances have to induce a distinct increase in the number of PCEs containing small and/or large micronuclei within the range of the historical positive control data or above.
A finding is considered positive, if the number of PCEs containing micronuclei is statistically significant and dose-related increased, and the number of PCEs containing micronuclei exceeds both the concurrent vehicle control value and the range of the historical vehicle control data.
A test substance is considered negative, if the number of cells containing micronuclei in the dose groups is not statistically significant increased above the concurrent vehicle control value and is within the range of the historical vehicle control data.
Results and discussion
Test results
- Sex:
- male
- Genotoxicity:
- negative
- Toxicity:
- yes
- Remarks:
- PCE to NCE ratio suggests a slight inhibition of erythropoiesis at 1000mg/kg after 48h
- Vehicle controls validity:
- valid
- Negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Additional information on results:
- Negative and positive controls :
Vehicle control male mice showed frequencies of micronucleated polychromatic erythrocytes within the historical vehicle control data range. The single oral administration of the vehicle DMSO/corn oil in a volume of 10 mL/kg body weight led to 0.9‰ polychromatic erythrocytes containing micronuclei after the 24-hour sacrifice interval or to 0.8‰ after the 48-hour sacrifice interval, respectively.
Both positive control substances, cyclophosphamide for clastogenicity and vincristine sulfate for spindle poison effects, led to the expected increase in the rate of polychromatic erythrocytes containing small or large micronuclei.
The positive control substance for clastogenicity, cyclophosphamide, led to a statistically significant increase (16.4‰) in the number of polychromatic erythrocytes containing exclusively small micronuclei, as expected.
Vincristine sulfate, a spindle poison, produced a statistically significant increase (24.8‰) in the number of polychromatic erythrocytes containing micronuclei. A significant portion increase, 8.5‰ was attributable to large micronuclei.
Results with the test susbtance:
After the single administration of the highest dose of 1 000 mg/kg body weight, 0.9‰ polychromatic erythrocytes containing micronuclei were found after 24 hours and 0.8‰ after 48 hours.
In the two lower dose groups, rates of micronuclei of 1.1‰ (500 mg/kg group) and 0.7‰ (250 mg/kg group) were detected at a sacrifice interval of 24 hours in each case.
The number of normochromatic erythrocytes containing micronuclei did not differ to any appreciable extent in the vehicle control group or in the various dose groups at any of the sacrifice intervals.
A slight inhibition of erythropoiesis induced by the treatment of mice with test substance was detected at 1 000 mg/kg body weight at 48 hours sacrifice interval. The ratio of polychromatic to normochromatic erythrocytes was influenced compared to the respective vehicle control group which is an indication of target organ toxicity.
Clinical signs :
The administration of the test substance did not lead to clinical signs of toxicity in the main experiment. However, lethality and clear clinical observations were found in the pretest at a two-fold higher dose of 2 000 mg/kg body weight.
Applicant's summary and conclusion
- Conclusions:
- Under the condition of this study, the test substance does not induce cytogenetic damage in bone marrow cells of NMRI mice in vivo.
- Executive summary:
The test substance was assessed for its potential to induce chromosomal damage (clastogenicity) or spindle poison effects (aneugenic activity) in NMRI mice using the micronucleus test method. For this purpose, the test substance, dissolved in DMSO and emulsified in corn oil, was administered once orally to 5 male animals per group at dose levels of 250 mg/kg, 500 mg/kg and 1 000 mg/kg body weight. The animals were sacrificed and the bone marrow of the two femora was prepared 24 hours (all dosages and control), and 48 hours (high dose and vehicle control) after administration. The preparations were stained, and 2 000 polychromatic erythrocytes were evaluated per animal. The normocytes with and without micronuclei occurring per 2 000 polychromatic erythrocytes were also recorded.
Vehicle control male mice showed frequencies of micronucleated polychromatic erythrocytes within the historical vehicle control data range. Both positive control substances, cyclophosphamide for clastogenicity and vincristine sulfate for spindle poison effects, led to the expected increase in the rate of polychromatic erythrocytes containing small or large micronuclei.
According to the results of the present study, there are thus no statistical significances or biologically relevant differences in the frequency of erythrocytes containing micronuclei either between the vehicle control groups and the three dose groups (250 mg/kg, 500 mg/kg and 1 000 mg/kg) or between the two sacrifice intervals (24 and 48 hours). The number of normochromatic or polychromatic erythrocytes containing small micronuclei (d < D/4) did not deviate from the vehicle control values at any of the sacrifice intervals and was within the historical vehicle control data range. Nor were large micronuclei (d = D/4) observed either in the vehicle control group or in the three dose groups treated with test substance.
Based on the pretest, 1 000 mg/kg body weight was defined as maximum tolerated dose (MTD) due to lethality observed at 2 000 mg/kg body weight. Although no signs of toxicity were found after treatment with 1 000 mg/kg body weight in the main experiment, bioavailability of the test substance in the target organ was shown by reduction of polychromatic erythrocytes at 48-hour sacrifice interval.
In this study, after single oral administration of the vehicle DMSO/corn oil the ratio of PCEs/NCEs in the vehicle control animals at both sacrifice intervals was within the normal range for the animal strain selected.
Thus, under the experimental conditions chosen here, the test substance has no chromosome-damaging (clastogenic) effect nor does it lead to any impairment of chromosome distribution in the course of mitosis (aneugenic activity) in bone marrow cells of NMRI mice in vivo.
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