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EC number: 688-147-2 | CAS number: 82428-30-6
- 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 gene mutation study in mammalian cells
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- March 2014
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 014
- Report date:
- 2014
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 476 (In Vitro Mammalian Cell Gene Mutation Test)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.17 (Mutagenicity - In Vitro Mammalian Cell Gene Mutation Test)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.5300 - In vitro Mammalian Cell Gene Mutation Test
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- mammalian cell gene mutation assay
Test material
- Reference substance name:
- {7-oxabicyclo[4.1.0]heptan-3-yl}methyl 2-methylprop-2-enoate
- EC Number:
- 688-147-2
- Cas Number:
- 82428-30-6
- Molecular formula:
- C11 H16 O3
- IUPAC Name:
- {7-oxabicyclo[4.1.0]heptan-3-yl}methyl 2-methylprop-2-enoate
- Test material form:
- liquid
- Details on test material:
- - Name: 3,4-Epoxycyclohexylmethyl methacrylate
- Chemical Name: 2-Propenoic acid, 2-methyl-7-oxabicyclo[4.1.0]hept-3-ylmethyl ester
- CAS No.: 82428-30-6
- Physical State / Colour: liquid / light yellow, transparent
- Density: 1.079 g/mL at 20 °C
- Molecular Weight: 196.2 g/mol
Constituent 1
Method
- Target gene:
- HPRT-Locus
Species / strain
- Species / strain / cell type:
- Chinese hamster lung fibroblasts (V79)
- Metabolic activation:
- with and without
- Metabolic activation system:
- S9 mix
- Test concentrations with justification for top dose:
- EXPERIMENT I:
- without metabolic activation: 0.25, 0.50, 1.00, 1.25, 1.5, 1.6, 1.7 and 1.8 mM
- with metabolic activation: 0.05, 0.1, 0.5, 1.0, 2.0, 3.0, 4.0 and 5.0 mM
EXPERIMENT II:
- without metabolic activation: 0.05, 0.10, 0.25, 0.5, 1.0, 1.2, 1.4 and 1.6 mM
- with metabolic activation: 2.8, 4.0, 4.4, 4.8, 5.2, 5.4, 5.6 and 5.8 mM - Vehicle / solvent:
- No vehicle, test item was dissolved in culture medium.
Controls
- Untreated negative controls:
- yes
- Remarks:
- treatment medium
- Negative solvent / vehicle controls:
- no
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- 7,12-dimethylbenzanthracene
- ethylmethanesulphonate
- Details on test system and experimental conditions:
- V79 cells in vitro have been widely used to examine the ability of chemicals to induce cytogenetic changes and thus identify potential carcinogens or mutagens. These cells are characterized by their high proliferation rate (12 - 14 h doubling time of the BSL BIOSERVICE stock cultures) and their high cloning efficiency of untreated cells, usually more than 50%. These facts are necessary for the appropriate performance of the study.
The V79 cells (ATCC, CCL-93) were stored over liquid nitrogen (vapour phase) in the cell bank of BSL BIOSERVICE. This allows the repeated use of the same cell culture batch in experiments. Each cell batch was routinely checked for mycoplasma infections (PCR). Thawed stock cultures were maintained in plastic culture flasks in minimal essential medium (MEM).
For purifying the cell population of pre-existing HPRT mutants cells were exposed to HAT medium containing 100 μM hypoxanthine, 0.4 μM aminopterin, 16 μM thymidine and 10.0 μM glycine for several cell doublings (2-3 days). - Evaluation criteria:
- ACCEPTABILITY OF THE ASSAY:
A mutation assay is considered acceptable if it meets the following criteria:
- Negative and/or solvent controls fall within the performing laboratories historical control data range;
- The absolute cloning efficiency: ([number of positive cultures x 100] /total number of seeded cultures) of the negative and /or solvent controls is > 50%;
- The positive controls (EMS and DMBA) induce significant increases (at least 3-fold increase of mutant frequencies related to the comparable negative control values and higher than the historical range of negative controls) in the mutant frequencies.
EVALUATION:
A test is considered to be negative if there is no biological relevant increase in the number of mutants.
There are several criteria for determining a positive result:
- a reproducible three times higher mutation frequency than the solvent control for at least one of the concentrations;
- a concentration related increase of the mutation frequency; such an evaluation may be considered also in the case that a three-fold increase of the mutant frequency is not observed;
- if there is by chance a low spontaneous mutation rate in the corresponding negative and solvent controls a concentration related increase of the mutations within their range has to be discussed. - Statistics:
- According to the OECD guidelines, the biological relevance of the results is the criterion for the interpretation of results, a statistical evaluation of the results is not regarded as necessary.
Results and discussion
Test results
- Key result
- Species / strain:
- Chinese hamster lung fibroblasts (V79)
- Metabolic activation:
- with and without
- Genotoxicity:
- positive
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- not applicable
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
Any other information on results incl. tables
PRECIPITATION
No precipitation of the test item was noted in the experiments.
TOXICITY
Biologically relevant growth inhibition was observed in experiment I and II with and without metabolic activation.
In experiment I without metabolic activation the relative growth was 17.3 and 21.4% for the two highest concentrations (1.7 and 1.8 mM) evaluated. The highest concentration evaluated with metabolic activation was 5 mM with a relative growth of 17.3 %.
In experiment II without metabolic activation the relative growth was 12.9 and 9.0% for the two highest concentrations (1.4 and 1.6 mM) tested. The highest concentration was not considered for evaluation of results, as the cytotoxicity was below the requested cytotoxicity frame of 10-20% cell survival. The highest concentrations evaluated with metabolic activation were 5.6 and 5.8 mM with a relative growth of 21.7 and 9.8%. Here the requested cytotoxicity frame of 10-20% cell survival was not reached, however, this cytotoxicity range was framed very closely by the two highest concentrations.
MUTAGENICITY
In experiment I without metabolic activation most mutant values of the negative controls and test item concentrations were within the historical control data of the test facility BSL BIOSERVICE (about 5-43 mutants per 106 cells). No dose-response relationship could be observed. The mutation frequency found in the highest dose group showed a slight increase, however, as the threshold of 3 was not reached the increase was not considered as biologically relevant.
Mutation frequencies with the negative control were found to be 27.76 and 17.47 mutants/106 cells and in the range of 18.24 to 55.56 mutants/106 cells with the test item, respectively. The highest mutation rate (compared to the negative control values) of 2.46 was found at a concentration of 1.8 mM with a relative growth of 21.4%.
With metabolic activation most mutant values of the negative controls and test item concentrations were within the historical control data of the test facility BSL BIOSERVICE (about 5-44 mutants per 106 cells). No dose-response relationship could be observed. The mutation frequency found in the highest dose group showed a slight increase, however, as the threshold of 3 was not reached the increase was not considered as biologically relevant.
Mutation frequencies of the negative control were found to be 21.51 and 35.65 mutants/106 cells and in the range of 16.94 to 73.08 mutants/106 cells with the test item, respectively. The highest mutation rate (compared to the negative control values) of 2.56 was found at a concentration of 5 mM with a relative growth of 17.3%.
In experiment II without metabolic activation most mutant values of the negative controls and test item concentrations found were within the historical control data of the test facility BSL BIOSERVICE (about 5-43 mutants per 106 cells). No dose-response relationship could be observed. The mutation frequency found in the highest dose group did show a slight increase. However, this effect was not considered as biologically relevant, as the toxicity of this highest dose group was below the requested toxicity frame of 10-20%.
Mutation frequencies of the negative control were found to be 19.68 and 24.49 mutants/106 cells and in the range of 13.23 to 49.48 mutants/106 cells with the test item, respectively. The highest mutation rate (compared to the negative control values) of 2.24 was found at a concentration of 1.6 mM with a relative growth of 9.0%.
In experiment II with metabolic activation the mutant values of the negative controls found were within the historical control data of the test facility BSL BIOSERVICE (about 5-44 mutants per 106 cells). Mutation frequencies of the negative controls were found tobe 33.01 and 23.08 mutants/106
cells and in the range of 23.08 to 113.73 mutants/106 cells for the test item, respectively.
The mutation frequencies found in the dose groups treated with the test item showed a biologically relevant increase compared to the negative controls. At concentrations of 4.8 mM (90.49 mutants per 106 cells) and 5.4 mM (113.73 mutants per 106 cells) the threshold of 3 was exceeded with mutant frequencies of 3.23 and 4.06, respectively. In the dose group 5.8 mM the threshold of 3 was nearly reached with a mutation frequency of 2.93 (82.22 mutants per 106 cells). Additionally, in all dose groups from concentrations of 4.0 mM and higher the historical range of the negative controls was exceeded with mutant frequencies between 44.52 and 113.73.
Due to the increase in mutant frequency and the concentration related increase in experiment II with metabolic activation, the detected effect is considered as biologically relevant.
DMBA (0.8 and 1.0 μg/mL) and EMS (300 μg/mL) were used as positive controls and showed distinct and biologically relevant effects in mutation frequency.
EXPERIMENT I without metabolic activation
dose group [mM] | cell density [cells/mL] | rel. growth [%] | CE [%] | mean mutant colonies | mutant colonies / 10E6 cells | MF |
NC 1 | 1120000 | 100 | 79 | 8.8 | 27.76 | - |
NC 2 | 1110000 | 100 | 83 | 5.8 | 17.47 | - |
0.25 | 1340000 | 120.2 | 72 | 11.8 | 41.11 | 1.82 |
0.50 | 1240000 | 111.2 | 77 | 7.2 | 23.38 | 1.03 |
1.00 | 1100000 | 98.7 | 77 | 5.6 | 18.24 | 0.81 |
1.25 | 999000 | 89.6 | 76 | 7.8 | 25.66 | 1.13 |
1.5 | 565000 | 50.7 | 77 | 12.0 | 39.22 | 1.73 |
1.6 | 433000 | 38.8 | 72 | 6.0 | 20.91 | 0.92 |
1.7 | 193000 | 17.3 | 79 | 9.0 | 28.39 | 1.26 |
1.8 | 239000 | 21.4 | 68 | 15.0 | 55.56 | 2.46 |
EMS 300 µg/mL | 1140000 | 102.2 | 68 | 68.8 | 254.81 | 11.27 |
EXPERIMENT I with metabolic activation
dose group [mM] | cell density [cells/mL] | rel. growth [%] | CE [%] | mean mutant colonies | mutant colonies / 10E6 cells | MF |
NC 1 | 1390000 | 100 | 86 | 7.4 | 21.51 | - |
NC 2 | 1430000 | 100 | 83 | 11.8 | 35.65 | - |
0.05 | 1440000 | 102.1 | 60 | 5.4 | 22.41 | 0.78 |
0.1 | 1470000 | 104.3 | 85 | 10.8 | 31.62 | 1.11 |
0.5 | 1460000 | 103.5 | 92 | 6.2 | 16.94 | 0.59 |
1.0 | 1260000 | 89.4 | 81 | 13.0 | 40.25 | 1.41 |
2.0 | 1270000 | 90.1 | 79 | 12.2 | 38.61 | 1.35 |
3.0 | 1280000 | 90.8 | 75 | 14.6 | 48.50 | 1.70 |
4.0 | 1160000 | 82.3 | 79 | 10.8 | 34.29 | 1.20 |
5.0 |
244000 |
17.3 |
78 |
22.8 |
73.08 |
2.56 |
DMBA 1 µg/mL | 1170000 | 83.0 | 68 | 88.8 | 327.68 | 11.46 |
EXPERIMENT II without metabolic activation
dose group [mM] | cell density [cells/mL] | rel. growth [%] | CE [%] | mean mutant colonies | mutant colonies / 10E6 cells | MF |
NC 1 | 2190000 | 100 | 94 | 7.4 | 19.68 | - |
NC 2 | 2160000 | 100 | 86 | 8.4 | 24.49 | - |
0.05 | 1900000 | 87.4 | 85 | 6.2 | 18.18 | 0.82 |
0.10 | 1970000 | 90.6 | 98 | 5.2 | 13.23 | 0.60 |
0.25 | 1630000 | 74.9 | 85 | 7.4 | 21.89 | 0.99 |
0.5 | 1310000 | 60.2 | 79 | 13.6 | 43.31 | 1.96 |
1.0 | 631000 | 29.0 | 72 | 10.8 | 37.63 | 1.70 |
1.2 | 446000 | 20.5 | 80 | 14.8 | 46.54 | 2.11 |
1.4 | 280000 | 12.9 | 73 | 6.0 | 20.55 | 0.93 |
1.6 | 195000 | 9.0 | 72 | 14.2 | 49.48 | 2.24 |
EMS 300 µg/mL | 1260000 | 57.9 | 73 | 229.2 | 790.34 | 35.79 |
EXPERIMENT II with metabolic activation
dose group [mM] | cell density [cells/mL] | rel. growth [%] | CE [%] | mean mutant colonies | mutant colonies / 10E6 cells | MF |
NC 1 | 1370000 | 100 | 77 | 10.2 | 33.01 | - |
NC 2 | 1380000 | 100 | 78 | 7.2 | 23.08 | - |
2.8 | 1310000 | 95.3 | 78 | 7.2 | 23.08 | 0.82 |
4.0 | 926000 | 67.3 | 71 | 12.6 | 44.52 | 1.59 |
4.4 | 843000 | 61.3 | 73 | 14.6 | 50.00 | 1.78 |
4.8 | 803000 | 58.4 | 66 | 23.8 | 90.49 | 3.23 |
5.2 | 525000 | 38.2 | 68 | 16.4 | 60.74 | 2.17 |
5.4 | 440000 | 32.0 | 64 | 29.0 | 113.73 | 4.06 |
5.6 | 298000 | 21.7 | 67 | 14.0 | 52.43 | 1.87 |
5.8 | 135000 | 9.8 | 68 | 22.2 | 82.22 | 2.93 |
DMBA 0.8 µg/mL | 1370000 | 99.6 | 77 | 48.8 | 158.96 | 5.67 |
DMBA 1 µg/mL | 1330000 | 96.7 | 68 | 70.2 | 257.14 | 9.17 |
Applicant's summary and conclusion
- Conclusions:
- In conclusion, in the described mutagenicity test under the experimental conditions reported, the test item 3,4-Epoxycyclohexylmethyl methacrylate is considered to be mutagenic in the HPRT locus using V79 cells of the Chinese Hamster.
- Executive summary:
The test item 3,4-Epoxycyclohexylmethyl methacrylate was assessed for its potential to induce mutations at the HPRT locus using V79 cells of the Chinese Hamster.
The selection of the concentrations was based on data from the pre-experiments. Experiment I with and without metabolic activation and experiment II with metabolic activation were performed as a 4 h short-term exposure assay. Experiment II without metabolic activation was performed as 20 h long time exposure assay.
The test item was investigated at the following concentrations:
Experiment I
- without metabolic activation: 0.25, 0.50, 1.00, 1.25, 1.5, 1.6, 1.7 and 1.8 mM
- with metabolic activation: 0.05, 0.1, 0.5, 1.0, 2.0, 3.0, 4.0 and 5.0 mM
Experiment II
- without metabolic activation: 0.05, 0.10, 0.25, 0.5, 1.0, 1.2, 1.4 and 1.6 mM
- with metabolic activation: 2.8, 4.0, 4.4, 4.8, 5.2, 5.4, 5.6 and 5.8 mM
No precipitation of the test item was noted in the experiments.
Biologically relevant growth inhibition was observed in experiment I and II with and without metabolic activation.
In experiment I without metabolic activation the relative growth was 17.3 and 21.4% for the two highest concentrations (1.7 and 1.8 mM) evaluated. The highest concentration evaluated with metabolic activation was 5 mM with a relative growth of 17.3 %.
In experiment II without metabolic activation the relative growth was 12.9 and 9.0% for the two highest concentrations (1.4 and 1.6 mM) tested. The highest concentration was not considered for evaluation of results, as the cytotoxicity was below the requested cytotoxicity frame of 10-20% cell survival. The highest concentrations evaluated with metabolic activation were 5.6 and 5.8 mM with a relative growth of 21.7 and 9.8%. Here the requested cytotoxicity frame of 10-20% cell survival was not reached, however, this cytotoxicity range was framed very closely by the two highest concentrations.
A biologically relevant increase of mutants was found after treatment with the test item in experiment II with metabolic activation. Moreover, a dose-response relationship was observed.
DMBA and EMS were used as positive controls and showed distinct and biologically relevant effects in mutation frequency.
In conclusion, in the described mutagenicity test under the experimental conditions reported, the test item 3,4-Epoxycyclohexylmethyl methacrylate is considered to be mutagenic in the HPRT locus using V79 cells of the Chinese Hamster.
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