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EC number: 212-833-9 | CAS number: 872-93-5
- 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
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- Nanomaterial catalytic activity
- Endpoint summary
- Stability
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- 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 cytogenicity / chromosome aberration study in mammalian cells
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 26-05-2020 to 08-06-2020
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 020
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 473 (In Vitro Mammalian Chromosomal Aberration Test)
- Version / remarks:
- Jul. 29, 2016
- Qualifier:
- according to guideline
- Guideline:
- other: Regulation on Test Methods for Chemical Substances - Notification No. 2019-23, National Institute of Environmental Research, Republic of Korea
- Version / remarks:
- Jun. 13, 2019
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- in vitro mammalian chromosome aberration test
Test material
- Reference substance name:
- 3-methyltetrahydrothiophene 1,1-dioxide
- EC Number:
- 212-833-9
- EC Name:
- 3-methyltetrahydrothiophene 1,1-dioxide
- Cas Number:
- 872-93-5
- Molecular formula:
- C5H10O2S
- IUPAC Name:
- 3-methyl-1λ⁶-thiolane-1,1-dione
- Test material form:
- liquid
Constituent 1
- Specific details on test material used for the study:
- Lot no. XXZ2J
99.9% purity (GC)
Method
Species / strain
- Species / strain / cell type:
- Chinese hamster lung (CHL/IU)
- Details on mammalian cell type (if applicable):
- CELLS USED
- Type and source of cells: CHI/IU, American Type Culture Collection U.S.A
- Suitability of cells: CHL/IU cell line has a high detection sensitivity, is commonly used in in vitro chromosome aberration studies and recommended in the regulatory guidelines.
- Normal cell cycle time (negative control): approximately 15 hours
For cell lines:
- Absence of Mycoplasma contamination: evaluation by using a Hoechst Stain Kit (MPBIOMEDICALS, Japan).
- Number of passages if applicable: 18
- Methods for maintenance in cell culture: Frozen cells were thawed in the fresh medium, cell morphology was evaluated following 70–80% proliferation on the bottom of the flask. 0.25% Trypsin-EDTA solution (Gibco, U.S.A) was added to detach cells. The suspended cells was harvested, transferred into a 50 mL tube and centrifuged at 1,000 rpm for 5 minutes. The supernatant was removed and the pellets were resuspended with EMEM supplemented with 10% FBS. Suspended cells were transferred into a 75 cm² flask and incubated in a 5% CO2 incubator at 37°C and more than two times to yield a final density of 5×104 cells/mL. The suspended cells were placed in a 6 well plate (2 mL/well, Nunc, Denmark), for the dose range finding study and in a 60 mm plate (5
mL/plate, BD, U.S.A.) and 6 well plate (2 mL/well) for the main study. Cells were incubated in a 5% CO2 incubator at 37°C for one day.
- Doubling time: approximately 15 hours
- Modal number of chromosomes: 25
MEDIA USED
100 mL of culture medium consisted of 10 mL Fetal Bovine Serum (FBS, Gibco, U.S.A.), 1 mL Penicillin-Streptomycin (Gibco, U.S.) and 89 mL Eagles modified eagle’s medium (EMEM, Lonza, U.S.). Conditions during incubation 5% CO2 incubator at 37°C.
- Metabolic activation:
- with and without
- Metabolic activation system:
- Type and composition of metabolic activation system:
S9 and Cofactor C from Oriental Yeast Co., LTD., Japan. Prepared from the liver of 7 weeks old male Sprague-Dawley rat [Crl:CD(SD)] treated with the enzyme inducing agents Phenobarbital (PB) and 5,6-benzoflavone (BF).
The preparation of S9 mix was conducted immediately prior to use. The frozen S9 (Lot No.: 19121310) and Cofactor C (Lot No.: C19121110) were thawed and mixed at a ratio of 2 to 4.7.
The composition of S9 mix is presented in Table 1 in any other information.
Used volume of S9 was 0.5 mL in the Dose Range Finding study and 2.17 mL in the main study. - Test concentrations with justification for top dose:
- The high dose of the test substance was 2,000 µg/mL, which is the limit dose recommended in the guidelines. The high dose was sequentially diluted to produce lower dose levels (1,000, 500, 250, 125, 62.5, 31.3, 15.6, 7.81, 3.91, 1.95, 0.977 and 0.488 µg/mL). In addition, the negative control group was set.
In the dose range finding study cytotoxicity and precipitation of the test substance was not evident in the short time treatments with and without metabolic activation and in the continuous treatment without metabolic activation. Therefore, the high dose was selected at 2,000 μg/mL in the main study (short time and continuous) and it was sequentially diluted by applying a geometric ratio of 2 to produce lower dose levels 1,000 and 500 μg/mL In addition, the positive and negative control groups were set. - Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: Vehicle of the test substance: water for injection. Vehicle for positive controls Dimethylsulfoxide lot no. K50270931 (Merck, Germany).
In order to produce a 10-fold stock of 2,000 µg/mL, which is the high dose of the dose range finding study, a preliminary solubility test was conducted. As a result, the test substance was dissolved in water for injection. Therefore, water for injection was selected as the vehicle for this study.
Controls
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- Remarks:
- Water for injection (JW Pharmaceutical Co., Ltd, Republic of Korea)
- Positive controls:
- yes
- Positive control substance:
- benzo(a)pyrene
- mitomycin C
- Details on test system and experimental conditions:
- METHOD OF TREATMENT/ EXPOSURE:
- Cell density at seeding (if applicable): 5×10-4 cells/mL
- Test substance added in medium; in suspension.
TREATMENT AND HARVEST SCHEDULE:
- Preincubation period: one day
- Exposure duration/duration of treatment: Short time treatment – 6 hours and Continuous treatment -24 hours
- Harvest time after the end of treatment (sampling/recovery times): after short time treatment of 6 hours, 18 hours of recovery
OBSERVATIONS:
The observation of slides was conducted in the order of the short time treatments and continuous treatment. Dose levels for chromosome observations were selected at 3 dose levels, at which 300 metaphases could be observed.
Three hundred metaphases per dose were observed using a microscope (600-fold magnification, BX51, Olympus, Japan)
Chromosomal aberrations were classified into structural aberration, numerical aberration and other.
Structural aberrations were classified into chromatid break (ctb), chromatid exchange (cte), chromosome break (csb), chromosome exchange (cse), chromatid gap (ctg), chromosome gap (csg) and fragmentation (frg). When several gaps or breaks were observed in metaphase, these were recorded as frg. An achromatic lesion narrower than the width of one chromatid was defi ned as a gap
In addition, numerical aberrations were classified into polyploidy (pol) and endoreduplication (end)
For the aforementioned aberrations, any cell with one or more aberrations was counted as an aberrant cell. For the gap, the number of cells including and excluding gaps was scored and recorded. Others which were not classified into the structural or numerical aberrations were recorded for the type and number of cells with aberrations. - Rationale for test conditions:
- In the dose range finding study cytotoxicity and precipitation of the test substance was not evident in the short time treatments with and without metabolic activation and in the continuous treatment without metabolic activation. Therefore, the high dose was selected at 2,000 μg/mL in the main study (short time and continuous) and it was sequentially diluted by applying a geometric ratio of 2 to produce lower dose levels 1,000 and 500 μg/mL In addition, the positive and negative control groups were set.
- Evaluation criteria:
- The results were considered to be positive when the frequency of cells with chromosome aberrations (excluding gap) met all of the following conditions: others were considered as negative
The frequency of cells with chromosome aberrations shows a statistically significant increase at more than one dose level in the test substance groups compared to the negative control group.
The cells with chromosome aberrations are increased in a dose-dependent manner.
The frequency of cells with chromosome aberrations increases over the 95% control limits of distribution of the historical control data in the negative control group. - Statistics:
- Statistical analysis on the frequency of cells with chromosome aberrations (excluding gap) was performed using SAS Program (version 9.3, SAS Institute Inc., U.S.A.).
For the aberration cell data, Fisher’s exact test was used for the comparison of the negative control group to the test substance group or the positive control group (significance levels: 0.05 and 0.01, two tailed) The test substance group was not significant, Cochran Armitage trend test was not conducted for dose dependency between the negative control group and the test substance group (significance levels: 0.05 and 0.01, two tailed).
Results and discussion
Test results
- Key result
- Species / strain:
- Chinese hamster lung (CHL/IU)
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Data on pH: the pH in the high dose group of the test substance did not change more than 1.0 compared to the control group
- Data on osmolality: the osmolality in the high dose group of the test substance did not change more than 50 mOsm/kg compared to the control group
- Water solubility: a preliminary solubility test was conducted and the test substance was dissolved in water for injection (vehicle)
- Precipitation and time of the determination: the precipitation of the test substance was not evident in the short time treatments with and without metabolic activation and in the continuous treatment without metabolic activation
RANGE-FINDING/SCREENING STUDIES (if applicable):
In the dose range finding study cytotoxicity and precipitation of the test substance was not evident in the short time treatments with and without metabolic activation and in the continuous treatment without metabolic activation.
STUDY RESULTS
- Concurrent vehicle negative and positive control data: The frequency of cells with structural chromosome aberrations in the negative control group was within the range of historical control data and the 95% control limits of the distribution of the historical control data. In addition, the frequency of cells with structural chromosome aberrations in the positive control group was within the range of historical control data and statistically significantly increased compared to the negative control group. At least 300 metaphases cells per dose were observed in the negative and positive control groups and the test substance groups.
Any other information on results incl. tables
Table 3: summary results of the main study
Test substance | Dose (µg/mL) | RPD(%) | PD | S9 mix | Trt-Rec time (hr) | No. of cell analyzed | Number of cells with structural aberrations | Number of cells with numerical aberrations | Others |
| ||||||||||
ctb | csb | cte | cse | frg | gap | total(%) | end | pol | total(%) |
| ||||||||||
ctg | csg | gap- | gap+ |
| ||||||||||||||||
Water for injection | 0 | 100 | 1.56 | - | 6-18 | 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 (0.0) | 0 (0.0) | 0 | 0 | 0 (0.0) | 0 |
|
|
|
|
|
| 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
|
| 0 | 0 |
|
|
| |
3-Methylsulfolane | 500 | 95.2 | - | - | 6-18 | 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 (0.0) | 0 (0.0) | 0 | 0 | 0 (0.0) | 0 |
|
|
|
|
|
| 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
|
| 0 | 0 |
|
|
| |
1000 | 90.6 | - | - | 6-18 | 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 (0.0) | 1 (0.3) | 0 | 0 | 0 (0.0) | 0 |
| |
|
|
|
|
| 150 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
|
| 0 | 0 |
|
|
| |
2000 | 85.8 | - | - | 6-18 | 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 (0.0) | 0 (0.0) | 0 | 0 | 0 (0.0) | 0 |
| |
|
|
|
|
| 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
|
| 0 | 0 |
|
|
| |
MMC | 0.1 | 58.6 | - | - | 6-18 | 150 | 8 | 0 | 27 | 0 | 0 | 0 | 0 | 59** (19.7) | 62 (20.7) | 0 | 0 | 0 (0.0) | 0 |
|
|
|
|
|
| 150 | 6 | 0 | 25 | 0 | 0 | 3 | 0 |
|
| 0 | 0 |
|
|
| |
Water for injection | 0 | 100 | 1.53 | + | 6-18 | 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 (0.0) | 0 (0.0) | 0 | 0 | 0 (0.0) | 0 |
|
|
|
|
|
| 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
|
| 0 | 0 |
|
|
| |
3-Methylsulfolane | 500 | 97.0 | - | + | 6-18 | 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 (0.0) | 0 (0.0) | 0 | 0 | 0 (0.0) | 0 |
|
|
|
|
|
| 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
|
| 0 | 0 |
|
|
| |
1000 | 90.2 | - | + | 6-18 | 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 (0.0) | 0 (0.0) | 0 | 0 | 0 (0.0) | 0 |
| |
|
|
|
|
| 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
|
| 0 | 0 |
|
|
| |
2000 | 85.2 | - | + | 6-18 | 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 (0.0) | 0 (0.0) | 0 | 0 | 0 (0.0) | 0 |
| |
|
|
|
|
| 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
|
| 0 | 0 |
|
|
| |
B[a]P | 20 | 51.1 | - | + | 6-18 | 150 | 5 | 0 | 21 | 0 | 0 | 0 | 0 | 47** (15.7) | 47 (15.7) | 0 | 0 | 0 (0.0) | 0 |
|
|
|
|
|
| 150 | 4 | 0 | 22 | 0 | 0 | 0 | 0 |
|
| 0 | 0 |
|
|
| |
Water for injection | 0 | 100 | 1.54 | - | 24-0 | 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 (0.0) | 0 (0.0) | 0 | 0 | 0 (0.0) | 0 |
|
|
|
|
|
| 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
|
| 0 | 0 |
|
|
| |
3-Methylsulfolane | 500 | 96.6 | - | - | 24-0 | 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (0.3) | 1 (0.3) | 0 | 0 | 0 (0.0) | 0 |
|
|
|
|
|
| 150 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
|
| 0 | 0 |
|
|
| |
1000 | 90.9 | - | - | 24-0 | 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 (0.0) | 0 (0.0) | 0 | 0 | 0 (0.0) | 0 |
| |
|
|
|
|
| 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
|
| 0 | 0 |
|
|
| |
2000 | 83.2 | - | - | 24-0 | 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 (0.0) | 0 (0.0) | 0 | 0 | 0 (0.0) | 0 |
| |
|
|
|
|
| 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
|
| 0 | 0 |
|
|
| |
MMC | 0.1 | 52.2 | - | - | 24-0 | 150 | 10 | 0 | 30 | 0 | 0 | 0 | 0 | 70** (23.3) | 72 (24.0) | 0 | 0 | 0 (0.0) | 0 |
|
|
|
|
|
| 150 | 8 | 0 | 28 | 0 | 0 | 2 | 0 |
|
| 0 | 0 |
|
|
|
Aberration: ctg: chromatid gap, csg: chromosome gap, ctb: chromatid break, cte: chromatid exchange, csb: chromosome break, cse: chromosome exchange, frg: fragmentation, end: endoreduplication, pol: polyploidy
MMC: Mitomycin C, B[a]P: Benzo[a]pyrene RPD : Relative Population Doubling, Trt-Rec time : Treatment-Recovery times gap-: Total number of cells with structural aberrations excluding gap, gap+: Total number of cells with structural aberrations including gap a): Others were excluded from the number of cells with chromosomal aberrations. Population Doubling (PD) = [log (Post-treatment cell number / Initial cell number)] ÷ log 2 Significant difference from negative control by Fisher’s exact test : ** p<0.01
Applicant's summary and conclusion
- Conclusions:
- The test substance is not cytogenic/mutagenic in the in vitro Mammalian Chromosomal Aberration Test performed according to OECD TG 473.
- Executive summary:
The potential of 3-Methyl Sulfolane to induce chromosomal aberrations in Chinese Hamster Lung (CHL/IU) cells was evaluated in a well performed OECD TG 473 under GLP conditions.
A dose range finding study was conducted. In which the following doses where applied in single wells: 2,000 1,000, 500, 250, 125, 62.5, 31.3, 15.6, 7.81, 3.91, 1.95, 0.977 and 0.488 μg/mL with metabolic activation (6 hour treatment time) and without metabolic activation (6 and 24 hour treatment time). The negative control was sterile water. No cytotoxicity or precipitation was observed.
The following dose levels were selected for the main study and tested in duplicate: 2,000 1,000, 500 μg/mL with metabolic activation (6 hour treatment time) and without metabolic activation (6 and 24 hour treatment time). The positive controls where MCC (without metabolic activation) and B[a]P (with metabolic activation). RPDs of all dose levels were 83.2% or more and precipitation was not observed. The frequency of cells with chromosome aberrations in the short time treatments with and without metabolic activation and in the continuous treatment without metabolic activation was not statistically significantly different when compared to the negative control group. In the positive control group, the frequency of cells with structural chromosome aberrations was statistically significantly increased when compared to the negative control group (p<0.01). The acceptance criteria where fulfilled.
In conclusion, the test substance, 3-Methylsulfolane, did not show any evidence to induce chromosomal aberration under the conditions of this study.
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