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EC number: 701-207-5 | CAS number: 1950616-36-0
- 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
- Remarks:
- Type of genotoxicity: gene mutation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: The study was conducted according to the O.E.C.D. test guideline 476 with GLP compliance.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 012
- Report date:
- 2012
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 476 (In Vitro Mammalian Cell Gene Mutation Test)
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- mammalian cell gene mutation assay
Test material
- Reference substance name:
- Reaction products of 2-methylimidazole and 2,2'-[(1- methylethylidene)bis(4,1-phenyleneoxymethylene)]bisoxirane
- EC Number:
- 701-436-0
- Molecular formula:
- (C15H16O2.C4H6N2.C3H5ClO)x
- IUPAC Name:
- Reaction products of 2-methylimidazole and 2,2'-[(1- methylethylidene)bis(4,1-phenyleneoxymethylene)]bisoxirane
- Test material form:
- other: Liquid at room temperature.
- Details on test material:
- As per IUCLID5 Sections 1.1. 1.2. 1.3. and 4.1.
Constituent 1
Method
- Target gene:
- Thymidine kinase
Species / strain
- Species / strain / cell type:
- mouse lymphoma L5178Y cells
- Details on mammalian cell type (if applicable):
- L5178Y cells, clone 3.7.2C, were obtained from Patricia Poorman-Allen, Glaxo Wellcome Inc., Research Triangle Park, NC Each lot of cryopreserved cells was tested using the agar culture and Hoechst staining procedures and found to be free of mycoplasma contamination. Prior to use in the assay, L5178Y cells were cleansed of spontaneous TK-/- cells by culturing in a restrictive medium (Clive and Spector, 1975).
- Additional strain / cell type characteristics:
- other: P53 gene defficient
- Metabolic activation:
- with and without
- Metabolic activation system:
- Aroclor 1254-induced rat liver S9 fraction.
- Test concentrations with justification for top dose:
- The concentrations chosen for cloning were 1.0, 2.0, 3.0, 4.0, and 5.0 µg/mL without S9 fraction activation and 5.0, 10, 25, and 50 µg/mL with S9 fraction metabolic activation.
- Vehicle / solvent:
- DMSO
Controls
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- methylmethanesulfonate
- Remarks:
- Methyl methanesulfonate at 15 and 20 ug/mL was used as the positive control for non-S9 fraction activated treatment. 7.12-Dimethylbenz(a)anthracene at concentrations of 1.25 and 1.5 ug/mL was used as the positive control for S9 fraction cultures.
- Details on test system and experimental conditions:
- The metabolic activation system was Aroclor 1254-induced rat liver S9 fraction was purchased by BioReliance from Moltox (Boone, NC) and stored at < 60oC until used. Immediately prior to use, the S9 fraction was mixed with the cofactors and Fischer's Medium for Leukemic Cells of Mice with 0.1% Pluronics (F0P) to contain 25 uL S9, 6.0 mg nicotinamide adenine dinucleotide phosphate (NADP), 11.25 mg DL-isocitric acid, and 975 uL F0P per mL S9-fraction activation mixture and kept on ice until used. The cofactor/F0P mixture was adjusted to pH 7.0 and filter-sterilized prior to the addition of S9.
The mutagenesis assay was performed in conical centrifuge tubes by combining 6 x 106 L5178Y/TK+/- cells, F0P medium (Fischer's Medium for Leukemic Cells of Mice with 0.1% Pluronics) or S9 activation mixture, and 100 uL dosing solution of test or control substance in solvent or solvent alone in a total volume of 10 mL. The positive controls were treated with MMS (at final concentrations in treatment medium of 15 and 20 ug/mL with a 4-hour exposure or 5.0 and 7.5 ug/ml with a 24-hour exposure) or 7,12 DMBA (at final concentrations in treatment medium of 1.5 and 1.25 ug/mL). Treatment tubes were gassed with 5±1% CO2 in air, capped tightly, and incubated with mechanical mixing for 4 or 24 hours at 37±1°C. The preparation and addition of the testsubstance dosing solutions were carried out under yellow lighting and the cells were incubated in the dark during the exposure period. After the treatment period, the cells were washed twice with F0P or F0P supplemented with 10% horse serum, 2 mM L-glutamine, 100 U penicillin/mL and 100 μg streptomycin/mL (F10P). After the second wash, the cells were resuspended in 20 mL F10P, gassed with 5±1% CO2 in air and placed on the roller drum apparatus at 37±1°C.
For expression of the mutant phenotype, TK-/- the cultures were counted using an electronic cell counter and adjusted to 3x105 cells/mL at approximately 24 and 48 hours after treatment in 20 and 10 mL total volume, respectively. For the 24-hour exposure, cultures were adjusted to 3x105 cells/mL in 20 mL immediately after test substance removal, then at 48 and 72 hours after treatment in 20 and 10 mL total volume, respectively. Cultures with less than 3x105 cells/mL were not adjusted.
For expression of the TK-/- cells, cells were placed in cloning medium (C.M.) containing 0.24% dissolved Noble agar in F0P plus 20% horse serum. Two flasks per culture to be cloned were labeled with the test substance concentration, activation condition, and either TFT (trifluorothymidine, the selective agent) or VC (viable count). Each flask was filled with 100 mL C.M. and placed in an incubator shaker at 37±1°C until used. The cells were centrifuged at 1000 rpm for 10 minutes and the supernatant was decanted. The cells were then diluted in C.M. to concentrations of 3x106 cells/100 mL C.M. for the TFT flasks and 600 cells/100 mL C.M. for the VC flasks. After the dilution, 1.0 mL of stock solution of TFT was added to the TFT flask (final concentration of 3 ug/mL) and both this flask and the VC flask were placed on the shaker at 125 rpm and 37±1°C. After 15 minutes, the flasks were removed and the cell suspension was dispensed equally into each of three appropriately labeled Petri dishes. To accelerate the gelling process, the plates were placed in cold storage (2-8°C) for approximately 30 minutes. The plates were then incubated at 37±1°C in a humidified 5±1% CO2 atmosphere for 10-14 days.
After the incubation period, the VC plates were counted for the total number of colonies per plate and the total relative growth determined. The TFT-resistant colonies were then counted for each culture with ≥ 10% total relative growth. The diameters of the TFT-resistant colonies for the positive and solvent controls and, in the case of a positive response, the test substance-treated cultures were determined over a range of approximately 0.2 to 1.1 mm. The rationale for this procedure is as follows: Mutant L5178Y TK-/- colonies exhibit a characteristic frequency distribution of colony sizes. Studies have demostrated that the small colony variants carry chromosome aberrations associated with chromosome 11, the chromosome on which the TK locus is located in the mouse. - Evaluation criteria:
- The International Workshop on Genotoxicity established a Global Evaluation Factor (GEF) for a positive response in the mouse lymphoma gene-mutation test at an Induced Mutation Frequency (IMF) of ≥ 90 mutants per 106 clonable cells at the Aberdeen meeting in 2003, published in Moore et al., 2006.
A result was considered positive if a concentration-related increase in induced mutant frequency was observed in the treated cultures and one or more treatment conditions with 10% or greater total growth exhibited induced mutant frequencies of >90 mutants per 106 clonable cells.
A result was considered negative if the treated cultures exhibited induced mutant frequencies of less than 90 mutants per 106 clonable cells (based on the average mutant frequency of duplicate cultures) and there was no concentration-related increase in mutant frequency. - Statistics:
- No data
Results and discussion
Test results
- Species / strain:
- mouse lymphoma L5178Y cells
- Metabolic activation:
- with and without
- Genotoxicity:
- positive
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Additional information on results:
- The test substance did not induce a significant increase of the TFT resitant mutant frequency without rat liver S9 metabolic activation. At the high concentration of 5 ug/mL without S9 metabolic activation and a 4 hr exposurse period the % Relative Total Growth was 5%. At the high concentration of 4 ug/mL without S9 metabolic activation and a 20 hr exposurse period the % Relative Total Growth was 23%. At the high concentration of 50 ug/mL with rat liver S9 metabolic activation and a 4 hr exposure period the % Relative Total Growth was 11%.
In the presence in of rat liver S9 metabolic activation and a 4 hr exposure the test substance induced a significant dose-related increase of the mean Induced Mutant Frequency of 92.5 at the high concentration of 50 ug/mL. The increase of the mutant frequency at 50 ug/mL was 2.65-fold the concurrent vehicle control mean mutant frequency value. Sizing of the TFT resistant mutants on the test substance S9 metabolic activation plates demonstrated an increase in the frequency of small colony mutants. - Remarks on result:
- other: strain/cell type:
- Remarks:
- Migrated from field 'Test system'.
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information):
positive with metabolic activation
The data demonstrate that the test substance is mutagenic to mouse lymphoma cells when metabolically converted to an ultimate mutagen. The increase in the frequency of small colony mutants under the conditions of S9 metabolic activation suggests that the test substance is capable of causing chromosome damage in chromosome 11 of these mouse cells. - Executive summary:
The test substance, Formaldehyde, polymer with 1,3 -benzenedimethanamine and phenol was evaluated to induce gene-mutation in mouse lymphoma cells in culture in an O.E.C.D. test guideline 476 study. The test substance did not induce gene-mutation in the absence of rat liver fraction S9 metabolic activation. However, the data demonstrate that the test substance is mutagenic to mouse lymphoma cells when metabolically converted to an ultimate mutagen. The increase in the frequency of small colony mutants under the conditions of S9 metabolic activation suggests that the test substance is capable of causing chromosome damage in chromosome 11 of these mouse cells.
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