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EC number: 434-080-7 | CAS number: 208343-47-9
- 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
Endpoint summary
Administrative data
Key value for chemical safety assessment
Genetic toxicity in vitro
Description of key information
An Ames test in E. coli and Salmonella (OECD 471) and a chromosome aberration assay (OECD 473) in mammalian cells was performed to evaluate the genotoxic potential of the test item. The substance did neither induce point mutations in bacterial DNA nor chromosomal damage in mammalian cells.
Moreover, an HPRT (OECD 476) conducted on a structural analogue is available. The read across substance and its metabolites did not show any mutagenic activity in this forward mutation system conducted in chinese hamster lung fibroblasts.
Link to relevant study records
- Endpoint:
- in vitro gene mutation study in bacteria
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1999
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- bacterial reverse mutation assay
- Target gene:
- His: Salmonella
Trp: E. coli - Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and E. coli WP2
- Metabolic activation:
- with and without
- Metabolic activation system:
- Phenobarbital and beta-Naphthoflavone-induced liver S9 mix from rats
- Test concentrations with justification for top dose:
- incorporation test (experiment I) and the preincubation test (experiment II) (with and without metabolic activation): 33; 100; 333; 1000; 2500; and 5000 µg/plate
- Vehicle / solvent:
- DMSO
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: TA 1535, TA 100: sodium azide, NaN3, TA1537, TA98: 4-nitro-o-phenylene-diamine, 4-NOPD, WP2 uvrA: methyl methane sulfonate, MMS
- Remarks:
- without metabolic activation
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: 2-aminoanthracene
- Remarks:
- with metabolic activation
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in agar (plate incorporation) and preincubation
DURATION
- Preincubation period: 60min
- Exposure duration: 48h
NUMBER OF REPLICATIONS: two
NUMBER OF CELLS EVALUATED: all colonies counted
DETERMINATION OF CYTOTOXICITY
- Method: mitotic index - Evaluation criteria:
- The Salmonella typhimurium and Escherichia coli reverse mutation assay is considered acceptable if it meets the following criteria:
- regular background growth in the negative and solvent control
- the spontaneous reversion rates in the negative and solvent control are in the range of our historical data
- the positive control substances should produce a significant increase in mutant colony frequencies
Evaluation of Results:
A test item is considered positive if either a dose related and reproducible increase in the number of revertants or a biologically relevant and reproducible increase for at least one test concentration is induced.
A test item producing neither a reproducible and dose related increase in the number of revertants, nor a biologically relevant and reproducibly positive response at any one of the test points is considered non-mutagenic in this system.
A mutagenic response is described as follows:
A test item is considered mutagenic if in the strains TA 98, TA 100, and WP2 uvrA the number of reversions will be at least twice as high and in the strains TA 1535 and TA 1537 at least three times higher as compared to the spontaneous reversion rate.
Also, a dose-dependent and reproducible increase in the number of revertants is regarded as an indication of possibly existing mutagenic potential of the test item regardless whether the highest dose induced the above described enhancement factors or not. - Statistics:
- No statistical evaluation of the data is required.
- Species / strain:
- other: TA 1535, TA 1537, TA 98, and TA 100, WP2 uvrA.
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- (5000 µg/plate)
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- True negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Precipitation: yes, at higher concentrations
RANGE-FINDING/SCREENING STUDIES:
In the pre-experiment the concentration range of the test item was 3 - 5000 ug/plate. The pre-experiment is reported as experiment I since no relevant toxic effects were observed and 5000 ug/plate were chosen as maximal concentration. The concentration range included two logarithmic decades. The following concentrations were tested.
COMPARISON WITH HISTORICAL CONTROL DATA: yes, for negative control without metabolic activation, solvent control wihtout metabolic activation, positive control without metabolic activation - Conclusions:
- The reverse bacterial mutation test did not reveal a genotoxicity potential.
- Endpoint:
- in vitro cytogenicity / chromosome aberration study in mammalian cells
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 473 (In Vitro Mammalian Chromosome Aberration Test)
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- in vitro mammalian chromosome aberration test
- Species / strain / cell type:
- Chinese hamster lung fibroblasts (V79)
- Details on mammalian cell type (if applicable):
- - Type and identity of media: MEM
- Properly maintained: yes
- Periodically checked for Mycoplasma contamination: yes
- Periodically checked for karyotype stability: yes - Metabolic activation:
- with and without
- Metabolic activation system:
- phenobarbital and beta-naphthoflavone induced rat liver S9 mix
- Test concentrations with justification for top dose:
- Without S-9 mix:
Experiment I: 3.2 - 1000 µg/ml
Experiment II: 1.0 - 1000 µg/ml
With S-9 mix:
Experiment I: 3.2 - 1000 µg/ml
Experiment II: 1.0 - 1000 µg/ml - Vehicle / solvent:
- DMSO
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- cyclophosphamide
- ethylmethanesulphonate
- Details on test system and experimental conditions:
- Without S-9 mix:
Experiment I: 3.2 - 1000 µg/ml; Exposure period = 4 hours ; Recovery = 14 hours; preparation interval = 18 hours
Experiment II: 1.0 - 1000 µg/ml; Exposure period =18; Preparation interval= 28 hours
10.0 - 1000 µg/ml; Exposure period = 28 hours; Preparation interval= 28 hours
With S-9 mix:
Experiment I: 3.2 - 1000 µg/ml; Exposure period = 4 hours ; Recovery = 14 hours; preparation interval = 18 hours
Experiment II: 1.0 - 1000 µg/ml; Exposure period = 4 hours; Recovery = 24 hours; Preparation interval= 28 hours
16 h and 26 h, respectively after the start of the treatment colcemid was added (0.2 µg/ml culture medium) to the cultures. 2 h later, the cells on the slides were treated in the chambers with hypotonic solution (0.4 % KCl) for 20 min at 37° C. After incubation in the hypotonic solution the cells were fixed with 3 + 1 methanol + glacial acetic acid. Per experiment both slides per group were prepared. After preparation the cells were stained with Giemsa.
Additionally, two cultures per test item and solvent control treatment group, not treated with Colcemid, were set up in parallel. These cultures were stained in order to determine microscopically the cell number within 10 defined fields per slide. The toxicity of the test item is given as reduction of % cells as compared to the solvent control. - Evaluation criteria:
- The chromosome aberration assay performed is considered acceptable if it meets the following criteria:
a) The number of structural aberrations found in the negative and/or solvent controls falls within the range of our historical laboratory control data: 0.00 % - 4.00 %.
b) The positive control substances should produce significant increases in the number of cells with structural chromosome aberrations, which are within the range of the laboratories historical control data.
A test item is classified as non-mutagenic if:
- the number of induced structural chromosome aberrations in all evaluated dose groups are in the range of historical control data (0.0 - 4.0 % aberrant cells exclusive gaps).
- no significant increase of the number of structural chromosome aberrations are observed.
A test item is classified as mutagenic if:
- the number of induced structural chromosome aberrations are not in the range of historical control data (0.0 - 4.0 % aberrant cells exclusive gaps).
- either a concentration-related or a significant increase of the number of structural chromosome aberrations are observed. A test item is classified as non-mutagenic if
- the number of induced structural chromosome aberrations in all evaluated dose groups are in the range of historical control data (0.0 - 4.0 % aberrant cells exclusive gaps).
- no significant increase of the number of structural chromosome aberrations are observed. - Statistics:
- Statistical significance was confirmed by means of the Fischer's exact test (p < 0.05).
- Species / strain:
- Chinese hamster lung fibroblasts (V79)
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- True negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Additional information on results:
- Precipitation: Precipitation of the test item in culture medium was observed at all applied concentrations.
However, 4 h after start of treatment, precipitation was observed at 31.6 µg/ml and above. Although no clear toxicity was observed, 1000 µg/ml were chosen as top concentration in experiment I for the evaluation of cytogenetic damage, to confirm the toxicity observed in the range-finding experiment. In experiment Il just as in experiment I no clear toxicity was observed. Therefore, the highest evaluated concentration was chosen considering the observed precipitation at 31.6 µg/ml and above as recommended in the OECD Guideline 473.
RANGE-FINDING/SCREENING STUDIES:
A pre-test on cell growth inhibition with 4 h and 24 h treatment was performed in order to determine the toxicity of the test item. Cytotoxicity was determined using concentrations separated by no more than a factor of 2 - 3.33. The general experimental conditions in this pre-test were the same as described below for the cytogenetic main experiment.
COMPARISON WITH HISTORICAL CONTROL DATA: yes, with control data V79 cell line since 1993 (positive and negtive control) - Conclusions:
- The in vitro chromosome aberration test in V79 cells did not reveal a genotoxicity potential at all concentrations. No cytotoxicity was observed even at concentrations that did produce precipitation.
- Endpoint:
- in vitro gene mutation study in mammalian cells
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reason / purpose for cross-reference:
- read-across source
- Key result
- Species / strain:
- Chinese hamster lung fibroblasts (V79)
- Remarks:
- mammalian cell line
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- True negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Conclusions:
- Based on the results of two independently performed experiments in the analogue substance and under the given experimental conditions, it is concluded that the test item and its metabolites did not show any mutagenic activity in this forward mutation system.
Referenceopen allclose all
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (negative)
Genetic toxicity in vivo
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
There are two reliable in vitro studies available to assess the potential of the test substance for gene mutations in bacteria and cytogenicity in mammalian cells.
In a GLP conform study according to OECD guideline 471, the potential of the test substance to induce gene mutations according to the plate incorporation test (experiment I) and the preincubation test (experiment II) using the Salmonella typhimurium strains TA 1535, TA 1537, TA 98, and TA 100, and the Escherichia coli strain WP2 uvrA was investigated. The assay was performed in two independent experiments both with and without liver microsomal activation. Each concentration, including the controls, was tested in triplicate. The test item was tested at the following concentrations: 33; 100; 333; 1000; 2500; and 5000 µg/plate. In experiment II, toxic effects, evident as a reduction in the number of revertants, were observed at the higher concentrations in strains TA 1537, TA 98, TA 100, and WP2 uvrA in the presence of metabolic activation. No substantial increase in revertant colony numbers of any of the five tester strains was observed following treatment with the test substance at any dose level, neither in the presence nor absence of metabolic activation (S9 mix). In conclusion, it can be stated that during the described mutagenicity test and under the experimental conditions reported, the test item did not induce gene mutations by base pair changes or frameshifts in the genome of the strains used.
In a GLP conform study according to OECD guideline 473, the test substance, formulated in DMSO, was assessed for its potential to induce structural chromosome aberrations in V79 cells of the Chinese hamster in vitro in two independent experiments. In each experimental group two parallel cultures were set up. Dose selection of the cytogenetic experiments was performed considering the toxicity data and the occurrence of precipitation with respect to the OECD Guideline 473.No clear toxic effects, either indicated by reduced mitotic indices or indicated by reduced cell numbers were observed in the absence and the presence of S9 mix. In both independent experiments, no biologically relevant increase in the number of cells carrying structural chromosomal aberrations was observed after treatment with the test item. No increase in the frequencies of polyploid metaphases was found after treatment with the test item as compared to the frequencies of the controls.In conclusion, it can be stated that in the study described and under the experimental conditions reported, the test item did not induce structural chromosome aberrations as determined by the chromosome aberration test in V79 cells (Chinese hamster cell line) in vitro.
There are no data on the mutagenic activity (HPRT test) of the test substance available. However, another structural analogue source substance was tested for this endpoint and the result can be transferred to the test substance in order to fill this data gap.
In detail, a GLP-compliant study according to OECD 476 was performed with another analogue substance. Based on preliminary toxicity test four concentrations were selected for the original mutagenicity experiment ranging from 18.52 to 500 µg/ml in the presence and absence of metabolic activation. 500 µg/ml was the highest attainable concentration due to the solubility limit inthe vehicle.The mutagenic activity was measured in the presence and absence of metabolic activation. Although the original experiment revealed statistically significant differences at some of the concentrations, both in the absence and in the presence of metabolic activation, the criteria for a positive response were not fullfilled. The increase was not concentration dependent in both parts and the number of mutant colonies differed from the respective number of the negative control by much less than the required 20. Furthermore, the effects were not reproducible. The positive controls induced a clear increase in mutant frequency. Based on the results of two independently performed experiments and under the given experimental conditions, it is concluded that the substance and its metabolites did not show any mutagenic activity in this forward mutation system.
Justification for classification or non-classification
The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008, as amended for the thirteenth time in Regulation (EU) No 2018/1480. As a result the substance is not considered to be classified for genotoxicity under Regulation (EC) No. 1272/2008.
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