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EC number: 425-020-0 | CAS number: 191680-81-6 CGL 116
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
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- Density
- Particle size distribution (Granulometry)
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- Oxidation reduction potential
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- Stability: thermal, sunlight, metals
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- Ecotoxicological Summary
- Aquatic toxicity
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- Short-term toxicity to fish
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- 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
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- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
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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
- Study period:
- August 31, 2012 - January 03, 2013
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP-compliant guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
- Report date:
- 2013
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 476 (In Vitro Mammalian Cell Gene Mutation Test)
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.17 (Mutagenicity - In Vitro Mammalian Cell Gene Mutation Test)
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.5300 - In vitro Mammalian Cell Gene Mutation Test
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- Harlan Cytotest Cell Research GmbH, In den Leppsteinswiesen 19, 64380 Rossdorf, Germany
- Type of assay:
- mammalian cell gene mutation assay
Test material
- Reference substance name:
- Reaction products of N,N'-ethane-1,2-diylbis(1,3-propanediamine), cyclohexane, peroxidized 4-butylamino-2,2,6,6-tetramethylpiperidine and 2,4,6-trichloro-1,3,5-triazine
- EC Number:
- 425-020-0
- EC Name:
- Reaction products of N,N'-ethane-1,2-diylbis(1,3-propanediamine), cyclohexane, peroxidized 4-butylamino-2,2,6,6-tetramethylpiperidine and 2,4,6-trichloro-1,3,5-triazine
- Cas Number:
- 191680-81-6
- Molecular formula:
- C50H77N11O2-C168H230N32O8
- IUPAC Name:
- N2-(2-{[4,6-bis({butyl[1-(cyclohexyloxy)-2,2,6,6-tetramethylpiperidin-4-yl]amino})-1,3,5-triazin-2-yl](3-{[4,6-bis({butyl[1-(cyclohexyloxy)-2,2,6,6-tetramethylpiperidin-4-yl]amino})-1,3,5-triazin-2-yl]amino}propyl)amino}ethyl)-N2-(3-{[4,6-bis({butyl[1-(cyclohexyloxy)-2,2,6,6-tetramethylpiperidin-4-yl]amino})-1,3,5-triazin-2-yl]amino}propyl)-N4,N6-dibutyl-N4,N6-bis[1-(cyclohexyloxy)-2,2,6,6-tetramethylpiperidin-4-yl]-1,3,5-triazine-2,4,6-triamine
- Details on test material:
- - Physical state: Solid, beige
- Storage condition of test material: At room temperature
Constituent 1
Method
- Target gene:
- hprt (hypoxanthine-guanine phosphoribosyl transferase)
Species / strain
- Species / strain / cell type:
- Chinese hamster lung fibroblasts (V79)
- Details on mammalian cell type (if applicable):
- - Type and identity of media: MEM (minimal essential medium) containing Hank’s salts supplemented with 10% foetal bovine serum (FBS), neomycin (5 µg/mL) and amphotericin B (1%).
- Properly maintained: yes
- Periodically checked for Mycoplasma contamination: yes
- Periodically checked for karyotype stability: yes
- Periodically checked for spontaneus mutant frequency: yes
- Metabolic activation:
- with and without
- Metabolic activation system:
- Phenobarbital/ß-naphthoflavone induced rat liver S9
- Test concentrations with justification for top dose:
- Experiment I:
4 hours, with and without S9 mix: 0.7, 2.0, 6.0, 18.0, 54.0, (162.0) µg/ml
Experiment II:
24 hours, without S9 mix: (0.7), 2.0, 6.0, 18.0, 54.0, 162.0 µg/ml
4 hours, with S9 mix: 0.7, 2.0, 6.0, 18.0, 54.0, (162.0) µg/ml
numbers in parantheses: these cultures were discontinued. - Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: THF (tetrahydrofuran)
Controls
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- 7,12-dimethylbenzanthracene
- ethylmethanesulphonate
- Remarks:
- without S9: EMS, 0.15 mg/ml; with S9: DMBA, 1.1 µg/ml
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in medium
DURATION
- Exposure duration: 4 h (with and without S9), 24h (without S9)
- Expression time (cells in growth medium): 7 days
- Selection time (if incubation with a selection agent): 8 days
- Fixation time (start of exposure up to fixation or harvest of cells): 18 - 20 days
SELECTION AGENT (mutation assays): 11 μg/mL 6-thioguanine
STAIN (for cytogenetic assays): 10% methylene blue in 0.01% KOH solution
NUMBER OF REPLICATIONS: two independent cultures were used
DETERMINATION OF CYTOTOXICITY
- Method: cloning efficiency, cell density - Evaluation criteria:
- A test item is classified as positive if it induces either a concentration-related increase of the mutant frequency or a reproducible and positive response at one of the test points.
A test item producing neither a concentration-related increase of the mutant frequency nor a reproducible positive response at any of the test points is considered non-mutagenic in this system.
A positive response is described as follows:
A test item is classified as mutagenic if it reproducibly induces a mutation frequency that is three times above the spontaneous mutation frequency at least at one of the concentrations in the experiment.
The test item is classified as mutagenic if there is a reproducible concentration-related increase of the mutation frequency. Such evaluation may be considered also in the case that a threefold increase of the mutant frequency is not observed.
However, in a case by case evaluation this decision depends on the level of the corresponding solvent control data. If there is by chance a low spontaneous mutation rate within the laboratory´s historical control data range, a concentration-related increase of the mutations within this range has to be discussed. The variability of the mutation rates of solvent controls within all experiments of this study was also taken into consideration. - Statistics:
- A linear regression (least squares) was performed to assess a possible dose dependent increase of mutant frequencies. The number of mutant colonies obtained for the groups treated with the test item were compared to the solvent control groups. A trend is judged as significant whenever the p-value (probability value) is below 0.05. However, both, biological and statistical significance was considered together.
Results and discussion
Test results
- Species / strain:
- Chinese hamster lung fibroblasts (V79)
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity, but tested up to precipitating concentrations
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Precipitation: Precipitation, visible to the unaided eye, was noted in experiment I at 18.0 μg/mL and above with and without metabolic activation. In experiment II precipitation occurred at 54.0 μg/mL and above without and at 18.0 μg/mL and above with metabolic activation.
RANGE-FINDING/SCREENING STUDIES:
No relevant toxic effect occurred up to the maximum concentration with and without metabolic activation following 4 and 24 hours treatment. An isolated reduction of the cloning efficiency noted at 1155 μg/mL following 4 hours treatment without metabolic activation was judged as precipitation artefact as there was no dose dependent cytotoxicity. The test medium was checked for precipitation or phase separation at the end of each treatment period (4 or 24 hours) prior to removal to the test item. Precipitation occurred at 18.0 μg/mL and above with and without metabolic activation after 4 and 24 hours treatment. In the pre-experiment there was no relevant shift of osmolarity and pH values of the medium even at the maximum concentration of the test item. Based on precipitation of the test item noted in the pre-experiment, the concentration range of the main experiments was selected.
COMPARISON WITH HISTORICAL CONTROL DATA:
The mutation frequency did not exceed the historical range of solvent controls.
ADDITIONAL INFORMATION ON CYTOTOXICITY:
No relevant cytotoxic effects indicated by a relative cloning efficiency I or cell density below 50% in both parallel cultures occurred in experiment I and II up to the maximum concentration with and without metabolic activation following 4 and 24 hours treatment. - Remarks on result:
- other: all strains/cell types tested
- Remarks:
- Migrated from field 'Test system'.
Any other information on results incl. tables
Summary of Results
concentration (µg/ml) | P | S9 Mix | relative cloning efficiency I (%) | relative cell density (%) | relative cloning efficiency II (%) | mutant colonies / 106cells | induction factor | relative cloning efficiency I (%) | relative cell density (%) | relative cloning efficiency II (%) | mutant colonies / 106cells | induction factor | |
Experiment I / 4h treatment | culture I | culture II | |||||||||||
solvent control (DMSO) | - | 100.0 | 100.0 | 100.0 | 15.0 | 1.0 | 100.0 | 100.0 | 100.0 | 18.6 | 1.0 | ||
positive control (EMS) | 150.0 | - | 81.8 | 103.1 | 85.3 | 144.7 | 9.6 | 83.7 | 140.4 | 105.6 | 67.6 | 3.6 | |
test item | 0.7 | - | 98.5 | 110.7 | 98.0 | 18.9 | 1.3 | 105.0 | 134.2 | 101.2 | 9.9 | 0.5 | |
test item | 2.0 | - | 85.1 | 100.2 | 93.6 | 15.5 | 1.0 | 95.7 | 126.3 | 103.3 | 14.1 | 0.8 | |
test item | 6.0 | - | 86.0 | 94.5 | 98.7 | 31.9 | 2.1 | 94.4 | 134.0 | 103.2 | 11.2 | 0.6 | |
test item | 18.0 | P | - | 89.1 | 166.1 | 106.4 | 13.4 | 0.9 | 102.8 | 137.8 | 100.5 | 14.9 | 0.8 |
test item | 54.0 | P | - | 77.1 | 108.7 | 93.0 | 14.8 | 1.0 | 70.3 | 132.1 | 102.3 | 13.9 | 0.7 |
test item | 162.0 | P | - | 36.6 | culture was not continued# | 45.5 | culture was not continued# | ||||||
solvent control (DMSO) | + | 100.0 | 100.0 | 100.0 | 13.6 | 1.0 | 100.0 | 100.0 | 100.0 | 9.7 | 1.0 | ||
positive control (DMBA) | 1.1 | + | 52.1 | 109.8 | 88.2 | 764.5 | 56.1 | 53.9 | 112.0 | 83.6 | 647.7 | 66.7 | |
test item | 0.7 | + | 103.7 | 92.6 | 97.6 | 16.1 | 1.2 | 95.0 | 92.4 | 92.2 | 18.7 | 1.9 | |
test item | 2.0 | + | 98.9 | 90.0 | 107.3 | 10.2 | 0.7 | 98.9 | 108.8 | 98.2 | 31.1 | 3.2 | |
test item | 6.0 | + | 96.3 | 100.2 | 87.4 | 13.4 | 1.0 | 100.0 | 113.1 | 91.6 | 18.2 | 1.9 | |
test item | 18.0 | P | + | 107.8 | 100.5 | 97.0 | 12.3 | 0.9 | 99.7 | 115.0 | 90.9 | 16.8 | 1.7 |
test item | 54.0 | P | + | 89.4 | 77.2 | 92.8 | 9.7 | 0.7 | 99.2 | 105.7 | 88.2 | 19.3 | 2.0 |
test item | 162.0 | P | + | 98.3 | culture was not continued# | 90.1 | culture was not continued# | ||||||
Experiment II / 24h treatment | |||||||||||||
solvent control (DMSO) | - | 100.0 | 100.0 | 100.0 | 12.3 | 1.0 | 100.0 | 100.0 | 100.0 | 8.9 | 1.0 | ||
positive control (EMS) | 150.0 | - | 92.8 | 79.9 | 89.0 | 394.0 | 31.9 | 96.9 | 249.6 | 76.8 | 222.8 | 25.0 | |
test item | 0.7 | - | 98.9 | culture was not continued## | 96.4 | culture was not continued## | |||||||
test item | 2.0 | - | 99.2 | 79.8 | 83.3 | 10.9 | 0.9 | 97.2 | 252.6 | 74.7 | 23.3 | 2.6 | |
test item | 6.0 | - | 99.4 | 99.6 | 101.8 | 17.3 | 1.4 | 91.3 | 214.1 | 77.1 | 14.0 | 1.6 | |
test item | 18.0 | - | 86.8 | 59.7 | 94.4 | 15.1 | 1.2 | 79.7 | 192.5 | 85.6 | 12.0 | 1.3 | |
test item | 54.0 | P | - | 82.5 | 87.1 | 101.9 | 6.6 | 0.5 | 75.8 | 231.8 | 87.0 | 17.6 | 2.0 |
test item | 162.0 | P | - | 58.6 | 46.5 | 98.5 | 19.4 | 1.6 | 60.4 | 144.2 | 81.6 | 13.2 | 1.5 |
Experiment II / 4h treatment | |||||||||||||
solvent control (DMSO) | + | 100.0 | 100.0 | 100.0 | 18.8 | 1.0 | 100.0 | 100.0 | 100.0 | 12.0 | 1.0 | ||
positive control (DMBA) | 1.1 | + | 56.8 | 83.7 | 82.6 | 418.8 | 22.2 | 55.4 | 49.0 | 77.6 | 554.9 | 46.3 | |
test item | 0.7 | + | 97.7 | 87.3 | 78.5 | 11.1 | 0.6 | 99.8 | 92.6 | 100.7 | 11.6 | 1.0 | |
test item | 2.0 | + | 97.9 | 96.1 | 107.4 | 15.1 | 0.8 | 98.0 | 78.0 | 100.0 | 9.2 | 0.8 | |
test item | 6.0 | + | 96.5 | 97.5 | 89.0 | 12.9 | 0.7 | 99.8 | 82.1 | 89.4 | 13.0 | 1.1 | |
test item | 18.0 | P | + | 98.2 | 102.7 | 88.5 | 18.3 | 1.0 | 96.3 | 104.0 | 95.9 | 14.8 | 1.2 |
test item | 54.0 | P | + | 95.2 | 73.9 | 83.3 | 12.0 | 0.6 | 94.8 | 66.3 | 93.0 | 9.5 | 0.8 |
test item | 162.0 | P | + | 94.4 | culture was not continued# | 85.2 | culture was not continued# |
P Precipitation
# culture was not continued to avoid analysis of too many precipitating concentrations
## culture was not continued as a minimum of only four analysable concentrations is required
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information):
negative
In conclusion it can be stated that under the experimental conditions reported the test item did not induce gene mutations at the HPRT locus in V79 cells and is therefore considered to be non-mutagenic in this HPRT assay. - Executive summary:
In a GLP-compliant genotoxicity study according to OECD guideline 476 the test item was assessed for its potential to induce gene mutations at the HPRT locus using V79 cells of the Chinese hamster. The study was performed in two independent experiments, using identical experimental procedures. In the first experiment the treatment period was 4 hours with and without metabolic activation. The second experiment was performed with a treatment time of 4 hours with and 24 hours without metabolic activation. The highest concentration of 2310 μg/mL used in the pre-experiment was limited by the solubility properties of the test item. The concentration range of the main experiments (0.7 – 162 µg/ml) was limited by precipitation of the test item. The test item was dissolved in THF. Precipitation, visible to the unaided eye, was noted in experiment I at 18.0 μg/mL and above with and without metabolic activation. In experiment II precipitation occurred at 54.0 μg/mL and above without and at 18.0 μg/mL and above with metabolic activation.
No relevant cytotoxic effects indicated by a relative cloning efficiency I or cell density below 50% in both parallel cultures occurred in experiment I and II up to the maximum concentration with and without metabolic activation following 4 and 24 hours treatment. No relevant and reproducible increase in mutant colony numbers/106 cells was observed in the main experiments up to the maximum concentration. The mutation frequency did not exceed the historical range of solvent controls. The induction factor exceeded the threshold of three times the corresponding solvent control in the second culture of the first experiment at 2.0 μg/mL with metabolic activation. The effect however, was based on a rather low solvent control of 9.7 mutant colonies/106 cells and has no biological relevance as it was neither dose dependent as indicated by the lacking statistical significance nor reproduced in the parallel culture. In both experiments of this study (with and without S9 mix) the range of the solvent controls was from 8.9 up to 18.8 mutants per 106 cells; the range of the groups treated with the test item was from 6.6 up to 31.9 mutants per 106 cells. EMS (150 μg/mL) and DMBA (1.1 μg/mL) were used as positive controls and showed a distinct increase in induced mutant colonies. In conclusion it can be stated that under the experimental conditions reported the test item did not induce gene mutations at the HPRT locus in V79 cells and is therefore considered to be non-mutagenic in this HPRT assay.
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