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EC number: 430-500-8 | CAS number: 204277-61-2
- 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 cytogenicity / chromosome aberration study in mammalian cells
- Remarks:
- Type of genotoxicity: chromosome aberration
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 26 October 1998 to 10 February 1999.
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP methodology followed and OCED guideline 473 used to performed the experiment.
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 999
- Report date:
- 1999
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 473 (In Vitro Mammalian Chromosome Aberration Test)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: EEC Directive 92/69, L 383 A, Annexe V, B 10, dated December 29, 1992
- Deviations:
- no
- Principles of method if other than guideline:
- None
- GLP compliance:
- yes
- Type of assay:
- in vitro mammalian chromosome aberration test
Test material
- Reference substance name:
- -
- EC Number:
- 430-500-8
- EC Name:
- -
- Cas Number:
- 204277-61-2
- Molecular formula:
- Hill formula: C23 H23 Cl N6 O8 CAS formula: C23 H23 Cl N6 O8
- IUPAC Name:
- methyl 2-({4-[2-(2-chloro-6-cyano-4-nitrophenyl)diazen-1-yl]-5-acetamido-2-methoxyphenyl}(2-methoxy-2-oxoethyl)amino)propanoate
- Test material form:
- other: solid
- Details on test material:
- None
Constituent 1
Method
- Target gene:
- Not applicable
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)
- Properly maintained: yes
- Periodically checked for Mycoplasma contamination: yes
- Periodically checked for karyotype stability: yes
- Metabolic activation:
- with and without
- Metabolic activation system:
- The S9 liver microsomal fraction was obtained from the livers of 8 - 12 weeks old male rats, strain Wistar Hanlbm.
- Test concentrations with justification for top dose:
- Pre-test:
Without S9 mix (4 hours and 24 hours exposure): 3.9 / 7.8 / 15.6 / 31.3 / 62.5 / 125.0 / 250.0 / 500 .0 microgr/ml.
With S9 mix (4 hours exposure; Rounded concentration due to technical reasons): 2 / 4 / 8 / 16 / 31 / 63 / 125 / 250 microgr/ml
Experiment I:
Without S9 mix (4 hours exposure): 7.5 / 15.0 / 30.0 / 60.0 / 90.0 / 120.0 microgr/ml.
With S9 mix (4 hours exposure): 7.5 / 15.0 / 30.0 / 60.0 / 90.0 / 120.0 microgr/ml
Experiment II:
Without S9 mix (continuous exposure 18 hours): 0.63 / 1.25 / 2.50 / 5.00 / 10.0 / 20.0 microg/ml (continuous exposure 28 hours): 0.63 / 1.25 / 2.50 / 5.00 / 10.0 / 20.0 microgr/ml.
With S9 mix (4 hours exposure): 3.8 / 7.5 / 15.0 / 30.0 / 60.0 / 90.0 microgr/ml. - Vehicle / solvent:
- - Vehicle /solvent used: FAT 41024/B was dissolved in DMSO
On the day of the experiment (immediately before treatment), the test article was dissolved in DMSO (E. MERCK, D-64293 Darmstadt; purity 99.5 %). The final concentration of DMSO in the culture medium did not exceed 1 % (v/v). The solvent was chosen to its solubility properties and its relative nontoxicity to the cell cultures.
Controls
- Untreated negative controls:
- yes
- Remarks:
- Concurrent negative (culture medium) and solvent controls (DMSO) were performed.
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- cyclophosphamide
- ethylmethanesulphonate
- Remarks:
- EMS (without metabolic activation); CPA (with metabolic activation)
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in medium
DURATION
- Exposure duration:4 / 18 and 28 hours
NUMBER OF REPLICATIONS: 2 cultures in paralell
NUMBER OF CELLS EVALUATED:
Per culture 100 metaphase plates were scored for structural chromosome aberrations. - Evaluation criteria:
- A test article is classified as non-mutagenic if:
- the number of induced structural chromosome aberrations in all evaluated dose groups are in the range of our 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 article is classified as mutagenic if:
- the number of induced structural chromosome aberrations are not in the range of our 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. - Statistics:
- Statistical significance was confirmed by means of the Fischer's exact test (10) (p < 0.05). However, both biological and statistical significance should be considered together. If the a.m. criteria for the test article are not clearly met, the classification with regard to the historical data and the
biological relevance is discussed and/or a confirmatory experiment is performed.
Results and discussion
Test results
- Species / strain:
- Chinese hamster lung fibroblasts (V79)
- Metabolic activation:
- with and without
- Genotoxicity:
- ambiguous
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- None
- Remarks on result:
- other: all strains/cell types tested
- Remarks:
- Migrated from field 'Test system'.
Any other information on results incl. tables
The test article FAT 41024/B, dissolved in DMSO, was assessed for its potential to induce structural chromosome aberrations in V79 cells of the Chinese hamster in vitro in the absence and presence of metabolic activation by S9 mix. Two independent experiments
were performed. The chromosomes were prepared 18 h (exp. I and II) and 28 h (exp. II) after start of treatment with the test article. In experiment I the exposure period was 4 h with and without metabolic activation. In experiment II the exposure period was 4 h with
metabolic activation, 18 h and 28 h without metabolic activation. In each experimental group two parallel cultures were set up. Per culture 100 metaphase plates were scored for structural chromosome aberrations.
The applicable concentration range of the test article for the cytogenetic experiments was determined in a range finder experiment using the reduction of cell numbers 24 h after start of treatment as indicator for cytotoxicity. The highest applied concentration in this pre-test
(500 ug/ml) was chosen with regard to the solubility properties of the test article and the current OECD Guideline for in vitro mammalian cytogenetic tests. Test article concentrations between 3.9 - 500 ug/ml (without S9 mix) and 1.9 - 250 ug/ml (with S9
mix) were chosen for the assessment of the cytotoxic potential. In the range finding experiment, toxic effects indicated by reduced cell numbers below 50 % of control were observed after 4 h treatment with 125 ug/ml in the absence of S9 mix (see table 4, page 24).
In addition, strongly reduced cell numbers were observed after 24 h continuous treatment with 15.6 ug/ml. In the presence of S9 no clear dose related toxicity was observed.
Precipitation of the test article in culture medium was observed after treatment with 62.5 ug/ml and above in the absence and 31.3 ug/ml and above in the presence of S9 mix. No influence of the test article on the pH value or osmolarity was observed (solvent control:
367 mOsm, pH 7.3 versus 394 mOsm and pH 7.3 at 500 ug/ml).
Toxic effects indicated by clearly reduced mitotic indices were observed in the absence of 59 mix after continuous treatment with 20 ug/ml (18 h: 43.9 % of control) and 10 ug/ml (28 h: 49.3 % of control). In the presence of S9 mix after 4 h treatment with 90 ug/ml the mitotic index was reduced at interval 28 h (39.4 % of control). In addition, reduced cell numbers were observed in the absence of S9 mix after 4 h treatment with 15, 30 and 60 ug/ml (58, 52 and 50 % of control). However, with the next higher concentrations (90 ug/ml and 120 ug/ml) lower reductions were found (57 and 69 % of control). This observation can be explained by different sizes of the precipitate, influencing the uptake of the precipitate by phagocytosis. In the presence of S9 mix the cell numbers were reduced at
both preparation intervals after treatment with 90 ug/ml (18 h: 50 % of control; 28 h: 54 % of control). However, in experiment I at interval 18 h, the next higher concentration (120 ug/ml) revealed higher cell numbers (70 % of control).
In experiment I, at preparation interval 18 h in the absence of S9 mix, the aberration frequency after treatment with 30 ug/ml was significantly increased to 4.0 % aberrant cells exclusive gaps. Since the increase was non dose related, within our historical control data range (0 - 4 % of control) and at a concentration exhibiting precipitation, the biological relevance is questionable. However, after 28 h continuos treatment in the absence of S9 mix a clearly dose related increase was observed after treatment with 0.0, 2.5, 5 and
10 ug/ml (1.0, 1.5, 3.0 and 9.0 % aberrant cells exclusive gaps). After 18 h continuous treatment no effect was observed.
In the presence of S9 mix only in experiment I significantly increased aberration frequencies beyond our historical control data range were observed. Evaluation of cultures after treatment with 30 and 90 ug/ml revealed slightly increased aberration frequencies (6.5 and 4.5 % aberrant cells exclusive gaps). In addition, a dose related increase was observed at experimental points without reduced cell numbers. Cultures after treatment with 0.0, 7.5, 15 and 30 ug/1 revealed a dose related increase in the number of aberrant cells exclusive gaps (1.0, 1.5, 3.0 and 6.5 % aberrant cells). The decrease after treatment with 90 ug/ml (4.5 % aberrant cells) might be caused by toxicity observed at this experimental point. However, the increase in the number of cells carrying exchanges after treatment with 30 and 90 ug/ml (3.5 % and 2.0 % aberrant cells) gives additional evidence for a clastogenic potential.
At interval 28 h in the presence of S9 mix, no increase was observed. The reason might be the late preparation interval. Aberrations, leading to cell death were not detected. Another point, which should be considered is the occurrence of aberrant cells only in the presence of precipitation (with S9 mix) or at the border of precipitation (without S9 mix). However, although the increased aberration frequencies were not reproduced, the overall assessment of the test article must be weakly clastogenic.
In both experiments, EMS (600 ug/ml and 800 ug/ml) and CPA (0.71 ug/ml) were used as positive controls and showed distinct increases in cells with structural chromosome aberrations.
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information):
positive weakly mutagenic
In conclusion, it can be stated that in the study described and under the experimental conditions reported, the test article FAT 41'024/B induced structural chromosome aberrations in V79 cells (Chinese hamster cell line). - Executive summary:
This in vitro assay was performed to assess the potential of FAT 41024/B to induce structural chromosome aberrations. Evaluation of cytogenetic damage induced in V79 cells (cell line from the lung of the Chinese Hamster) in the absence and the presence of metabolic activation was performed in two independent experiments at one preparation interval (18 h) in experiment I and two preparation intervals (18 h and 28 h) in experiment II.
The experiment was performed according to the OECD Guideline 473 (In vitro Mammalian Chromosome Aberration Test) and follows GLP methodology.
The test article FAT 41024/B, dissolved 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. Following study design was performed:
Without S9 -mix Without S9 -mix Without S9 -mix With S9 -mix With S9 -mix Exp. I Exp. II Exp.II Exp. I Exp II Exposure period 4 h 18 h 28 h 4 h 4 h Recovery 14 h - - 14 h 24 h Preparation interval 18 h 18 h 28 h 18 h 28 h In each experimental group two parallel cultures were set up. Per culture 100 metaphase plates were scored for structural chromosome aberrations.
The highest applied concentration in the range finder was chosen with regard to the solubility properties of the test article. Dose selection of the cytogenetic experiments was performed considering the toxicity data and the occurrence of precipitation.
Toxic effects indicated by clearly reduced mitotic indices were observed in the absence of S9 mix after 18 h (20 ug/ml) and 28 h (10 ug/ml) continuous treatment and in the presence of S9 mix after 4 h treatment with 90 ug/ml at interval 28 h . In addition, reduced cell numbers were observed in the absence of S9 mix after 4 h treatment with 1 5 - 6 0 ug/ml and in the presence of S9 mix after treatment with 90 ug/ml.
In the absence of S9 mix, a clearly dose related increase in the number of structural aberrations was observed after 28 h continuous treatment. In the presence of S9 mix slightly but dose related increased aberration frequencies were observed at interval 18 h at concentrations exhibiting precipitation only. These effects were not observed at interval 28 h.
In this study, no increase in the frequencies of polyploid metaphases was found after treatment with the test article as compared to the frequencies of the controls. Appropriate mutagens were used as positive controls. They induced statistically significant
increases (p < 0.05) in cells with structural chromosome aberrations.
Conclusion
In conclusion, it can be stated that in the study described and under the experimental conditions reported, the test article did induce structural chromosome aberrations as determined by the chromosome aberration test in V79 cells (Chinese hamster cell line) in
vitro.
Therefore, FAT 41'024/B is considered to be mutagenic, (weakly mutagenic), in this chromosome aberration test.
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