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EC number: 617-560-2 | CAS number: 84377-83-3
- 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
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 01 August - 27 November 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 018
- Report date:
- 2018
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 473 (In Vitro Mammalian Chromosome Aberration Test)
- Version / remarks:
- Adopted 29 July 2016
- Deviations:
- yes
- Remarks:
- Validity, integrity and result of the study were not affected by the deviations from study plan
- Qualifier:
- according to guideline
- Guideline:
- other: Japanese Ministry of Health, Labour and Welfare (MHLW), Ministry of Economy Trade and Industry (METI) and Ministry of the Environment (MOE) Guidelines
- Version / remarks:
- 31 March 2011
- Deviations:
- no
- Principles of method if other than guideline:
- The required number of cells and concentrations were analyzed except for the ‘A’ culture for the positive control in the 4(20)-hour exposure group in the absence of S9-mix. An
additional 62 cells were scored for chromosomal damage a due to a poor positive response in the first 150 cells. Therefore a total of 212 cells were analyzed.
This unplanned deviation is thought not to affect the validity, integrity or the result of the study - GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- in vitro mammalian chromosome aberration test
Test material
- Reference substance name:
- 1-{[(6R,7R)-7-[(2Z)-2-({[1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl]oxy}imino)-2-{2-[(triphenylmethyl)amino]-1,3-thiazol-4-yl}acetamido]-2-carboxylato-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}pyridin-1-ium
- EC Number:
- 617-560-2
- Cas Number:
- 84377-83-3
- Molecular formula:
- C45H44O7S2.5/2(C3H7NO)
- IUPAC Name:
- 1-{[(6R,7R)-7-[(2Z)-2-({[1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl]oxy}imino)-2-{2-[(triphenylmethyl)amino]-1,3-thiazol-4-yl}acetamido]-2-carboxylato-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}pyridin-1-ium
- Reference substance name:
- N,N-dimethylformamide
- EC Number:
- 200-679-5
- EC Name:
- N,N-dimethylformamide
- Cas Number:
- 68-12-2
- Molecular formula:
- C3H7NO
- IUPAC Name:
- N,N-dimethylformamide
- Test material form:
- solid: particulate/powder
Constituent 1
additive 1
Method
- Target gene:
- Not relevant - The study examined gross chromosomal aberrations
Species / strain
- Species / strain / cell type:
- lymphocytes: human
- Details on mammalian cell type (if applicable):
- Donor for Preliminary toxicity test: male, aged 28 years
Donor for Main Experiment: female, aged 23 years
non-smokers and not knowingly exposed to high levels of radiation or hazardous chemicals and not knowingly recently suffered from a viral infection - Additional strain / cell type characteristics:
- not applicable
- Metabolic activation:
- with and without
- Metabolic activation system:
- S9-mix Microsomal enzyme fractions
- Test concentrations with justification for top dose:
- Preliminary toxicity test: 0, 9.77, 19.53, 39.06, 78.13, 156.25, 312.5, 625, 1250 and 2500 μg/ml
Main experiment: 0, 8 (not for the 24h exposure without S9), 16, 32, 64, 128, (192 only for 24h exposure without S9-mix), 256 and 320 μg/ml
Dose levels for the main test were selected after the results of the preliminary one. Mitotic index data was used to estimate the test item toxicity.
Maximum dose for the Preliminary Toxicity Test was the maximum achievable concentration. - Vehicle / solvent:
- DMSO
Controls
- Negative solvent / vehicle controls:
- yes
- Remarks:
- DMSO
- Positive controls:
- yes
- Positive control substance:
- cyclophosphamide
- mitomycin C
- Details on test system and experimental conditions:
- Duplicate lymphocyte cultures (A and B) were established for each dose level by mixing the following components, giving, when dispensed into sterile plastic flasks for each culture:
9.05 ml minimal essential medium (MEM) and 10% foetal bovine serum (FBS), 0.1 ml Li-heparin, 0.1 ml phytohaemaglutinin, 0.75 ml heparinised whole blood.
Three exposure groups were used in the Preliminary Toxicity Test:
i) 4h exposure to the test item without S9 mix, followed by a 20h recovery period in treatment-free media
ii) 4h exposure to the test item with S9 mix (2%), followed by a 20h recovery period in treatmentt-free media
iii) 24h continuous exposure to the test item without S9-mix
The preliminary toxicity test was performed using all three of the exposure conditions as described for the main experiment, but using single cultures only.
Three exposure groups were used for the Main Experiment:
i) 4h exposure to the test item without S9-mix, followed by 20h culture in treatment-free media prior to cell harvest.
ii) 4h exposure to the test item with S9-mix (2%), followed by 20h culture in treatment-free media prior to cell harvest.
iii) 24h continuous exposure to the test item without S9-mix prior to cell harvest - Evaluation criteria:
- Data evaluation
The following criteria were used to determine a valid assay:
- The frequency of cells with structural chromosome aberrations (excluding gaps) in the vehicle control cultures was within the laboratory historical control data range
- All the positive control chemicals induced a positive response (p<=0.01) and demonstrated the validity of the experiment and the integrity of the S9-mix
- The study was performed using all three exposure conditions using a top concentration which meets the requirements of the current testing guideline
- The required number of cells and concentrations were analysed except for the 'A' culture for the positive control in the 4(20)-hour in the absence of S9-mix where 212 cells were analysed due to a poor positive response in the first 150 cells.
Criteria for determining the study conclusion
Provided that all acceptibility criteria are fulfilled, a test item can be considered to be clearly negative if, in any of the experimental conditions examined:
1) The number of cells with structural aberrations in all evaluated dose groups is within the range of the laboratory historical control data
2) No toxicologically or statistically significant increase of the number of cells with structural chromosome aberrations is observed following statistical analysis
3) There is no concentration-related increase at any dose level
A test item can be classified as genotoxic if:
1) The number of cells with structural chromosome aberrations is outside the range of the laboratory historical control data
2) At least one concentration exhibits a statistically significant increase in the number of cells with structural chromosome aberrations compared to the concurrent negative control
3) The observed increase in the frwquency of cells with structural aberrations is considered to be dose-related
When all of the above criteria are met, the test item can be considered able to induce chromosomal aberrations in human lymphocytes - Statistics:
- The frequency of cells with aberration excluding gaps and the frequency of polyploid cells was compared, where necessary, with the concurrent vehicle control value using Fisher's Exact test (Richardson et al. 1989). A toxicologically significant response is recorded when the p value, calculated from the statistical analysis of the frequency of cells with aberrations excluding gaps, is less than 0.05 when compared to its concurrent control and there is a dose-related increase in the frequency of cells with aberrations which is reproducible, Incidences where marked statistically significant increases are observes only with gap-type aberrations were assessed on a case by case basis.
Results and discussion
Test results
- Key result
- Species / strain:
- lymphocytes: human
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Remarks:
- up to 320 μg/ml
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Additional information on results:
- Precipitate observations were made at the end of exposure in blood-free cultures and was noted at and above 256 μg/ml levels in the 4(20)-h exposures with and without S9, whereas precipitate were present at and above 192 μg/ml in the 24h continuous exposure group. No haemolysis was observed in any of the exposure groups, either with or without S9-mix.
In the 4(20)-h exposures with and without S9, no dose-related inhibitions of mitotic index were observed. The maximum dose level selected for metaphase analysis was, therefore, the lowest precipitating dose level for both exposure groups (256 μg/ml). In the 24h continuous exposure group, a dose related inhibition of mitotic index was noted, where 13%, 32% and 50% Mitotic Inhibition was observed at 64, 128 and 192 μg/ml respectively. Therefore, maximum dose level selected for metaphase analysis was 192 μg/ml, as this achieved optimum toxicity as defined by the OECD Guideline 473 (55+/- 5%) and was the lowest precipitating dose level
The test item did not induce any statistically significant increases in the frequency of cells with aberrations either in the absence or presence of metabolic activation.
The test item did not induce any polyploid cells at any dose level in any of the exposure groups.
Any other information on results incl. tables
- The frequency of cells with chromosome aberrations (excluding gaps) in the vehicle control cultures were within the current historical control data range
- All the positive control chemicals induced a demonstrable positive response (p <= 0.01) and confirmed the validity and sensitivity of the assay and the integrity of the S9-mix
- The study was performed using all three exposure conditions using a top concentration which meets the requirements of the current testing guideline
- The required number of cells and concentrations were analysed except for the 'A' culture for the positive control in the 4(20)-h in the absence of S9 -mix where 212 cells were analysed due to a poor positive response in the first 150 cells.
The assay was considered valid as it met all of the following criteria:
For detailed results, please refer to the attached document CQ_CA_tables and figures.pdf
Applicant's summary and conclusion
- Conclusions:
- The substance did not induce a statistically significant increase in the frequency of cells with chromosome aberrations, in ehtier the absence or presence of a liver enzyme metabolising system. The test item was, therefore, considered to be non-clastogenic to the human lymphocytes in vitro.
- Executive summary:
1.1 Introduction
This report describes the results of an in vitro study for the detection of structurla chromosomal aberrations in cultured mammalian cells. It supplements microbial systams insofar as it identifies potential mutagens that produce chromosomal aberrations rather than gene mutations.
1.2 Methods
Duplicate cultures of human lymphocytes, treated with the test item, were evaluated for chromosome aberrations at three dose levels, together with vehicle and positive controls. In this study, three exposure conditions were investigated; 4 hours exposure in the presence of an induced rat liver homogenate metabolising system (S9), at a 2% final concentration with cell harvest after a 20 -hour expression period, 4 hours exposure in the absence of metabolic activation (S9) with a 20 -hour expression period and a 24 -hour exposure in the absence of metabolic activation.
The dose levels used in the Main Experiment were selected using data from the preliminary toxicity test where the results indicated that the maximum concentration should be limited on precipitate to 320 μg/ml. The dose levels selected for the Main Test were as follows:
- Group 4(20)-hour with and without S9: 0, 8, 16, 32, 64, 128, 256, 320 μg/ml
- Group 24 -hour without S9: 0, 16, 32, 64, 128, 192, 256, 320 μg/ml
1.3 Results
All vehicle (dimethyl sulfoxide (DMSO)) controls had frequencies of cells with aberrations within the range expected for normal human lymphocytes. All the positive control items induced statistically significant increases in the frequency of cells with aberrations. Thus, the sensitivity of the assay and the efficacy of the S9 -mix were validated.
The test item was toxic to human lymphocytes but did not induce any statistially significant increases in the frequency of cells with aberrations, using a dose range that included a dose level that was the lowest precipitating dose level.
1.4 Conclusion
The test item, Substance CQ, was considered to be non-clastogenic to human lymphocytes in vitro.
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