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EC number: 217-057-4 | CAS number: 1732-08-7
- 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 bacteria
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 16 November 2017 - 11 January 2018
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- Study performed according to OECD test guideline No. 471 and in compliance with GLP.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 018
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Version / remarks:
- Adopted on 21st July 1997
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.13/14 (Mutagenicity - Reverse Mutation Test Using Bacteria)
- Deviations:
- no
- Principles of method if other than guideline:
- Not applicable
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- French GLP Compliance Programme for chemical products (inspected on 13-15 April 2016 / signed on 02 November 2016)
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- Dimethyl heptanedioate
- EC Number:
- 217-057-4
- EC Name:
- Dimethyl heptanedioate
- Cas Number:
- 1732-08-7
- Molecular formula:
- C9H16O4
- IUPAC Name:
- 1,7-dimethyl heptanedioate
- Test material form:
- liquid
- Details on test material:
- Name: Dimethyl Pimelate
Batch no.: 1601070000
Appearance: Oily liquid, colorless
CAS No.: 1732-08-7
EINECS-No.: 217-057-4
Molecular formula: C9H16O4
Purity: 98.54 % w/w
Production date: 04 Jul. 2016
Expiry date: 01. Aug. 2019
Storage: Fridge (2-8°C), keep away from humidity
Constituent 1
Method
- Target gene:
- S. typhimurium: Histidine gene
Species / strainopen allclose all
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102
- Details on mammalian cell type (if applicable):
- not applicable
- Additional strain / cell type characteristics:
- not applicable
- Species / strain / cell type:
- S. typhimurium TA 100
- Remarks:
- Third experiment
- Details on mammalian cell type (if applicable):
- not applicable
- Additional strain / cell type characteristics:
- not applicable
- Cytokinesis block (if used):
- No
- Metabolic activation:
- with and without
- Metabolic activation system:
- Rat liver S9-mix (10% v/v)
- Test concentrations with justification for top dose:
- Preliminary test: with and without S9-mix: 10, 100, 500, 1000, 2500 and 5000 µg/plate ; direct plate incorporation method (tested in the TA 98, TA 100 and TA 102 strains, one plate/dose level)
First test: with and without S9-mix: 312.5, 625, 1250, 2500 and 5000 µg/plate ; direct plate incorporation method
Second test: without S9-mix: 312.5, 625, 1250, 2500 and 5000 µg/plate ; direct plate incorporation method / with S9-mix: 156.3, 312.5, 625, 1250, 2500 and 5000 µg/plate ; pre-incubation method
Third test: with S9-mix: 156.3, 312.5, 625, 1250, 2500 and 5000 µg/plate ; direct plate incorporation method and pre-incubation method
The highest dose level will be selected according to the following criteria specified in international regulations and on the basis of the data obtained in the preliminary toxicity test:
- for non-toxic, freely soluble test items, the highest dose level will be 5000 μg/plate,
- for non-toxic, poorly soluble test items, the highest dose level will be at least the lowest precipitating dose level,
- for toxic test items, irrespective of solubility, the highest dose level will be based on the level of toxicity: clearing of the bacterial lawn and/or reduction in the number of revertants when compared to the vehicle controls. However, precipitation should not interfere with the scoring of the test.
Since the test item was found freely soluble in the final treatment medium and non-toxic in the preliminary test, the highest dose level selected for the main experiments was 5000 µg/plate, according to the criteria specified in the international guidelines. - Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: dimethylsulfoxide (DMSO)
- Justification for choice of solvent/vehicle: Not specified
Controlsopen allclose all
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- sodium azide
- Remarks:
- Without S9 mix, 1 µg/plate in DMSO for strains TA100 and TA1535
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- 9-aminoacridine
- Remarks:
- Without S9 mix, 50 µg/plate in DMSO for strain TA1537
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- 2-nitrofluorene
- Remarks:
- Without S9 mix, 0.5 µg/plate in DMSO for strain TA98
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- mitomycin C
- Remarks:
- Without S9 mix, 0.5 µg/plate in water for strain TA102
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: 2-Anthramine
- Remarks:
- With S9 mix, 2 µg/plate in DMSO for strains TA1535, TA1537 and TA98
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: 2-Anthramine
- Remarks:
- With S9 mix, 20 µg/plate in DMSO for strain TA102
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- benzo(a)pyrene
- Remarks:
- With S9 mix, 5 µg/plate in DMSO for strain TA100
- Details on test system and experimental conditions:
- TEST SYSTEM: The five strains of Salmonella typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102 were supplied by Moltox (Molecular Toxicology, INC, Boone, NC 28607, USA) or Culture Collections (Public Health England, Porton Down, Salisbury, SP4 0JG, UK). These bacterial strains are stored in cryoprotective medium (1 mL nutrient broth and 0.09 mL dimethylsulfoxide) at -80°C. The day before treatment, cultures were inoculated from frozen permanents. Cultures were seeded under sterile conditions into approximately 13 mL of nutrient broth. The nutrient broth was then placed under agitation in an incubator at 37°C for about 12 hours, to produce bacterial suspensions.
METHOD OF APPLICATION: three independent tests
- First test: direct plate incorporation method (with and without S9-mix)
- Second test: direct plate incorporation method (without S9-mix) and pre-incubation method (with S9-mix)
- Third test: direct plate incorporation method and pre-incubation method (with S9-mix for both tests)
DURATION :
- Preincubation period: 60 minutes at 37°C with shaking
- Exposure duration: 48 to 72 hours of incubation at 37°C
NUMBER OF REPLICATIONS: Triplicate plates per dose level.
DETERMINATION OF CYTOTOXICITY
- Method: The evaluation of the toxicity was performed on the basis of the observation of a decrease in the number of revertant colonies and/or a thinning of the bacterial lawn.
ACCEPTANCE CRITERIA:
Each main experiment was considered valid if the following criteria are fully met:
- the mean number of revertants in the vehicle controls is consistent with our historical data, in each strain and test condition,
- at least five analyzable dose levels (i.e. including at least three non-cytotoxic dose levels) are obtained for each strain and test condition,
- the mean number of revertants in the positive controls is higher than that of the vehicle controls (at least 2-fold increase (for the TA 98, TA 100 and TA 102 strains) or at least 3-fold increase (for the TA 1535 and TA 1537 strains)). - Evaluation criteria:
- In all cases, biological relevance (such as reproducibility and reference to historical data) was taken into consideration when evaluating the results.
The test item is considered to have shown mutagenic activity in this study if:
- a reproducible 2-fold increase (for the TA 98, TA 100 and TA 102 strains) or 3-fold increase (for the TA 1535 and TA 1537 strains) in the mean number of revertants compared with the vehicle controls is observed, in any strain, at any dose level,
- and/or a reproducible dose-response relationship is evidenced.
The test item is considered to have shown no mutagenic activity in this study if:
- neither an increase in the mean number of revertants, reaching 2-fold (for the TA 98, TA 100 and TA 102 strains) or 3-fold (for the TA 1535 and TA 1537 strains) the vehicle controls value, is observed at any of the tested dose levels,
- nor any evidence of a dose-response relationship is noted. - Statistics:
- None
Results and discussion
Test resultsopen allclose all
- Key result
- Species / strain:
- S. typhimurium, other: TA 98 and TA 100
- Metabolic activation:
- with
- Genotoxicity:
- positive
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium, other: TA 1535, TA 1537, TA 98, TA 100 and TA 102
- Metabolic activation:
- without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Precipitation: No precipitate was observed in the Petri plates when scoring the revertants at any dose levels, either with or without S9 mix.
RANGE-FINDING/SCREENING STUDIES:
Using a test item concentration of 100 mg/mL in the vehicle (i.e. DMSO) and a treatment volume of 50 µL/plate, the highest recommended dose level of 5000 µg/plate was achievable. Thus, the dose levels selected for the preliminary test were: 10, 100, 500, 1000, 2500 and 5000 µg/plate.
In the absence of S9 mix, no noteworthy toxicity (decrease in the number of revertants or thinning of the bacterial lawn) was noted at any dose levels, in any strains.
In the presence of S9 mix, a moderate thinning of the bacterial lawn was noted at 2500 µg/plate in the TA 98 strain and at 1000 µg/plate in the TA 102 strain. This observation being not dose-related, it was considered not to be biologically relevant and therefore was not taken into consideration for the selection of the highest dose level to be tested in the mutagenicity experiments.
HISTORICAL CONTROL DATA
- The concurrent positive controls verified the sensitivity of the assay and the metabolising activity of the liver preparations. The mean revertant colony counts for the vehicle controls were within or close to the current historical control range for the laboratory.
ADDITIONAL INFORMATION ON CYTOTOXICITY
- Experiments without S9 mix: A moderate toxicity (decrease in the number of revertants or thinning of the bacterial lawn) was noted at 5000 µg/plate in the TA 98 strain in the second experiment, and at dose levels >= 1666.7 µg/plate in the TA 102 strain in both experiments. No other noteworthy toxicity was noted at any dose levels, in any other strains.
- Experiments with S9 mix: A moderate to strong toxicity (thinning of the bacterial lawn) was noted at dose levels >= 1666.7 µg/plate in the TA 98 strain using both the direct plate incorporation and pre-incubation methods and in the TA 1535 and TA 100 strains using the pre-incubation method only. No other noteworthy toxicity was noted at any dose levels, in any other strains or incubation methods.
MUTAGENICITY RESULTS
In the first experiment using the direct plate incorporation method, the test item did not induce any noteworthy increase in the number of revertants at any dose levels, in any of the five strains with or without metabolic activation.
In the second experiment using the pre-incubation method, noteworthy increases in the number of revertants were observed in the TA 98 and TA 100 strains. These increases exceeded the positive threshold of 2-fold the vehicle control value at 5000 µg/plate in the TA 98 strain (3.1-fold the vehicle control value) and at dose levels ≥ 625 µg/plate in the TA 100 strain (up to 6.6-fold the vehicle control value) with an evidence of a dose response relationship. Moreover, the corresponding mean numbers of revertants were above the vehicle control historical range.
A third confirmatory experiment was performed both according to the direct plate incorporation method and pre-incubation method for comparative purposes in the TA 100 strain only.
Using the direct plate incorporation method, the test item did not induce any noteworthy increase in the number of revertants at any dose levels in the TA 100 strain.
Using the pre-incubation method, noteworthy increases in the number of revertants were again observed in the TA 100 strain. These increases exceeded the positive threshold of 2-fold the vehicle control value at dose levels ≥ 625 µg/plate (up to 4.8-fold the vehicle control value) with an evidence of a dose response relationship. Moreover, the corresponding mean numbers of revertants were above the vehicle control historical range.
Since the results obtained with the TA 100 strain in the first and second experiments with S9 mix were reproduced in this third experiment, they were considered to be biologically relevant, and to show a clear positive response using the pre-incubation method. As a consequence, checking for reproducibility of the increase observed in the TA 98 strain in the second experiment with S9 mix was considered unneedful and no additional experiment was undertaken. - Remarks on result:
- other: Evidence of mutagenic activity
- Remarks:
- Only with pre-incubation method
Any other information on results incl. tables
None
Applicant's summary and conclusion
- Conclusions:
- Under the experimental conditions of this study, the test item Dimethyl Pimelate showed a mutagenic activity in the presence of a rat liver metabolizing system using the pre-incubation method in the bacterial reverse mutation test with Salmonella typhimurium strains.
- Executive summary:
In a reverse gene mutation assay performed according to the OECD test guideline No. 471 and the EU Method B.13/14 and in compliance with GLP, several Salmonella typhimurium strains were treated with the test item using the direct plate incorporation method or the pre-incubation method.
A preliminary toxicity test was performed to define the dose levels of Dimethyl Pimelate, diluted in dimethylsulfoxide (DMSO), to be used for the mutagenicity experiments. The test item was then tested in a total of three independent experiments. The two first experiments were performed with and without a metabolic activation system, the S9 mix, prepared from a liver post‑mitochondrial fraction (S9 fraction) of rats induced with Aroclor 1254. A third experiment was then performed with S9 mix.
The preliminary test, both experiments without S9 mix and the first experiment with S9 mix were performed according to the direct plate incorporation method. The second experiment with S9 mix was performed according to the pre-incubation method (i.e.60 minutes). The third experiment with S9 mix was performed both according to the direct plate incorporation method and pre-incubation method for comparative purposes, at the request of the Sponsor.
In the two first experiments, five strains of bacteria Salmonella typhimurium were used: TA 1535, TA 1537, TA 98, TA 100 and TA 102, whereas only the TA 100 strain was used in the third experiment (with S9 mix). Each strain was exposed to at least five dose levels of the test item (three plates/dose level). After 48 to 72 hours of incubation at, the revertant colonies were scored.
The evaluation of the toxicity was performed on the basis of the observation of the decrease in the number of revertant colonies and/or a thinning of the bacterial lawn.
Since the test item was found freely soluble in the final treatment medium and non-toxic in the preliminary test, the highest dose level selected for the main experiments was 5000 µg/plate, according to the criteria specified in the international guidelines.
The mean number of revertants for the vehicle and positive controls met the acceptance criteria. Also, there were at least five analyzable dose levels for each strain and test condition. The study was therefore considered to be valid. No precipitate was observed in the Petri plates when scoring the revertants at any dose levels, either with or without S9 mix.
Experiments without S9 mix:
The selected dose levels were: 312.5, 625, 1250, 2500 and 5000 µg/plate for the five strains, in both experiments. No noteworthy toxicity was noted at any dose levels, in any strains, in either experiment.
The test item did not induce any noteworthy increase in the number of revertants at any dose levels, in any of the five strains, in either experiment. These results met thus the criteria of a negative response.
Experiments with S9 mix:
A moderate toxicity (thinning of the bacterial lawn) was noted at 5000 µg/plate in the TA 1535, TA 98 and TA 102 strains using the pre-incubation method (i.e.in the second experiment). No other noteworthy toxicity was noted in any other strains or test conditions.
- In the first experiment using the direct plate incorporation method, the test item did not induce any noteworthy increase in the number of revertants at any dose levels, in any of the five strains.
- In the second experimentusing the pre-incubation method,noteworthy increases in the number of revertants were observed in the TA 98 and TA 100 strains. These increases exceeded the positive threshold of 2-fold the vehicle control value at 5000 µg/plate in the TA 98 strain (3.1-fold the vehicle control value) and at dose levels ≥ 625 µg/plate in the TA 100 strain (up to 6.6-fold the vehicle control value) with an evidence of a dose-response relationship. Moreover,the corresponding mean numbers of revertants were abovethe vehicle control historical range.
- A third confirmatory experiment was performed both according to the direct plate incorporation method and pre-incubation method for comparative purposes in the TA 100 strain only.
Using the direct plate incorporation method, the test item did not induce any noteworthy increase in the number of revertants at any dose levels in the TA 100 strain.
Using the pre-incubation method, noteworthy increases in the number of revertants were again observed in the TA 100 strain. These increases exceeded the positive threshold of 2-fold the vehicle control value at dose levels ≥ 625 µg/plate (up to 4.8-fold the vehicle control value) with an evidence of a dose‑response relationship. Moreover, the corresponding mean numbers of revertantswere abovethe vehicle control historical range.
Since the results obtained with the TA 100 strain in the first and second experiments with S9 mix were reproduced in this third experiment,they were considered to be biologically relevant, and to show a clear positive response using the pre-incubation method. As a consequence,checking for reproducibility of the increase observed in the TA 98 strain in the second experiment with S9 mix was considered unneedful andno additional experiment was undertaken.
Under the experimental conditions of this study, the test item Dimethyl Pimelate showed a mutagenic activity in the presence of a rat liver metabolizing system using the pre-incubation method inthe bacterial reverse mutation test with Salmonella typhimurium strains.
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