Registration Dossier
Registration Dossier
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EC number: 262-334-5 | CAS number: 60623-04-3
Endpoint summary
Administrative data
Key value for chemical safety assessment
Genetic toxicity in vitro
Description of key information
The registered substance was tested under OECD 471 guidelines and was found not to induce point mutations for frame-shift mutations with and without metabolic activation in TA 97, TA 98, TA 100, TA 102 or TA 1535 stains of E coli. Sasol (LAUS 2016). The results of this study it is concluded that 2,2 -bis[[(2 -hexyl-1 -oxodecyl)oxy]methyl]-1,3 -propanediyl bis(2 -hexyldecanoate), the registered substance, is not mutagenic in the Salmonella typhimurium strains TA97a, TA98, TA100, TA102 and TA1535 in the absence and presence of metabolic activation under the experimental conditions in this study.
A mouse lymphoma assay for 85186 -89 -6 (now 85566 -29 -6) under OECD 476 guidelines and a chromosal aberration test to human lymphocytes for 403507 -18 -6 under OECD 473 guidelines were negative.
Link to relevant study records
- Endpoint:
- in vitro gene mutation study in bacteria
- Remarks:
- Type of genotoxicity: gene mutation
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- GLP compliant
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Version / remarks:
- adopted 21 July 1997
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.13/14 (Mutagenicity - Reverse Mutation Test Using Bacteria)
- Version / remarks:
- adopted 31 May 2008
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- bacterial reverse mutation assay
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Production plant, Batch no. 04549/MA
- Expiration date of the lot/batch: 15 May 2018
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature - Species / strain / cell type:
- S. typhimurium, other: TA97a
- Species / strain / cell type:
- S. typhimurium TA 98
- Species / strain / cell type:
- S. typhimurium TA 100
- Species / strain / cell type:
- S. typhimurium TA 102
- Species / strain / cell type:
- S. typhimurium TA 1535
- Metabolic activation:
- with and without
- Metabolic activation system:
- S9 enzymes from the livers male Sprague-Dawley rats, treated with 500 mg Aroclor 1254/kg bw intraperitoneally
- Test concentrations with justification for top dose:
- Experiment using the plate incorporation method: 5000 / 1500 / 500 / 150 / 50 µg/plate
Repetition experiment using the preincubation method: 5000 / 2500 / 1250 / 625 / 313 / 156 µg/plate - Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: tetra hydrofurane (THF)
- Justification for choice of solvent/vehicle: In a preliminary test, the solubility of the test item was determined in a concentration of 50 g/L in demineralised water, DMSO, Ethanol; and in 200 g/L in THF. THF was chosen as vehicle, because the test item was sufficiently soluble, and this solvent does not have any effects on the viabilty of the bacteria or the number of spontaneous revertants in the tested concentrations. - Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- Remarks:
- THF and DMSO
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: 4-Nitro-1,2-phenylene, 20 µg/plate in DMSO with strains TA97a, TA98 and TA102; Sodium Azide, 1 µg/plate in H2O with strains TA100 and TA1535
- Remarks:
- without metabolic activation
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- Remarks:
- THF and DMSO
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: 2-Amino-anthracene, 1 µg/plate in DMSO with strains TA97a, TA100, TA102 and TA1535; Benzo-a-pyrene, 20 µg/plate in DMSO with strain TA98
- Remarks:
- with metabolic activation
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in agar (plate incorporation) in the first experiment; pre-incubation in the second experiment
DURATION
- Preincubation period: 20 min (only in the second experiment)
- Exposure duration: 48 h
NUMBER OF REPLICATIONS: 3
DETERMINATION OF CYTOTOXICITY:
- Method: In the pre-experiment: determination of titre (the test item was considered non-toxic, if the quotient titre/toxicity is below 2), in the main experiments: evaluation of background lawn, reduction in number of revertants in comparison to negativ/solvents control
OTHER EXAMINATIONS:
- Visual counting of mutant colonies, a spreadsheet software (Microsoft Excel) was used to calculate mean values and standard deviations.
- Quality control of bacterial strains: genotype confirmation for each batch of bacteria before stock culture preparation: All bacterial strains were tested for histidine requirement, ampicillin resistence, crystal violet sensitivity, UV sensitivity and spontaneous revertants, furthermore the following examinations were performed: determination of titre, toxicity control, sterility control and positive control.
- Visual inspection of precipitation: Plates were checked for precipitation of test item at the end of the incubation - Evaluation criteria:
- The colonies were counted visually, the numbers were recorded. A spreadsheet software (Microsoft Excel®) was used to calculate mean values and standard deviations of each treatment, solvent control and positive control. The increase factor f(I) of revertant induction (mean revertants divided by mean spontaneous revertants) and the absolute number of revertants (revertants less mean spontaneous revertants) were also calculated.
A substance is considered to have mutagenic potential, if a reproducible increase of revertant colonies per plate in at least one strain exceeding an increase factor of 2 (in tester strains TA 97a, TA98, TA100 and TA102) and an increase factor of 3 (in tester strain TA1535) as compared to the reversion rate of the solvent control can be observed. A concentration-related increase over the range tested can also be taken as a sign of mutagenic activity. - Statistics:
- not performed
- Key result
- Species / strain:
- S. typhimurium, other: TA 97a
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 100
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 102
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 1535
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Water solubility: not soluble in water
- Precipitation: Precipitated/undissolved test item was not observed at any of the concentrations tested.
- Other confounding effects: nothing mentioned
COMPARISON WITH HISTORICAL CONTROL DATA: Nearly all determined values for the spontaneous revertants of the negative controls were in the normal range of the test laboratory, differences were only marginal and no critical impact on the outcome of the study was expected. All positive control showed mutagenic effects with and without metabolic activation and all were within the historical control data ranges.
For the solvent control THF, no historical data are available. This can be seen as uncritical, because the values of the spontaneous revertants are in normal range of the data for the other solvent controls (demin. water and DMSO) in the test facility. - Conclusions:
- Based on the results of this study it is concluded that the test item is not mutagenic in the Salmonella typhimurium test strains TA97a, TA98, TA100, TA102 and TA1535 in the absence and presence of metabolic activation under the experimental conditions in the present study.
- Executive summary:
The study procedures described in this report were based on the most recent OECD and EC guidelines and performed under the principles of GLP. The test item 2,2-bis[[(2-hexyl-1-oxodecyl)oxy]methyl]-1,3-propanediyl bis(2-hexyldecanoate) was tested in the Salmonella typhimurium reverse mutation assay with five strains of Salmonella typhimurium (TA97a, TA98, TA100, TA102 and TA1535). The test was performed in three experiments in the presence and absence of S9-mix (rat liver S9-mix induced by Aroclor 1254). In the first experiment, 2,2-bis[[(2-hexyl-1-oxodecyl)oxy]methyl]-1,3-propanediyl bis(2-hexyldecanoate) (dissolved in THF) was tested up to nominal concentrations of 5000 μg/plate in the absence and presence of S9-mix (0.74 % final concentration in the treatment) in the strains TA97a, TA98, TA100, TA102 and TA1535 using the plate incorporation method. 2,2-bis[[(2-hexyl-1-oxodecyl)oxy]methyl]-1,3-propanediyl bis(2-hexyldecanoate) showed no precipitates on the plates at any of the concentrations. The bacterial background lawn was not reduced at any of the concentrations and no relevant decrease in the number of revertants was observed in all bacteria strains. The test item 2,2-bis[[(2-hexyl-1-oxodecyl)oxy]methyl]-1,3-propanediyl bis(2-hexyldecanoate) showed no signs of toxicity towards the bacteria strains in both the absence and presence of metabolic activation. The results of this experiment showed that none of the tested concentrations showed a significant increase in the number of revertants in all tested strains, in the presence and the absence of metabolic activation. On the base of the first experiment, 2,2-bis[[(2-hexyl-1-oxodecyl)oxy]methyl]-1,3-propanediyl bis(2-hexyldecanoate) was tested up to nominal concentrations of 5000 μg/plate in the absence and presence of S9-mix (0.74% final concentration in the treatment) in all bacteria strain using the pre-incubation method. 2,2-bis[[(2-hexyl-1-oxodecyl)oxy]methyl]-1,3-propanediyl bis(2-hexyldecanoate) showed no precipitates on the plates at any of the concentrations. The bacterial background lawn was not reduced at any of the concentrations and no relevant decrease in the number of revertants was observed in all bacteria strains. The test item 2,2-bis[[(2-hexyl-1-oxodecyl)oxy]methyl]-1,3-propanediyl bis(2-hexyldecanoate) showed no signs of toxicity towards the bacteria strains in both the absence and presence of metabolic activation. The results of this experiments showed that the test item 2,2-bis[[(2-hexyl-1-oxodecyl)oxy]methyl]-1,3-propanediyl bis(2-hexyldecanoate) caused no increase in the number of revertants in all bacteria strains compared to the solvent control, in both the absence and presence of metabolic activation. The test item 2,2-bis[[(2-hexyl-1-oxodecyl)oxy]methyl]-1,3-propanediyl bis(2-hexyldecanoate) did not induce a dose-related increase in the number of revertants colonies in all strains, in the presence and absence of metabolic activation.
Based on the results of this study it is concluded that 2,2-bis[[(2-hexyl-1-oxodecyl)oxy]methyl]-1,3-propanediyl bis(2-hexyldecanoate) is not mutagenic in the Salmonella typhimurium strains TA97a, TA98, TA100, TA102 and TA1535 in the absence and presence of metabolic activation under the experimental conditions in this study.
- 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:
- 26 Mar - 08 June 2010
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- GLP - Guideline study. According to the ECHA guidance document "Practical guide 6: How to report read-across and categories (March 2010)", the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 476 (In Vitro Mammalian Cell Gene Mutation Test)
- Version / remarks:
- adopted in 1997
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.17 (Mutagenicity - In Vitro Mammalian Cell Gene Mutation Test)
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- mammalian cell gene mutation assay
- Target gene:
- TK locus
- Species / strain / cell type:
- mouse lymphoma L5178Y cells
- Details on mammalian cell type (if applicable):
- - Type and identity of media: RPMI 1640 supplemented with 5% (v/v) heat-inactivated horse serum
- Properly maintained: yes
- Periodically checked for Mycoplasma contamination: yes
- Periodically "cleansed" against high spontaneous background: yes - Metabolic activation:
- with and without
- Metabolic activation system:
- co-factor supplemented post-mitochondrial fraction (S9-mix), prepared from rats pretreated with phenobarbital and ß-naphthoflavone
- Test concentrations with justification for top dose:
- First experiment: 0.3, 1, 3, 10, 33, 100, 333 and 750 µg/mL (with and without metabolic activation (8%, v/v))
Second experiment: 0.3, 1, 3, 10, 33, 100, 333 and 750 µg/mL (with and without metabolic activation (12%, v/v)) - Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: DMSO
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Remarks:
- + S9: cyclophosphamide, 15 and 5 µg/mL for 3 and 24 h treatment, respectively; - S9: methylmethanesulfonate, 7.5 µg/mL
- Positive control substance:
- cyclophosphamide
- methylmethanesulfonate
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in suspension
DURATION
- Preincubation period: No
- Exposure duration: cells were exposed to the test material for 3 h and 24 h in the presence and absence of S9-mix, respectively.
- Expression time (cells in growth medium): For the expression of the mutant phenotype, the cells were separated by 2 centrifugation steps and cultures for 48 h after the treatment period. For determination of the mutation frequency cells were plated and incubated for 11-12 days. After that, cells were stained for 2 h by adding 0.5 mg/mL MTT (Sigma) to each well. The plates were scored for cloning efficiency and mutation frequency with the naked eye or with the microscope.
SELECTION AGENT (mutation assays): RPMI 1640 supplemented with 20% (v/v) heat-inactivated horse serum and 5 µg/mL trifluorothymidine (TFT).
DETERMINATION OF CYTOTOXICITY
- Method: relative total growth - Evaluation criteria:
- Several criteria including a concentration-related, or a reproducible increase in mutation frequencies determined a positive result.
- Species / strain:
- mouse lymphoma L5178Y cells
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity, but tested up to precipitating concentrations
- Remarks:
- at and above 333 µg/mL
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Precipitation: at and above 333 µg/mL
RANGE-FINDING/SCREENING STUDIES: Yes, cytotoxicity data was obtained by treating cells for 3 h and 24 h respectively with a number of increasing test substance concentrations. The highest concentration tested was 750 µg/ml due to poor solubility of the test substance. No toxicity was observed with and without metabolic activation up to and at the maximum dose level tested with 3 h or 24 h incubation.
COMPARISON WITH HISTORICAL CONTROL DATA: Yes, all controls were in the range of the historical controls - Remarks on result:
- other: all strains/cell types tested
- Conclusions:
- Interpretation of results (migrated information):
negative - Endpoint:
- in vitro cytogenicity / chromosome aberration study in mammalian cells
- Remarks:
- Type of genotoxicity: chromosome aberration
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 06. Oct. - 16. Feb. 2004
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Guideline study (OECD). (Purity of test substance not given, evalation criteria not given.)
- Justification for type of information:
- see chapter 13 read-across justification
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 473 (In Vitro Mammalian Chromosome Aberration Test)
- Deviations:
- yes
- Remarks:
- purity of test substance is not given (responsibility of the sponsor)
- GLP compliance:
- yes
- Type of assay:
- in vitro mammalian chromosome aberration test
- Target gene:
- not applicable
- Species / strain / cell type:
- lymphocytes: cultured peripheral human lymphocytes
- Details on mammalian cell type (if applicable):
- - Type and identity of media: Eagles essential medium with HEPES buffer (MEM), supplemented with:
L-glutamine, penicillin/streptomycin, amphotericin B, 15% foetel calf serum
- Properly maintained: yes - Metabolic activation:
- with and without
- Metabolic activation system:
- co-factor supplemented post-mitochondrial fraction (S9 mix), prepared from the livers of rats pretreated with phenobarbitone (80 mg/kg) and ß-naphtoflavone (100 mg/kg)
- Test concentrations with justification for top dose:
- Experiment I:
4 hour (with and without): 40, 80, 160, 240*, 320*, 400* µg/mL
Experiment II
4 hour (with): 40, 80, 160, 240*, 320*, 400* µg/mL
24 hour (without): 40, 80, 160, 240*, 320*, 400* µg/mL
* Dose levels (plus control dose) selected for metaphase analysis - Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: acetone
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: Mitomycin C (MMC; 0.2 and 0.4 µg/mL; -S9), cyclophosphamide (CP; 10 µg/mL; +S9)
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in medium
DURATION
- Exposure duration: 4 h (with and without S9), 24 h (without)
- Fixation time (start of exposure up to fixation or harvest of cells): 4 h treatment: 20 h; 24 h treatment: 0 h
SPINDLE INHIBITOR (cytogenetic assays): Colcemid 0.1 µg/mL (demecolcine)
STAIN (for cytogenetic assays): 5% Gurrs Giemsa for 5 minutes
NUMBER OF REPLICATIONS: 2
NUMBER OF CELLS EVALUATED: 200 per culture
DETERMINATION OF CYTOTOXICITY
- Method: mitotic index of 2000 cells
OTHER EXAMINATIONS:
- Determination of polyploidy: yes - Evaluation criteria:
- no data
- Statistics:
- The frequency of cells with aberrations excluding gaps and the frequency of polyploid cells was compared, where necessary, with the concurrent vehicle control value using Fisher's exact test.
- Species / strain:
- lymphocytes: cultured peripheral human lymphocytes
- 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 examined
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Precipitation: cloudy precipitates were observed at and above 40 and 80 µg/mL in the 24-hour continuous and 4-hour pulse treatment groups, respectively
RANGE-FINDING/SCREENING STUDIES:
The dose range tested was 10-320 µg/mL. The test material produced some weak toxicity in the 4-hour treatment group but not the 24-hour treatment group. Toxicity could not be reproduced in the main experiment (scorable metaphases at every dose level).
COMPARISON WITH HISTORICAL CONTROL DATA:
The results are in range with historical control data. - Remarks on result:
- other: all strains/cell types tested
- Conclusions:
- Interpretation of results (migrated information):
negative
Referenceopen allclose all
| Table #1: Salmonella typhimurium reverse mutation assay without metabolic activation, plate incorporation test | ||||||||||
| Concentration [µg/plate] | Revertant colonies / plate | |||||||||
| TA 97a | TA98 | TA100 | TA102 | TA1535 | ||||||
| mean*±SD | f(l) | mean*±SD | f(l) | mean*±SD | f(l) | mean*±SD | f(l) | mean*±SD | f(l) | |
| Negative control (H2O) | 73 ± 8.5 | - | 10 ± 3.1 | - | 62 ± 2.0 | - | 263 ± 25.5 | - | 20 ± 2.1 | - |
| Solvent control (DMSO) | 82 ± 3.2 | - | 9 ± 2.5 | - | 64 ± 9.3 | - | 235 ± 68.5 | - | 17 ± 2.6 | - |
| Solvent control (THF) | 69 ± 11.9 | - | 12 ± 3.5 | - | 61 ± 1.0 | - | 352 ± 13.9 | - | 21 ± 2.6 | - |
| 5000 | 59 ± 9.3 | 0.86 | 13 ± 3.5 | 1.08 | 61 ± 5.1 | 1.00 | 379 ± 8.3 | 1.08 | 16 ± 2.5 | 0.76 |
| 1500 | 68 ± 6.5 | 0.99 | 10 ± 2.1 | 0.83 | 61 ± 4.4 | 1.00 | 359 ± 24.1 | 1.02 | 17 ± 4.5 | 0.81 |
| 500 | 76 ± 4.7 | 1.10 | 10 ± 1.5 | 0.83 | 65 ± 8.4 | 1.07 | 291 ± 34.9 | 0.83 | 16 ± 0.6 | 0.76 |
| 150 | 68 ± 8.7 | 0.99 | 15 ± 1.2 | 1.42 | 61 ± 3.5 | 1.00 | 363 ± 20.1 | 1.03 | 17 ± 1.2 | 0.81 |
| 50 | 64 ± 4.6 | 0.93 | 15 ± 2.1 | 1.25 | 67 ± 4.9 | 1.10 | 311 ± 2.3 | 0.88 | 19 ± 0.6 | 0.90 |
| Positive controls | 740 ± 170.9 | 9.02 | 311 ± 49.7 | 34.56 | 315 ± 26.1 | 5.08 | 725 ± 63.3 | 3.09 | 341 ± 81.0 | 17.05 |
| SD = Standard deviation f(l) = increase factor of revertant induction (mean revertants divided by mean spontaneous revertants) | ||||||||||
| *mean from 3 replicates | ||||||||||
| Table #2: Salmonella typhimurium reverse mutation assay with metabolic activation, plate incorporation test | ||||||||||
| Concentration [µg/plate] | Revertant colonies / plate | |||||||||
| TA 97a | TA98 | TA100 | TA102 | TA1535 | ||||||
| mean*±SD | f(l) | mean*±SD | f(l) | mean*±SD | f(l) | mean*±SD | f(l) | mean*±SD | f(l) | |
| Negative control (H2O) | 114 ± 7.9 | - | 14 ± 3.8 | - | 66 ± 4.0 | - | 291 ± 26.0 | - | 20 ± 2.1 | - |
| Solvent control (DMSO) | 128 ± 8.3 | - | 13 ± 1.2 | - | 63 ± 2.0 | - | 309 ± 28.4 | - | 17 ± 2.6 | - |
| Solvent control (THF) | 82 ± 8.3 | - | 17 ± 0.6 | - | 73 ± 1.5 | - | 359 ± 23.4 | - | 21 ± 2.6 | - |
| 5000 | 116 ± 18.9 | 1.41 | 11 ± 3.1 | 0.65 | 71 ± 16.9 | 0.97 | 369 ± 19.7 | 1.03 | 16 ± 2.5 | 0.95 |
| 1500 | 112 ± 10.5 | 1.37 | 16 ± 1.0 | 0.94 | 66 ± 11.0 | 0.90 | 355 ± 9.2 | 0.99 | 17 ± 4.5 | 0.74 |
| 500 | 104 ± 8.7 | 1.27 | 15 ± 2.0 | 0.88 | 69 ± 8.1 | 0.95 | 267 ± 66.0 | 0.74 | 16 ± 0.6 | 0.79 |
| 150 | 89 ± 22.2 | 1.09 | 11 ± 2.0 | 0.65 | 69 ± 10.0 | 0.95 | 330 ± 44.2 | 0.92 | 17 ± 1.2 | 1.00 |
| 50 | 75 ± 6.0 | 0.91 | 16 ± 2.5 | 0.94 | 75 ± 3.5 | 1.03 | 299 ± 52.8 | 0.83 | 19 ± 0.6 | 0.79 |
| Positive controls | 567 ± 84.5 | 4.43 | 59 ± 3.5 | 5.54 | 627 ± 41.1 | 9.95 | 671 ± 151.4 | 2.17 | 341 ± 81.0 | 6.84 |
| SD = Standard deviation f(l) = increase factor of revertant induction (mean revertants divided by mean spontaneous revertants) | ||||||||||
| *mean from 3 replicates | ||||||||||
| Table #3: Salmonella typhimurium reverse mutation assay without metabolic activation, pre-incubation test | ||||||||||
| Concentration [µg/plate] | Revertant colonies / plate | |||||||||
| TA 97a | TA98 | TA100 | TA102 | TA1535 | ||||||
| mean*±SD | f(l) | mean*±SD | f(l) | mean*±SD | f(l) | mean*±SD | f(l) | mean*±SD | f(l) | |
| Negative control (H2O) | 86 ± 13.7 | - | 12 ± 3.1 | - | 90 ± 17.3 | - | 428 ± 64.4 | - | 21 ± 2.5 | - |
| Solvent control (DMSO) | 88 ± 4.7 | - | 12 ± 1.2 | - | 94 ± 5.3 | - | 332 ± 43.3 | - | 21 ± 3.5 | - |
| Solvent control (THF) | 86 ± 2.1 | - | 15 ± 2.0 | - | 99 ± 12.0 | - | 351 ± 28.1 | - | 28 ± 3.0 | - |
| 5000 | 94 ± 4.0 | 1.09 | 10 ± 0.6 | 0.67 | 92 ± 16.8 | 0.93 | 398 ± 45.3 | 1.13 | 26 ± 5.2 | 0.93 |
| 2500 | 101 ± 5.0 | 1.17 | 9 ± 1.7 | 0.60 | 104 ± 11.0 | 1.05 | 413 ± 26.6 | 1.18 | 24 ± 6.7 | 0.86 |
| 1250 | 97 ± 15.3 | 1.13 | 13 ± 1.2 | 0.87 | 117 ± 1.0 | 1.18 | 388 ± 56.0 | 1.11 | 24 ± 3.6 | 0.86 |
| 625 | 94 ± 18.2 | 1.09 | 15 ± 1.0 | 1.00 | 106 ± 8.3 | 1.07 | 383 ± 53.7 | 1.09 | 25 ± 1.2 | 0.8 |
| 312 | 111 ± 17.4 | 1.29 | 19 ± 2.3 | 1.27 | 104 ± 7.2 | 1.05 | 292 ± 13.9 | 0.83 | 24 ± 7.2 | 0.86 |
| 156 | 108 ± 9.0 | 1.29 | 16 ± 6.1 | 1.07 | 106 ± 13.9 | 1.07 | 280 ± 6.9 | 0.80 | 21 ± 6.1 | 0.75 |
| Positive controls | 565 ± 196.3 | 6.42 | 467 ± 32.2 | 38.92 | 525 ± 54.0 | 5.83 | 1296 ± 57.7 | 3.90 | 284 ± 32.7 | 13.52 |
| SD = Standard deviation f(l) = increase factor of revertant induction (mean revertants divided by mean spontaneous revertants) | ||||||||||
| *mean from 3 replicates | ||||||||||
| Table #4: Salmonella typhimurium reverse mutation assay with metabolic activation, pre-incubation test | ||||||||||
| Concentration [µg/plate] | Revertant colonies / plate | |||||||||
| TA 97a | TA98 | TA100 | TA102 | TA1535 | ||||||
| mean*±SD | f(l) | mean*±SD | f(l) | mean*±SD | f(l) | mean*±SD | f(l) | mean*±SD | f(l) | |
| Negative control (H2O) | 90 ± 4.2 | - | 15 ± 3.5 | - | 101 ± 11.0 | - | 336 ± 64.0 | - | 22 ± 3.0 | - |
| Solvent control (DMSO) | 87 ± 6.7 | - | 12 ± 1.5 | - | 89 ± 7.8 | - | 407 ± 67.7 | - | 23 ± 3.1 | - |
| Solvent control (THF) | 78 ± 14.4 | - | 17 ± 1.5 | - | 95 ± 6.2 | - | 405 ± 70.5 | - | 18 ± 3.0 | - |
| 5000 | 116 ± 16.0 | 1.49 | 16 ± 2.5 | 0.94 | 127 ± 22.1 | 1.32 | 417 ± 77.4 | 1.03 | 24 ± 4.7 | 1.33 |
| 2500 | 100 ± 12.5 | 1.28 | 10 ± 2.3 | 0.59 | 124 ± 11.5 | 1.29 | 391 ± 63.8 | 0.97 | 24 ± 1.5 | 1.33 |
| 1250 | 116 ± 16.5 | 1.49 | 19 v 8.9 | 1.12 | 112 ± 18.2 | 1.17 | 421 ± 54.5 | 1.04 | 23 ± 4.5 | 1.28 |
| 625 | 98 ± 21.2 | 1.26 | 23 ± 2.6 | 1.35 | 129 ± 7.5 | 1.34 | 368 ± 26.2 | 0.91 | 21 ± 4.0 | 1.17 |
| 312 | 95 ± 9.6 | 1.22 | 16 ± 3.0 | 0.94 | 116 ± 12.2 | 1.21 | 319 ± 28.9 | 0.79 | 22 ± 1.7 | 1.22 |
| 156 | 107 ± 3.6 | 1.37 | 15 ± 4.4 | 0.88 | 93 ± 2.3 | 0.97 | 297 ± 12.9 | 0.73 | 23 ± 6.0 | 1.28 |
| Positive controls | 672 ± 184.7 | 7.72 | 77 ± 18.2 | 6.42 | 507 ± 67.4 | 5.70 | 931 ± 30.3 | 2.29 | 106 ± 33.0 | 4.61 |
| SD = Standard deviation f(l) = increase factor of revertant induction (mean revertants divided by mean spontaneous revertants) | ||||||||||
| *mean from 3 replicates | ||||||||||
Table 1: Results of experiment 1
Dose (µg/ml) |
RSG (%) |
CE day2 (%) |
RS day2 (%) |
RTG (%) |
mutation frequency x 10E6 |
|
|
|
|
|
total |
Without metabolic activation, 3 h treatment |
|||||
SC1 |
100 |
104 |
100 |
100 |
74 |
SC2 |
85 |
97 |
|||
0.3 |
99 |
98 |
104 |
102 |
74 |
1 |
101 |
102 |
108 |
109 |
71 |
3 |
100 |
101 |
107 |
107 |
94 |
10 |
93 |
98 |
104 |
97 |
67 |
33 |
120 |
94 |
100 |
120 |
63 |
100 |
113 |
101 |
107 |
121 |
61 |
333* |
104 |
113 |
120 |
124 |
64 |
750* |
405 |
101 |
107 |
112 |
74 |
MMS |
71 |
68 |
72 |
51 |
835 |
With 8% (v/v) metabolic activation, 3 h treatment |
|||||
SC1 |
100 |
70 |
100 |
100 |
65 |
SC2 |
69 |
64 |
|||
0.3 |
96 |
60 |
86 |
83 |
74 |
1 |
115 |
68 |
98 |
113 |
60 |
3 |
109 |
40 |
57 |
62 |
84 |
10 |
127 |
72 |
104 |
132 |
52 |
33 |
114 |
46 |
66 |
75 |
84 |
100 |
122 |
76 |
108 |
133 |
63 |
333* |
115 |
62 |
89 |
102 |
72 |
750* |
104 |
58 |
84 |
87 |
53 |
CP |
50 |
32 |
45 |
22 |
1617 |
Table 2: Results of experiment 2
Dose (µg/ml) |
RSG (%) |
CE day2 (%) |
RS day2 (%) |
RTG (%) |
mutation frequency x 10E6 |
|
|
|
|
|
total |
Without metabolic activation, 24 h treatment |
|||||
SC1 |
100 |
66 |
100 |
100 |
90 |
SC2 |
79 |
75 |
|||
0.3 |
112 |
77 |
106 |
119 |
88 |
1 |
116 |
80 |
110 |
128 |
82 |
3 |
117 |
72 |
100 |
117 |
79 |
10 |
120 |
85 |
117 |
140 |
66 |
33 |
114 |
74 |
101 |
116 |
83 |
100 |
121 |
69 |
95 |
115 |
83 |
333* |
116 |
70 |
97 |
112 |
70 |
750* |
116 |
66 |
91 |
106 |
71 |
MMS |
101 |
49 |
67 |
68 |
1502 |
With 12% (v/v) metabolic activation, 3 h treatment |
|||||
SC1 |
100 |
93 |
100 |
100 |
80 |
SC2 |
93 |
76 |
|||
0.3 |
103 |
84 |
90 |
93 |
74 |
1 |
113 |
83 |
89 |
101 |
81 |
3 |
107 |
97 |
104 |
112 |
60 |
10 |
105 |
94 |
101 |
107 |
80 |
33 |
103 |
93 |
100 |
103 |
67 |
100 |
102 |
105 |
114 |
116 |
57 |
333* |
106 |
91 |
99 |
104 |
74 |
750* |
103 |
93 |
100 |
103 |
73 |
CP |
72 |
75 |
81 |
58 |
1082 |
RSG: Relative Suspension Growth; CE: Cloning efficiency; RS: Relative Survival; RTG: Relative Total Growth; SC: Solvent Control (DMSO); MMS: Methylmethansulfonate; CP: Cyclophosphamide
*: Precipitation of test substance
Table 3 + 4: Test results of experiment I.
Test item |
Concentration |
Mitotic Index |
Aberrant cells in % |
|
Experiment I |
in µg/mL |
in % |
with gaps |
without gaps |
Exposure period 4h, fixation time 20h, without S9 mix |
||||
control |
0 |
100 |
1 |
0 |
MMC |
0.4 |
35 |
53 |
37 |
Test substance |
240 |
98P |
0.5 |
0 |
320 |
110P |
0 |
0 |
|
400 |
91P |
0.5 |
0.5 |
|
Exposure period 4h, fixation time 20h, with S9 mix |
||||
control |
0 |
100 |
1 |
0.5 |
CP |
10 |
20 |
35.5 |
28.5 |
Test substance |
240 |
89P |
1.5 |
0 |
320 |
89P |
0.5 |
0 |
|
400 |
108P |
3.5 |
1 |
|
Test item |
Concentration |
Mitotic Index |
Aberrant cells in % |
|
Experiment II |
in µg/mL |
in % |
with gaps |
without gaps |
Exposure period + fixation time 24h, without S9 mix |
||||
control |
0 |
100 |
1.5 |
0 |
MMC |
0.4 |
41 |
70 |
67 |
Test substance |
240 |
61 |
0.5 |
0.5 |
320 |
53 |
0.5 |
0 |
|
400 |
83 |
0 |
0 |
|
Exposure period 4h, fixation time 20h, with S9 mix |
||||
control |
0 |
100 |
0.5 |
0 |
CP |
10 |
30 |
67 |
56 |
Test substance |
240 |
103 |
1 |
0 |
320 |
76 |
1 |
0 |
|
400 |
110 |
1.5 |
0.5 |
|
Table5 +6: Mean Frequency of Polyploid Cells (%)
Experiment I dose level µg/mL |
harvest time 24 hours |
|
4 hours without S9 |
4 hours with S9 |
|
0 |
0.0 |
0.0 |
240 |
0.0 |
0.0 |
320 |
0.0 |
0.0 |
400 |
0.0 |
0.0 |
MMC 0.4 |
0.0 |
NA |
CP 10 |
NA |
0.0 |
dose level µg/mL |
harvest time 24 hours |
|
24 hours without S9 |
4 hours with S9 |
|
0 |
0.5 |
0.0 |
240 |
0.0 |
0.0 |
320 |
0.0 |
0.0 |
400 |
0.0 |
0.5 |
MMC 0.4 |
0.0 |
NA |
CP 10 |
NA |
0.0 |
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (negative)
Genetic toxicity in vivo
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
The registered substance is substantially similar to CAS 85566 -29 -6 (formerly 85186 -89 -6), and CAS 403507 -18-6 which are part of the polyol ester category. In summary, several studies are available to assess the mutagenic potential in bacteria within the polyol esters category all providing negative results. Furthermore, no cytogenicity in mammalian cells in-vitro and no mutagenicity in mammalian cells in-vitro were observed with other members of the polyol esters category.
In conclusion, all available and reliable in vitro and in vivo studies conducted with polyol esters category members revealed no effects on genetic toxicity.
Short description of key category
information:
In none of these studies mutagenicity in bacteria could be observed.
In none of these studies clastogenic effects in mammalian cells could be
observed.
In none of these studies mutagenicity in mammalian cells could be
observed.
Endpoint Conclusion: No adverse effect observed (negative)
The category justification is in IUCLID section 13.
Justification for classification or non-classification
According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint".Since the category concept is applied to the polyol esters, data gaps will be filled by interpolation, as part of a read across approach from a representative category member(s) to avoid unnecessary animal testing. Additionally, once the category concept is applied, substances will be classified and labelled on this basis. Therefore, based on the group concept, all available data on genetic toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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