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EC number: 500-276-7 | CAS number: 89800-10-2
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:
- 8 - 27 Nov 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 guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Version / remarks:
- adopted in 1997
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- Departement of Health of the Government of the United Kingdom
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- ε-Caprolactone, oligomers, esters with acrylic acid and 2,2,2',2'-tetrakis (hydroxymethyl)-3,3'-oxydipropan-1-ol
- EC Number:
- 500-276-7
- EC Name:
- ε-Caprolactone, oligomers, esters with acrylic acid and 2,2,2',2'-tetrakis (hydroxymethyl)-3,3'-oxydipropan-1-ol
- Cas Number:
- 89800-10-2
- Molecular formula:
- {(C10H16O7).(C3H3O)b.[(C6H10O2)m.(C3H3O)a]} (i.e., UVCB substance)
- IUPAC Name:
- ε-Caprolactone, oligomers, esters with acrylic acid and 2,2,2',2'-tetrakis (hydroxymethyl)-3,3'-oxydipropan-1-ol
Constituent 1
Method
- Target gene:
- his, trp operon
Species / strainopen allclose all
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
- Additional strain / cell type characteristics:
- not applicable
- Species / strain / cell type:
- E. coli WP2 uvr A
- Additional strain / cell type characteristics:
- not applicable
- Metabolic activation:
- with and without
- Metabolic activation system:
- post mitochondrial supernatant (S9) prepared from livers of Phenobarbital/β-naphthoflavone-induced male rats
- Test concentrations with justification for top dose:
- Experiment 1 (plate incorporation): 1.5, 5, 15, 50, 150, 500, 1500 and 5000 μg/plate
Experiment 2 (preincubation): 15, 50, 150, 500, 1500, 5000 μg/plate - Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: DMSO
- Justification for choice of solvent/vehicle: due to good solubility
Controls
- Untreated negative controls:
- yes
- Remarks:
- untreated
- Negative solvent / vehicle controls:
- yes
- Remarks:
- DMSO
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- 4-nitroquinoline-N-oxide
- 9-aminoacridine
- benzo(a)pyrene
- other: N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG), 2-aminoanthracene (2AA)
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: plate incorporation test for the initial mutation test and a pre-incubation test for the confirmatory mutation test
DURATION
- Preincubation period: 20 min
- Exposure duration: 48 h
NUMBER OF REPLICATIONS: triplicate
DETERMINATION OF CYTOTOXICITY
- Method: background lawn - Evaluation criteria:
- A test item is considered mutagenic, if one or more criteria are fulfilled:
- a dose-related increase in the number of revertants occurs
- a reproducible increase at one or more concentrations
- biological relevance against in-house historical control ranges
- statistical analysis of data as determined by UKEMS
- fold increase > 2 times the concurrent solvent control (3 times for TA1535 and TA1537) for any tester strain (especially if accompanied by an out-of-historical range response)
A test item will be considered non-mutagenic (negative) in the test system if the above criteria are not met.
Although most experiments will give clear positive or negative results, in some instances the data generated will prohibit making a definite judgment about test item activity. Results of this type will be reported as equivocal.
The tests (Initial and Confirmatory Mutation Tests) are considered valid if:
- All bacterial strains must have demonstrated the required characteristics as determined by their respective strain checks according to Ames et al., (1975), Maron and Ames (1983), Mortelmans and Zeiger (2000), Green and Muriel (1976) and Mortelmans and Riccio (2000).
- All tester strain cultures should exhibit a characteristic number of spontaneous revertants per plate in the vehicle and untreated controls (negative controls).
- All tester strain cultures should be in the range of 0.9 - 9 x 10^9 bacteria per mL.
- Diagnostic mutagens (positive control chemicals) must be included to demonstrate both the intrinsic sensitivity of the tester strains to mutagen exposure and the integrity of the S9-mix. All of the positive control chemicals used in the study should induce marked increases in the frequency of revertant colonies, both with or without metabolic activation.
- There should be a minimum of four non-toxic test item dose levels.
- There should be no evidence of excessive contamination. - Statistics:
- Statistical significance was confirmed by using Dunnetts Regression Analysis (* = p < 0.05) for those values that indicate statistically significant increases in the frequency of revertant colonies compared to the concurrent solvent control. Values that the program concluded as statistically significant but were within the in-house historical profile were not reported.
Results and discussion
Test resultsopen allclose all
- Key result
- Species / strain:
- S. typhimurium TA 1535
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 1537
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
- 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 nor precipitates, but tested up to recommended limit concentrations
- 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 nor precipitates, but tested up to recommended limit concentrations
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- E. coli WP2 uvr A
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Other confounding effects: A fine test item film (greasy in appearance) was noted at 5000 μg/plate, this observation did not prevent the scoring of revertant colonies.
RANGE-FINDING/SCREENING STUDIES: There was no visible reduction in the growth of the bacterial background lawn at any dose level, either in the presence or absence of metabolic activation (S9-mix), in the first mutation test (plate incorporation method). Consequently, the same maximum dose level was used as the maximum dose in the second mutation test.
HISTORICAL CONTROL DATA (with ranges, means and standard deviation and confidence interval (e.g. 95%)
please refer to table 3 in "any other information on results incl. tables"
Any other information on results incl. tables
Table 1: Test results (experiment 1, plate incorporation)
With or without S9-Mix |
Test substance concentration (μL/plate) |
Mean number of revertant colonies per plate |
||||
Frameshift type |
Base-pair substitution type |
|||||
TA98 |
TA1537 |
TA100 |
TA1535 |
WP2 uvr A |
||
– |
Negative control (untreated) |
16 |
7 |
78 |
16 |
21 |
Solvent control (DMSO) |
16 ± 3.8 |
12 ± 1.5 |
78 ± 7.0 |
14 ± 3.5 |
20 ± 4.4 |
|
1.5 |
12 ± 1.0 |
7 ± 1.5 |
74 ± 4.2 |
16 ± 4.2 |
19 ± 1.7 |
|
5 |
18 ± 2.5 |
9 ± 0.6 |
73 ± 11.5 |
16 ± 3.6 |
17 ± 2.6 |
|
15 |
20 ± 7.5 |
11 ± 3.5 |
78 ± 12.5 |
14 ± 3.2 |
20 ± 2.0 |
|
50 |
13 ± 4.0 |
13 ± 3.8 |
86 ± 13.7 |
15 ± 1.5 |
17 ± 2.5 |
|
150 |
14 ± 2.1 |
7 ± 3.0 |
81 ± 4.6 |
16 ± 7.8 |
14 ± 8.1 |
|
500 |
15 ± 5.5 |
6 ± 3.6 |
82 ± 10.6 |
14 ± 2.3 |
23 ± 3.6 |
|
1500 |
18 ± 7.2 |
10 ± 0.6 |
79 ± 11.9 |
18 ± 5.8 |
23 ± 6.1 |
|
5000 |
14 ± 5.3 |
10 ± 4.5 |
94 ± 3.2 |
19 ± 3.0 |
24 ± 4.0 |
|
Positive controls (µg/plate) |
4NQO |
9AA |
ENNG |
ENNG |
ENNG |
|
Mean No. of colonies/plate (average of 3 plates) |
150 ± 37.8 |
239 ± 15.6 |
369 ± 82.7 |
225 ± 88.6 |
568 ± 149.2 |
|
+ |
Solvent control (DMSO) |
19 ± 4.4 |
12 ± 3.8 |
81 ± 6.6 |
13 ± 2.3 |
33 ± 5.1 |
1.5 |
16 ± 5.5 |
8 ± 3.0 |
79 ± 6.0 |
12 ± 3.5 |
19 ± 6.1 |
|
5 |
17 ± 4.4 |
10 ± 6.4 |
87 ± 1.2 |
13 ± 2.1 |
25 ± 4.6 |
|
15 |
20 ± 2.6 |
10 ± 0.6 |
90 ± 12.9 |
18 ± 2.3 |
22 ± 3.6 |
|
50 |
16 ± 4.6 |
7 ± 1.5 |
85 ± 3.6 |
17 ± 7.0 |
23 ± 2.6 |
|
150 |
17 ± 1.5 |
11 ± 2.5 |
79 ± 10.1 |
12 ± 8.7 |
24 ± 5.1 |
|
500 |
19 ± 4.6 |
10 ± 2.6 |
90 ± 13.5 |
18 ± 4.0 |
18 ± 2.9 |
|
1500 |
18 ± 4.4 |
6 ± 2.3 |
84 ± 4.0 |
16 ± 4.4 |
28 ± 4.6 |
|
5000 |
22 ± 2.5 |
9 ± 6.1 |
81 ± 10.1 |
17 ± 7.0 |
25 ± 2.3 |
|
Positive controls (µg/plate) |
B(a)P |
2AA |
2AA |
2AA |
2AA |
|
Mean No. of colonies/plate (average of 3 plates) |
184 ± 10.4 |
249 ± 59.0 |
1732 ± 563.3 |
260 ± 15.7 |
205 ± 16.0 |
|
2AA = 2-aminoanthracene
4NQO = 4-nitroquinoline-N-oxide
9AA = 9-aminoacridine
B(a)P = benzo(a)pyrene
ENNG = N-ethyl-N'-nitro-N-nitrosoguanidine
Table 2: Test results (experiment 2, preincubation)
With or without S9-Mix |
Test substance concentration (μL/plate) |
Mean number of revertant colonies per plate |
||||
Frameshift type |
Base-pair substitution type |
|||||
TA98 |
TA1537 |
TA100 |
TA1535 |
WP2 uvr A |
||
– |
Negative control (untreated) |
23 |
17 |
101 |
13 |
29 |
Solvent control (DMSO) |
25 ± 7.0 |
18 ± 5.0 |
84 ± 9.5 |
11 ± 1.2 |
32 ± 6.0 |
|
15 |
20 ± 2.1 |
21 ± 2.9 |
84 ± 5.5 |
9 ± 3.1 |
34 ± 4.7 |
|
50 |
19 ± 2.6 |
20 ± 3.2 |
88 ± 17.0 |
12 ± 4.6 |
26 ± 8.5 |
|
150 |
19 ± 5.5 |
13 ± 2.9 |
85 ± 10.4 |
12 ± 0.6 |
23 ± 5.3 |
|
500 P |
18 ± 3.5 |
16 ± 7.0 |
81 ± 8.5 |
11 ± 1.7 |
28 ± 3.6 |
|
1500 P |
19 ± 2.3 |
18 ± 3.1 |
87 ± 5.3 |
10 ± 0.6 |
30 ± 5.3 |
|
5000 P |
21 ± 3.2 |
16 ± 4.4 |
87 ± 20.9 |
11 ± 2.3 |
30 ± 1.2 |
|
Positive controls (µg/plate) |
4NQO |
9AA |
ENNG |
ENNG |
ENNG |
|
Mean No. of colonies/plate (average of 3 plates) |
185 ± 5.6 |
260 ± 64.7 |
639 ± 44.4 |
723 ± 101.3 |
880 ± 24.9 |
|
+ |
Solvent control (DMSO) |
26 ± 3.0 |
18 ± 5.6 |
90 ± 12.9 |
13 ± 2.3 |
50 ± 7.5 |
15 |
26 ± 2.6 |
18 ± 6.5 |
88 ± 16.8 |
11 ± 4.9 |
51 ± 8.5 |
|
50 |
29 ± 3.1 |
18 ± 3.5 |
97 ± 14.0 |
9 ± 1.0 |
48 ± 9.1 |
|
150 |
21 ± 4.4 |
20 ± 4.6 |
86 ± 5.0 |
12 ± 4.6 |
46 ± 8.1 |
|
500 P |
27 ± 5.6 |
16 ± 3.6 |
94 ± 8.0 |
11 ± 0.0 |
47 ± 7.2 |
|
1500 P |
22 ± 3.0 |
16 ± 4.0 |
88 ± 7.4 |
11 ± 1.5 |
46 ± 5.9 |
|
5000 P |
23 ± 6.0 |
18 ± 4.2 |
89 ± 10.6 |
10 ± 0.6 |
40 ± 2.6 |
|
Positive controls (µg/plate) |
B(a)P |
2AA |
2AA |
2AA |
2AA |
|
Mean No. of colonies/plate (average of 3 plates) |
128 ± 10.5 |
284 ± 19.3 |
1041 ± 141.0 |
296 ± 9.7 |
173 ± 18.0 |
|
2AA = 2-aminoanthracene
4NQO = 4-nitroquinoline-N-oxide
9AA = 9-aminoacridine
B(a)P = benzo(a)pyrene
ENNG = N-ethyl-N'-nitro-N-nitrosoguanidine
Table 3: Historical control values (2016)
|
S9-Mix |
Mean number of revertant colonies per plate [mean ± SD] |
||||
TA 100 |
TA 1535 |
WP2 uvr A |
TA 98 |
TA 1537 |
||
Negative/ vehicle controls |
- |
90 ± 14.5 |
15 ± 4.5 |
22 ± 5.8 |
21 ± 4.8 |
12 ± 3.5 |
+ |
93 ± 14.3 |
15 ± 5.2 |
27 ± 6.3 |
25 ± 5.7 |
13 ± 3.5 |
|
Positive controls |
- |
724 ± 320.4 |
854 ± 664.9 |
718 ± 338.6 |
186 ± 49.8 |
406 ± 227.0 |
+ |
1264 ± 562.6 |
240 ± 62.1 |
240 ± 98.2 |
188 ± 230.8 |
290 ± 92.7 |
|
Applicant's summary and conclusion
- Conclusions:
- Based on the results of the conducted study, the test substance did not exhibit mutagenic properties in bacterial cells.
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