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EC number: 617-849-3 | CAS number: 86404-04-8
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:
- 28 June - 12 July 2007
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 007
- Report date:
- 2007
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Deviations:
- yes
- Remarks:
- only duplicate plating in the absence of scientific justification
- Qualifier:
- according to guideline
- Guideline:
- other: Guidelines for genotoxicity studies of drugs by Ministry of Health, Labour and Welfare, Japan (Notification No. 1604, November 1, 1999)
- Deviations:
- yes
- GLP compliance:
- yes
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- (5R)-5-[(1S)-1,2-dihydroxyethyl]-4-ethoxy-3-hydroxy-2,5-dihydrofuran-2-one
- EC Number:
- 617-849-3
- Cas Number:
- 86404-04-8
- Molecular formula:
- C8H12O6
- IUPAC Name:
- (5R)-5-[(1S)-1,2-dihydroxyethyl]-4-ethoxy-3-hydroxy-2,5-dihydrofuran-2-one
- Details on test material:
- - Name of test material (as cited in study report): VCE
- Substance type: powder
Storage condition of test material: at room temperature in a tightly sealed container protected from light
Constituent 1
Method
- Target gene:
- his operon (for S. typhimurium strains)
trp operon (for E. coli strain)
Species / strainopen allclose all
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
- Species / strain / cell type:
- E. coli WP2 uvr A pKM 101
- Metabolic activation:
- with and without
- Metabolic activation system:
- co-factor supplemented post-mitochondrial fraction (S9 mix), prepared from the livers of rats treated with i.p. injections of phenobarbital (30 and 60 mg/kg bw) and 5,6-benzoflavone (80 mg/kg bw)
- Test concentrations with justification for top dose:
- Pre-experiment: 312.5, 625, 1250, 2500 and 5000 µg/ plate with and without metabolic activation
Main experiment: 312.5, 625, 1250, 2500 and 5000 µg/ plate with and without metabolic activation - Vehicle / solvent:
- - Solvent used: water
- Justification for choice of solvent: The choice of the solvent was based on a preliminary solubility test.
Controls
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- Remarks:
- water
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: sodium azide (NaN3), 2-nitrofluorene (2-NF), 2-aminoanthracene (2-AA), 9-aminoacridine (9-AA), 4-nitroquinoline 1-oxide (4-NQO)
- Remarks:
- +S9: 2-AA (1.0 µg/plate, TA98 and TA100; 2 µg/plate, TA1535, TA1537 and WP2uvrA(pKM101)); -S9: 2-NF (5.0 µg/plate, TA98); 9-AA (80 µg/plate, TA1537); NaN3 (1.5 µg/plate, TA100 and TA1535); 4-NQO (5.0 µg/plate, WP2uvrA(pKM101))
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: preincubation
DURATION
- Preincubation period: 20 min
-Number of replicates: duplicate plates for the test substance and control groups in two independent experiments
DETERMINATION OF CYTOTOXICITY
- The background lawn was examined with a microscope. - Evaluation criteria:
- Validity of the test result:
Evaluation of the validity of the study was performed based on the following criteria;
- The mean number of revertant colonies for negative and positive controls shall be within the range of historical control data.
- Each test strain should exhibit a remarkable increase in average mutagen induced revertant colonies above the average number of colonies for the negative control, when treated with positive control.
- The results of preliminary dose range-finding test and bacterial reverse mutation test should be reproducible. Otherwise, reproducibility should be clarified by further testing.
Criteria for assessing mutagenic potential:
The test substance was considered positive if the following conditions are met:
- The number of revertant colonies in each dose level treated with the test substance should be increased at least twice as compared with that of the negative control group.
- The number of revertant colonies should be dose dependently increased.
- The results should be reproducible.
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:
- not examined
- 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:
- not examined
- 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:
- not examined
- 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:
- not examined
- Positive controls validity:
- valid
- Key result
- Species / strain:
- E. coli WP2 uvr A pKM 101
- 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:
- not examined
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Precipitation: No deposition was observed on the plates in the absence and presence of metabolic activation in any of the experiments.
Any other information on results incl. tables
Table 1. Test results of the pre-experiment (preincubation).
With or without S9-Mix |
Test substance concentration [μg/plate] |
Mean number of revertant colonies per plate (average of 2 plates ± SD) |
||||
Base-pair substitution type |
Frameshift type |
|||||
TA100 |
TA1535 |
WP2 uvrA (pKM101) |
TA98 |
TA1537 |
||
- |
0 (water) |
116 ± 28 |
15 ± 1 |
146 ± 1 |
20 ± 4 |
9 ± 4 |
- |
312.5 |
99 ± 6 |
18 ± 4 |
154 ± 3 |
17 ± 4 |
11 ± 1 |
- |
625 |
115 ± 9 |
13 ± 6 |
126 ± 1 |
25 ± 4 |
10 ± 0 |
- |
1250 |
109 ± 6 |
15 ± 4 |
144 ± 3 |
17 ± 0 |
10 ± 1 |
- |
2500 |
108 ± 2 |
11 ± 1 |
144 ± 13 |
18 ± 10 |
12 ± 2 |
- |
5000 |
110 ± 13 |
15 ± 0 |
138 ± 8 |
19 ± 2 |
8 ± 2 |
Positive controls, –S9 |
Name |
NaN3 |
NaN3 |
4-NQO |
2-NF |
9-AA |
Concentrations [μg/plate] |
1.5 |
1.5 |
5.0 |
5.0 |
80 |
|
Mean No. of colonies/plate (average of 2 plates ± SD) |
435 ± 4 |
361 ± 23 |
490 ± 92 |
426 ± 41 |
555 ± 50 |
|
+ |
0 (water) |
108 ± 4 |
12 ± 1 |
114 ± 16 |
28 ± 3 |
13 ± 6 |
+ |
312.5 |
130 ± 31 |
14 ± 7 |
147 ± 16 |
22 ± 4 |
9 ± 3 |
+ |
625 |
119 ± 4 |
15 ± 6 |
147 ± 28 |
33 ± 2 |
12 ± 1 |
+ |
1250 |
112 ± 11 |
17 ± 6 |
155 ± 7 |
25 ± 3 |
10 ± 4 |
+ |
2500 |
116 ± 15 |
17 ± 3 |
156 ± 19 |
19 ± 0 |
15 ± 0 |
+ |
5000 |
132 ± 6 |
15 ± 7 |
156 ± 8 |
31 ± 5 |
13 ± 1 |
Positive controls, +S9 |
Name |
2-AA |
2-AA |
2-AA |
2-AA |
2-AA |
Concentrations [μg/plate] |
1.0 |
2.0 |
2.0 |
1.0 |
2.0 |
|
Mean No. of colonies/plate (average of 2 plates ± SD) |
331 ± 8 |
192 ± 24 |
383 ± 38 |
330 ± 9 |
131 ± 16 |
|
NaN3: sodium azide
2-NF: 2-nitrofluorene
2-AA: 2-aminoanthracene
9-AA: 9-aminoacridine
4-NQO: 4-nitroquinoline 1-oxide
Table 2. Test results of the main experiment (preincubation).
With or without S9-Mix |
Test substance concentration [μg/plate] |
Mean number of revertant colonies per plate (average of 2 plates ± SD) |
||||
Base-pair substitution type |
Frameshift type |
|||||
TA100 |
TA1535 |
WP2 uvrA (pKM101) |
TA98 |
TA1537 |
||
- |
0 (water) |
110 ± 8 |
11 ± 1 |
112 ± 23 |
33 ± 1 |
8 ± 4 |
- |
312.5 |
127 ± 12 |
12 ± 1 |
171 ± 30 |
24 ± 4 |
7 ± 1 |
- |
625 |
107 ± 7 |
17 ± 6 |
179 ± 4 |
33 ± 6 |
10 ± 2 |
- |
1250 |
113 ± 20 |
11 ± 1 |
160 ± 28 |
34 ± 8 |
9 ± 2 |
- |
2500 |
107 ± 4 |
10 ± 0 |
150 ± 9 |
28 ± 2 |
6 ± 1 |
- |
5000 |
112 ± 4 |
10 ± 1 |
132 ± 15 |
29 ± 1 |
10 ± 6 |
Positive controls, –S9 |
Name |
NaN3 |
NaN3 |
4-NQO |
2-NF |
9-AA |
Concentrations [μg/plate] |
1.5 |
1.5 |
5.0 |
5.0 |
80 |
|
Mean No. of colonies/plate (average of 2 plates ± SD) |
524 ± 16 |
366 ± 8 |
466 ± 112 |
616 ± 49 |
623 ± 155 |
|
+ |
0 (water) |
115 ± 15 |
11 ± 3 |
136 ± 7 |
20 ± 2 |
8 ± 2 |
+ |
312.5 |
113 ± 11 |
11 ± 4 |
151 ± 9 |
31 ± 4 |
13 ± 2 |
+ |
625 |
99 ± 4 |
15 ± 4 |
156 ± 4 |
19 ± 1 |
11 ± 1 |
+ |
1250 |
115 ± 11 |
16 ± 4 |
164 ± 22 |
25 ± 7 |
12 ± 6 |
+ |
2500 |
105 ± 13 |
11 ± 2 |
163 ± 23 |
17 ± 1 |
14 ± 4 |
+ |
5000 |
117 ± 1 |
11 ± 2 |
155 ± 6 |
21 ± 1 |
12 ± 0 |
Positive controls, +S9 |
Name |
2-AA |
2-AA |
2-AA |
2-AA |
2-AA |
Concentrations [μg/plate] |
1.0 |
2.0 |
2.0 |
1.0 |
2.0 |
|
Mean No. of colonies/plate (average of 2 plates ± SD) |
341 ± 35 |
125 ± 39 |
553 ± 100 |
304 ± 21 |
127 ± 35 |
|
NaN3: sodium azide
2-NF: 2-nitrofluorene
2-AA: 2-aminoanthracene
9-AA: 9-aminoacridine
4-NQO: 4-nitroquinoline 1-oxide
Applicant's summary and conclusion
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