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EC number: 944-870-8 | CAS number: -
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Endpoint summary
Administrative data
Key value for chemical safety assessment
Genetic toxicity in vitro
Description of key information
In a bacterial reverse mutation test (plate incorporation test) according to OECD TG 471 the test item was not mutagenic in the absence and presence of a rat liver metabolizing system (S9 mix) (reference 7.6.1-1).
Link to relevant study records
- Endpoint:
- in vitro gene mutation study in bacteria
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- April 24, 2018- May 04, 2018
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Version / remarks:
- 1997
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- JAPAN: Guidelines for Screening Mutagenicity Testing Of Chemicals
- Version / remarks:
- 1993
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.13/14 (Mutagenicity - Reverse Mutation Test Using Bacteria)
- Version / remarks:
- 2008
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- bacterial reverse mutation assay
- Target gene:
- All Salmonella typhimurium strains contain mutations in the histidine operon, thus imposing a requirement for histidine in the growth medium. The Escherichia coli strain carries a defect in one of the genes for tryptophan biosynthesis, imposing a requirement for tryptophan in the growth medium.
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
- Species / strain / cell type:
- E. coli WP2 uvr A
- Metabolic activation:
- with and without
- Metabolic activation system:
- Due to migration, the value was transferred to one of the current document's attachments
- Test concentrations with justification for top dose:
- 5; 15.8; 50; 158; 500; 1580; 5000 µg/plate (with and without S9 mix)
The test material concentrations used were selected according to the EEC, OECD and Japanese guidelines for this test system. - Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: DMSO
- Justification for choice of solvent/vehicle for test item: DMSO showed best performance and was thus used for this experiment at a maximum concentration of 17.8 µL/plate.
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- Remarks:
- ultrapure water
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: Daunomycin
- Remarks:
- without metabolic activation, 2 µg/plate, TA98
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- Remarks:
- DMSO
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- 4-nitroquinoline-N-oxide
- Remarks:
- without metabolic activation, 2 µg/plate, E.coli WP2 uvrA
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- Remarks:
- ultrapure water
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- sodium azide
- Remarks:
- without metabolic activation, 2 µg/plate, TA100, TA 1535
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- Remarks:
- ethanol
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- 9-aminoacridine
- Remarks:
- without metabolic activation, 50 µg/plate, TA1537
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: 2-Aminoanthracene
- Remarks:
- with metabolic activation, all strains
- Details on test system and experimental conditions:
- NUMBER OF REPLICATIONS:
- Number of cultures per concentration: 3 parallel plates were used for each concentration step of the test material and the positive controls. Twice as many solvent control plates were used for each bacterial strain.
METHOD OF TREATMENT/ EXPOSURE:
- Test substance in agar (plate incorporation)
TREATMENT AND HARVEST SCHEDULE:
- Exposure duration/duration of treatment: The incubation of plates was performed at 36 - 38 °C for 2 days.
- Evaluation criteria:
- A test material was to be defined as positive or mutagenic in this assay if
- the assay is considered valid and
- a biologically relevant increase in the mean number of revertants above a threshold of 2-fold (TA 98, TA 100, WP2 uvrA) or 3-fold (TA 1535, TA 1537) as compared to the concurrent negative controls is observed
- an increase exceeding the threshold at only one concentration is considered as biologically meaningful if reproduced in a second independent experiment
- a concentration-dependent increase is considered biologically meaningful if the threshold is exceeded at more than one concentration
A test material is defined as negative or non-mutagenic in this assay if
- the assay is considered valid and
- none of the above-mentioned criteria are met - 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:
- 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
- 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
- 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
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- 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
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Precipitation and time of the determination: Following treatment with the test item, precipitation of the test material on the agar plates occurred at concentrations > 5000 µg/plate.
Ames test:
- Signs of toxicity : No toxicity to the bacteria was observed.
- Mean number of revertant colonies per plate and standard deviation : see Tables 1 and 2
- Conclusions:
- The test item did not induce gene mutations by base-pair or frameshift changes in the genome of the strains used. Therefore, it was concluded that with and without addition of S9 mix as the exogenous metabolizing system, the test item was not mutagenic in this Salmonella typhimurium and Escherichia coli reverse mutation test.
- Executive summary:
The test item was examined for its mutagenic activity in an in vitro bacterial reverse mutation test according OECD TG 471 employing Salmonella typhimurium TA 98, TA 100, TA 1535 and TA 1537, and Escherichia coli WP2 uvrA as indicator organisms. The plate incorporation test with and without addition of liver S9 mix from Phenobarbital/p-Naphthoflavone-pretreated rats was used. In this study, two experimental series were performed. In the experiments with S9 mix, 10% and 20% S9 in the S9 mix were used. Treatments of all tester strains were performed using formulations prepared in DMSO in the absence and in the presence of S9 mix, using final concentrations between 5 and 5000 µg/plate, plus vehicle and positive controls.
The mean numbers of revertant colonies of the current negative controls were within the range of historical negative control values.
The strain-specific positive controls, namely daunomycin, sodium azide, 4-nitroquinolin-N-oxide, and 9-aminoacridine in the absence of S9 mix, yielded the expected mutant frequencies that were greatly exceeding the negative controls. The genotype of the tester strains used was thus confirmed. 2-Aminoanthracene which requires metabolic activation, was strongly mutagenic. This indicates that the exogenous metabolizing system used in the present investigation (S9 mix) was active. Thus, the requirements predetermined have been met in total and the study is considered valid. Following treatment with the test item, precipitation of the test material on the agar plates occurred at concentrations > 5000 µg/plate. No toxicity to the bacteria was observed.
Under the conditions described, there were no relevant increases in revertant numbers observed after exposure to the test item in the absence and presence of S9 mix.
Reference
Table 1: Summary 1st Series
Metabolic Activation |
Test Material |
Concentr. [µg/plate] |
Revertants per plate (Mean ± SD) |
||||
TA 98 |
TA 100 |
TA1535 |
TA 1537 |
WP2 uvrA |
|||
Without Activation |
DMSO |
|
23±7 |
121±8 |
17±6 |
12±4 |
37±6 |
Test item |
5.00 |
21± 7 |
126 ±6 |
16 ±5 |
9±5 |
33 ±7 |
|
15.8 |
15 ± 2 |
128 ±9 |
21 ±8 |
13±4 |
43 ±1 |
||
50.0 |
20 ±1 |
125 ±11 |
18±2 |
12±2 |
42 ±6 |
||
158 |
16 ±7 |
112 ±23 |
16±4 |
13±4 |
43 ±7 |
||
500 |
20 ±2 |
121 ±5 |
19 ±3 |
9±7 |
38 ±3 |
||
1580 |
21±7 |
126 ±15 |
23±3 |
10±2 |
39 ±9 |
||
5000 |
21 ±4E |
122 ±16E |
16±4E |
17±2E |
31 ±4E |
||
DAUN |
2.00 |
67 ±1 |
|
|
|
|
|
NaN3 |
2.00 |
|
1478 ±27 |
747 ±34 |
|
|
|
9-AA |
50.0 |
|
|
|
938±130 |
|
|
NQO |
2.00 |
|
|
|
|
1857±103 |
|
With Activation |
DMSO |
|
21 ±8 |
122 ±13 |
13±4 |
12±4 |
32 ±4 |
Test item |
5.00 |
19 ±5 |
119±9 |
16±3 |
12±3 |
31 ± 11 |
|
15.8 |
19 ±6 |
136 ±2 |
16±1 |
11±4 |
28 ± 12 |
||
50.0 |
13±3 |
113±10 |
13±5 |
11±7 |
31±3 |
||
158 |
22±10 |
137±5 |
12±2 |
11±3 |
43±14 |
||
500 |
23±2 |
142±3 |
9±1 |
12±2 |
36±4 |
||
1580 |
17±2 |
143±6 |
12±6 |
11±2 |
31±12 |
||
5000 |
26±2E |
128±6E |
20±7E |
9±5E |
34±6E |
||
2-AA |
2.00 |
195 ±38 |
1310±17 |
|
|
|
|
2-AA |
5.00 |
|
|
173±17 |
413±6 |
|
|
2-AA |
10.0 |
|
|
|
|
319±18 |
Key to Positive Controls Key to Plate Postfix Codes
NaN3 Sodium azide E Precipitation until end of experiment
2-AA 2-Aminoanthracene
9-AA 9-Aminoacridine
DAUN Daunomycin
NQO 4-Nitroquinoline-N-oxide
Table 2 Summary 2nd Series
Metabolic Activation |
Test Material |
Concentr. [µg/plate] |
Revertants per plate (Mean ± SD) |
||||
TA 98 |
TA 100 |
TA 1535 |
TA 1537 |
WP2 uvrA |
|||
Without Activation |
DMSO |
|
24±12 |
115±15 |
23±4 |
9±5 |
32±5 |
Test tem |
50.0 |
26 ±6 |
106 ±10 |
17±5 |
11±6 |
33±2 |
|
158 |
35 ±9 |
121±7 |
23±1 |
13±7 |
40±5 |
||
500 |
27±4 |
126 ±4 |
20 ±5 |
8±5 |
44 ±8 |
||
1580 |
28±1 |
115 ±9 |
20±3 |
7±1 |
42 ±6 |
||
5000 |
28 ±4E |
136 ±10E |
24±5E |
12±5E |
36 ±6E |
||
DAUN |
2.00 |
243±64 |
|
|
|
|
|
NaN3 |
2.00 |
|
1728±58 |
957±15 |
|
|
|
9-AA |
50.0 |
|
|
|
2031±574 |
|
|
NQO |
2.00 |
|
|
|
|
1785±210 |
|
With Activation |
DMSO |
|
31±11 |
120 ±12 |
15±7 |
10±4 |
40±6 |
Test item |
50.0 |
28±3 |
130±15 |
19±4 |
15±3 |
43±5 |
|
158 |
25±3 |
132±13 |
18±4 |
10±2 |
43±2 |
||
500 |
29±8 |
148±12 |
16±5 |
7±2 |
42±3 |
||
1580 |
41±6 |
143±12 |
18±7 |
12±3 |
41±8 |
||
5000 |
55±3 |
125±14 |
19±5 |
9±3 |
33±5 |
||
2-AA |
2.00 |
485±55 |
788±72 |
|
|
|
|
2-AA |
5.00 |
|
|
247±47 |
219±24 |
|
|
2-AA |
10.0 |
|
|
|
|
330±28 |
Key to Positive Controls Key to Plate Postfix Codes
NaN3 Sodium azide E Precipitation until end of experiment
2-AA 2-Aminoanthracene
9-AA 9-Aminoacridine
DAUN Daunomycin
NQO 4-Nitroquinoline-N-oxide
Table 3: Historical Data
The historical data have been obtained in experiments between 01/2017 and 12/2017.
Negative Controls
Strain |
TA 98 |
TA 100 |
TA 1537 |
WP2 uvrA |
TA 1538 |
|||||
S9 Mix |
Without |
With |
Without |
With |
Without |
With |
Without |
With |
Without |
With |
Compound |
Solvent |
Solvent |
Solvent |
Solvent |
Solvent |
Solvent |
Solvent |
Solvent |
Solvent |
Solvent |
Total Plates |
486 |
486 |
482 |
488 |
394 |
394 |
434 |
433 |
44 |
44 |
Number of Values |
90 |
90 |
89 |
90 |
68 |
68 |
77 |
77 |
11 |
11 |
Minimum |
19 |
20 |
94 |
90 |
4 |
6 |
19 |
28 |
6 |
11 |
Maximum |
52 |
58 |
159 |
172 |
11 |
16 |
44 |
47 |
15 |
21 |
Mean |
36 |
42 |
118 |
123 |
8 |
10 |
30 |
3 |
12 |
15 |
Standard Deviation |
7.1 |
7.3 |
12.1 |
13.4 |
1.5 |
2.3 |
4.9 |
4.3 |
2.9 |
2.7 |
Positive Controls
Strain |
TA 98 |
TA 100 |
TA 1537 |
WP2 uvrA |
TA 1538 |
|||||
S9 Mix |
Without |
With |
Without |
With |
Without |
With |
Without |
With |
Without |
With |
Compound |
DAUN |
2-AA |
NaN3t |
2-AA |
9-AA |
2-AA |
NQO |
2-AA |
2-NF |
2-AA |
Total Plates |
243 |
243 |
242 |
244 |
203 |
203 |
217 |
217 |
22 |
22 |
Number of Values |
90 |
90 |
89 |
90 |
70 |
70 |
77 |
77 |
11 |
11 |
Minimum |
68 |
112 |
821 |
437 |
247 |
72 |
317 |
154 |
1087 |
461 |
Maximum |
779 |
3015 |
2376 |
3429 |
1485 |
705 |
2275 |
696 |
2511 |
1323 |
Mean |
243 |
738 |
1550 |
1386 |
736 |
293 |
1677 |
353 |
1909 |
1038 |
Standard Deviation |
134.2 |
508.4 |
213.6 |
724.3 |
284.9 |
161.7 |
381.9 |
129.2 |
470.3 |
285.3 |
Table 4: Optical Density
Salmonella typhimurium
Optical Density at 650 nm (Range 0.75- 1.45) |
||||
|
TA 98 |
TA 100 |
TA 1535 |
TA 1537 |
1stseries |
1.093 |
0.979 |
1.033 |
1.032 |
2ndseries |
1.123 |
1.006 |
1.075 |
1.037 |
Escherichia coli
Optical Density at 650 nm (Range 0.8-1.2) |
|
|
WP2 uvrA |
1stseries |
0.981 |
2ndseries |
1.074 |
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (negative)
Genetic toxicity in vivo
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
The test item was examined for its mutagenic activity in an in vitro bacterial reverse mutation test according OECD TG 471 employing Salmonella typhimurium TA 98, TA 100, TA 1535 and TA 1537, and Escherichia coli WP2 uvrA as indicator organisms.The plate incorporation test with and without addition of liver S9 mix from Phenobarbital/p-Naphthoflavone-pretreated rats was used. In this study, two experimental series were performed. In the experiments with S9 mix, 10% and 20% S9 in the S9 mix were used.Treatments of all tester strains were performed using formulations prepared in DMSO in the absence and in the presence of S9 mix, using final concentrations between 5 and 5000 µg/plate, plus vehicle and positive controls.
The mean numbers of revertant colonies of the current negative controls were within the range of historical negative control values.
The strain-specific positive controls, namely daunomycin, sodium azide, 4-nitroquinolin-N-oxide, and 9-aminoacridine in the absence of S9 mix, yielded the expected mutant frequencies that were greatly exceeding the negative controls. The genotype of the tester strains used was thus confirmed. 2-Aminoanthracene which requires metabolic activation, was strongly mutagenic. This indicates that the exogenous metabolizing system used in the present investigation (S9 mix) was active. Thus, the requirements predetermined have been met in total and the study is considered valid.Following treatment with the test item, precipitation of the test material on the agar plates occurred at concentrations > 5000 µg/plate. No toxicity to the bacteria was observed.
Under the conditions described, there were no relevant increases in revertant numbers observed after exposure tothe test item in the absence and presence of S9 mix (reference 7.6.1-1).
Justification for classification or non-classification
Classification, Labeling, and Packaging Regulation (EC) No 1272/2008
The available test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Thus, the test item is considered not to be classified for genotoxicity under Regulation (EC) No 1272/2008, as amended for the twelfth time in Regulation (EU) No 2019/521.
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