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EC number: 205-741-5 | CAS number: 149-45-1
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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:
- 15 Feb - 13 Mar 2017
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 017
- Report date:
- 2017
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Version / remarks:
- Adopted in 1997
- Deviations:
- yes
- Remarks:
- 2-Aminoanthracene was used as sole indicator of the efficacy of the S9-mix.
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- Slovak National Accreditation Service, Bratislava, Slovak Republic
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- Disodium 4,5-dihydroxybenzene-1,3-disulphonate
- EC Number:
- 205-741-5
- EC Name:
- Disodium 4,5-dihydroxybenzene-1,3-disulphonate
- Cas Number:
- 149-45-1
- Molecular formula:
- C6H6O8S2.2Na
- IUPAC Name:
- disodium 4,5-dihydroxybenzene-1,3-disulphonate
- Test material form:
- solid: particulate/powder
Constituent 1
Method
- Target gene:
- his operon (for S. typhimurium strains)
trp operon (for E. coli strains)
Species / strainopen allclose all
- Species / strain / cell type:
- other: S. typhimurium TA 97, TA 98, TA 100 and TA 1535
- Species / strain / cell type:
- E. coli WP2 uvr A
- Metabolic activation:
- with and without
- Metabolic activation system:
- cofactor supplemented post-mitochondrial fraction (S9 mix), prepared from the livers of male rats treated with Aroclor 1254
- Test concentrations with justification for top dose:
- Range-finding assay: 50, 150, 500, 1500, 2500 and 5000 µg/plate (TA 97, TA 100, and TA 1535 without metabolic activation)
Main (plate incorporation) assay: 50, 150, 500, 1500 and 5000 µg/plate (TA 97, TA 98, TA 100, TA 1535, and WP2uvrA with and without metabolic activation)
Preincubation assay: 15, 50, 150, 500, 1500 and 5000 µg/plate (TA 97, TA 98, TA 100, TA 1535, and WP2uvrA without metabolic activation) - Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: deionized water
- Justification for choice of solvent/vehicle: due to good test material solubility in deionized water
Controls
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- Remarks:
- deionized water
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- 4-nitroquinoline-N-oxide
- 9-aminoacridine
- 2-nitrofluorene
- sodium azide
- other: 2-Aminoanthracene
- Remarks:
- 2-AA was used as the sole indicator of the efficacy of the S9-mix. If 2-AA is used, each batch of S9 should also be characterised with a mutagen that requires metabolic activation by microsomal enzymes, e.g., benzo(a)pyrene, dimethylbenzanthracene.
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in medium (preincubation); in agar (plate incorporation)
- Cell density at seeding (if applicable): approximately 1 x 10e9 cells per mL
DURATION
- Preincubation period: 20 min
- Exposure duration: 48 - 72 h
NUMBER OF REPLICATIONS: triplicate plates in each of three independent experiments
DETERMINATION OF CYTOTOXICITY
- Method: mitotic index; relative total growth; the number of revertant colonies per plate were hand counted, not further specified - Evaluation criteria:
- The test material is considered positive if the assay is valid and the following conditions are met:
- concentration-related increase over the tested range and reproducible increase at one or more concentrations in the number of revertant colonies per plate in at least one strain with or without metabolic activation
- Mutation factor >2 (mutation factor is determined by [mean revertants (test)/ mean revertants (vehicle)]
A positive result indicates that the test material induces mutations in S. typhimurium or E.coli cells.
The test material for which results do not meet the above criteria is considered non-mutagenic in this test. Negative results indicate that under the test conditions, the test material does not produce mutations in S. typhimurium or E. coli cells. - Statistics:
- The mutation frequency at each dose concentration level of the test material was compared to the one observed in negative and positive controls. The statistical analysis was carried out using unpaired T-test.
Mean values and standard deviations were also calculated.
Results and discussion
Test resultsopen allclose all
- Key result
- Species / strain:
- S. typhimurium TA 97
- 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:
- 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:
- 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:
- not examined
- Positive controls validity:
- valid
- Additional information on results:
- HISTORICAL CONTROL DATA (with ranges, means and standard deviation)
- Historical control data: The mean revertants for controls for Salmonella tester strains and E.coli WP2 uvr were within the range of historical control values
Test Period: From 2015 to 2017
Negative Control (Revertants per plate)
Bacterial Strain TA 100 TA 1535 WP2uvrA TA 97 TA 98
Strain S9-mix -S9 +S9 -S9 +S9 -S9 +S9 -S9 +S9 -S9 +S9
Mean 199 179 21 23 42 47 166 200 25 37
SD 33 30 7 8 13 10 30 32 7 11
Min 131 123 6 11 25 35 114 148 12 19
Max 272 231 39 43 68 70 227 286 43 85
Positive Control (Revertants per plate)
Bacterial Strain TA 100 TA 1535 WP2uvrA TA 97 TA 98
Strain S9-mix -S9 +S9 -S9 +S9 -S9 +S9 -S9 +S9 -S9 +S9
Mean 718 1056 639 193 480 356 1191 931 243 805
SD 166 454 163 134 274 170 524 355 145 441
Min 440 398 376 34 82 194 400 376 117 256
Max 1148 2888 964 604 912 648 2776 1616 680 1644
Any other information on results incl. tables
Results for AF-378
Range Finding Assay |
|||
S9-Mix |
Without |
||
Test Item (mg/plate) |
Base-pair substitution type |
Frameshift type |
|
TA 100 |
TA 1535 |
TA 97 |
|
VC |
230 |
17 |
146 |
50 |
219 |
11* |
145 |
150 |
230 |
16 |
164 |
500 |
217 |
22 |
151 |
1500 |
239 |
16 |
154 |
2500 |
228 |
22 |
152 |
5000 |
230 |
20 |
162 |
PC (mg/plate) |
NaN3(1.5) |
NaN3(1.5) |
9-AA (75) |
776* |
573* |
833* |
VC = Vehicle control; PC = Positive control
NaN3= Sodium azide
9-AA = 9-Aminoacridene
-- = no value
* = different from Vehicle control p<0.05
EXPERIMENT 1 (Standard Plate Test) |
||||||||
S9-Mix |
Without |
|||||||
Test Item (mg/plate) |
Base-pair substitution type |
Frameshift type |
||||||
WP2uvrA |
TA 98 |
|||||||
VC |
47 |
20 |
31 |
|||||
50 |
41 |
22 |
37 |
|||||
150 |
32* |
24 |
30 |
|||||
500 |
49 |
21 |
37 |
|||||
1500 |
48 |
20 |
36 |
|||||
5000 |
38* |
17* |
35 |
|||||
PC (mg/plate) |
4-NQO (2.5) |
2-NF (3.0) |
2-NF (3.0) |
|||||
405* |
126* |
179* |
||||||
S9-Mix |
With |
|||||||
Test Item (mg/plate) |
Base-pair substitution type |
Frameshift type |
||||||
TA 100 |
TA 1535 |
WP2uvrA |
TA 98 |
TA 97 |
||||
VC |
213 |
14 |
45 |
44 |
26 |
157 |
||
50 |
215 |
15 |
48 |
43 |
20* |
142 |
||
150 |
209 |
16 |
44 |
45 |
29 |
162 |
||
500 |
204 |
15 |
35 |
48 |
23 |
172 |
||
1500 |
222 |
12 |
31* |
42 |
23 |
180* |
||
5000 |
223 |
13 |
33 |
37 |
21 |
182* |
||
PC (mg/plate) |
2AA (5) |
2AA (5) |
2AA (5) |
2AA (5) |
2AA (5) |
2AA (5) |
||
1359* |
115* |
501* |
241* |
789* |
721* |
VC = Vehicle control; PC = Positive control
NaN3= Sodium azide
4-NQO = 4-Nitroquinoline-N-oxide
2-NF = 2-Nitrofluorene
9-AA = 9-Aminoacridene
2AA = 2-Aminoanthracene
* = different from Vehicle control p<0.05
EXPERIMENT 2 (Standard Plate Test with Preincubation) |
||||||
S9-Mix |
Without |
|||||
Test Item (mg/plate) |
Base-pair substitution type |
Frameshift type |
||||
TA 100 |
TA 1535 |
WP2uvrA |
TA 98 |
TA 97 |
||
VC |
221 |
19 |
47 |
19 |
34 |
167 |
15 |
210 |
21 |
43 |
22 |
-- |
160 |
50 |
237 |
19 |
41 |
20 |
35 |
150* |
150 |
242 |
21 |
32* |
19 |
33 |
132* |
500 |
213 |
18 |
49 |
19 |
37 |
147* |
1500 |
213 |
17 |
48 |
23 |
27* |
159 |
5000 |
215 |
17* |
38* |
18 |
40 |
155* |
PC (mg/plate) |
NaN3(1.5) |
NaN3(1.5) |
4-NQO (2.5) |
2-NF (1.5) |
2-NF (3.0) |
9-AA (75) |
752* |
379* |
405* |
83* |
146* |
729* |
VC = Vehicle control; PC = Positive control
NaN3= Sodium azide
4-NQO = 4-Nitroquinoline-N-oxide
2-NF = 2-Nitrofluorene
9-AA = 9-Aminoacridene
2AA = 2-Aminoanthracene
-- = not tested
* = different from Vehicle control p<0.05
Remarks onstatistical significant results
Salmonella typhimuriumTA100:
Positive control (sodium azide) induced statistically significant increase (p<0.001) of revertant frequency under experimental conditions without activation (MF = 3.37).
Positive control (sodium azide) induced statistically significant increase (p<0.001) of revertant frequency under experimental conditions without activation (MF = 3.41).
Salmonella typhimuriumTA1535:
Statistical significance (p<0.05) recognised at test item concentration of 0.05 mg/plate was without biological relevance (mutation factor (MF)=0.65). Positive control (sodium azide) induced statistically significant increase (p<0.001) of revertant frequency under experimental conditions without activation (MF = 33.08). Positive control (sodium azide) induced statistically significant increase (p<0.001) of revertant frequency under experimental conditions without activation (MF = 19.96).
Salmonella typhimuriumTA97:
Positive control (9-aminoacridine) induced statistically significant increase (p<0.001) of revertant frequency under experimental conditions without activation (MF = 5.69). In experiments with preincubation the test item was tested in concentration range from 0.015 to 5.0 mg/plate. Statistical significance (p<0.05) recognized at test item concentration of 0.05, 0.15 and 0.5 mg/plate was without biological relevance (MF=0.89, 0.79 and 0.88, respectively). Positive control (9-aminoacridine) induced statistically significant increase (p<0.001) of revertant frequency under experimental conditions without activation (MF = 4.36). In experiment with activation the test item was tested in concentration range from 0.05 to 5.0 mg/plate. Statistical significance (p<0.05) recognized at test item concentration of 1.5 mg/plate and 5 mg/plate was without biological relevance (MF=1.15, and 1.16 respectively).
Salmonella typhimuriumTA98:
In the main tests without activation the test item was tested in concentration range from 0.05 to 5.0
mg/plate. The test item did not induce any statistically significant increases of revertant frequency.
Statistical significance (p<0.05) recognized at test item concentration of 5.0 mg/plate was without biological relevance (MF=0.86). Positive control (2NF) induced statistically significant increase (p<0.001) of revertant frequency (MF=6.41and 5.71). In experiments with pre incubation the test item was tested in concentration range from 0.015 to 5.0 mg/plate. Positive control (2-nitrofluorene) induced statistically significant increase (p<0.001) of revertant frequency under experimental conditions without activation (MF = 4.37, and 4.24).
E.coliWP 2 uvrA:
In experiments without activation, the test item was tested in concentration range from 0.05 to 5.0
mg/plate. Positive control (4-nitroquinoline 1-oxide) induced statistically significant increase of revertant frequency MF = 8.32). In experiments with preincubation the test item was tested in concentration range from 0.015 to 5.0 mg/plate. Statistical significance (p<0.05) recognized at test item concentration of 0.15 mg/plate and 5.0 mg/plate was without biological relevance (MF=0.67 and 0.81 ,respectively). Positive control induced statistically significant increase (p<0.001) of revertant frequency under experimental conditions without activation (MF = 8.61 Statistical significance (p<0.05)
recognized at test item concentration of 1.5 mg/plate in the first experiment was without biological relevance (MF=0.70).
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results: the test material AF-378 was negative for mutagenicity (non-mutagenic) with and without metabolic activation.
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