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EC number: 200-372-6 | CAS number: 58-27-5
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
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:
- 07 August 2017 - 11 September 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 017
- Report date:
- 2017
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Version / remarks:
- 21 July 1997
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.13/14 (Mutagenicity - Reverse Mutation Test Using Bacteria)
- Version / remarks:
- 31 May 2008
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- dd 3 November 2015
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- Menadione
- EC Number:
- 200-372-6
- EC Name:
- Menadione
- Cas Number:
- 58-27-5
- Molecular formula:
- C11H8O2
- IUPAC Name:
- 2-methyl-1,4-dihydronaphthalene-1,4-dione
- Test material form:
- solid: particulate/powder
- Details on test material:
- - Physical appearance: yellow crystalline powder
- Storage conditions: at room temperature protected from light
Constituent 1
- Specific details on test material used for the study:
- - No correction factor for purity required.
Method
- Target gene:
- Salmonella typhimurium: histidine gene
Escherichia coli: tryptophan gene
Species / strain
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and E. coli WP2
- Metabolic activation:
- with and without
- Metabolic activation system:
- Rat liver microsomal enzymes (S9 homogenate; 5 and 10%), prepared from male Sprague Dawley rats injected with Aroclor 1254 (500 mg/kg body weight).
- Test concentrations with justification for top dose:
- Dose range finding test (TA100 and WP2uvrA, with and without 5% S9): 1.7, 5.4, 17, 52, 164, 512, 1600 and 5000 μg/plate (reported as part of experiment 1)
Based on the cytotoxicity observed in the dose-range finding test, the dose-range for the following experiments were selected.
First experiment (TA1535, TA 1537 and TA98, with and without 5% S9): 0.55, 1.7, 5.4, 17, 52 and 164 μg/plate
Second experiment (TA1535, TA1537, TA98 and TA100, without S9): 8.5, 15, 27, 48, 86, and 154 μg/plate
Second experiment (TA1535, TA1537, TA98 and TA100, with 10% S9): 15, 27, 48, 86, 154 and 275 μg/plate
Second experiment (WP2uvrA, without S9): 27, 48, 86, 154, 275 and 492 μg/plate
Second experiment (WP2uvrA, with 10% S9): 86, 154, 275, 492, 878 and 1568 μg/plate
Third experiment (WP2uvrA without S9): 275, 492, 878, 1568 and 2800 μg/plate
Third experiment (TA98 with 10% S9): 50, 75, 100, 125, 150, 175 and 200 μg/plate - Vehicle / solvent:
- - Solvent used: dimethyl sulfoxide
- Justification for choice of solvent: A solubility test was performed based on visual assessment.
Controls
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- 4-nitroquinoline-N-oxide
- 2-nitrofluorene
- sodium azide
- methylmethanesulfonate
- other: ICR-191; 2-aminoanthracene
- Remarks:
- For more details on positive controls see section 'other information on materials and methods incl. tables'
- Details on test system and experimental conditions:
- Three experiments were performed. In the first experiment the test item was tested both in the presence and absence of 5% (v/v) S9-mix. In the second experiment the test item was tested both in the presence and absence of 10% (v/v) S9-mix. To verify and check the results from the second experiment, a third experiment was performed with strains TA98 (with 10% S9-mix) and WP2uvrA (without 10% S9-mix) only.
METHOD OF APPLICATION: in agar (plate incorporation)
DURATION
- Exposure duration: 48 +/- 4 hours
NUMBER OF REPLICATIONS: 3
METHOD: Top agar in top agar tubes was melted by heating to 45 ± 2°C. The following solutions were successively added to 3 ml molten top agar: 0.1 mL of a fresh bacterial culture (10^9 cells/mL) of one of the tester strains, 0.1 mL of a dilution of the test item in Milli-Q water and either 0.5 mL S9-mix (in case of activation assays) or 0.5 mL 0.1 M phosphate buffer (in case of non-activation assays). The ingredients were mixed on a Vortex and the content of the top agar tube was poured onto a selective agar plate. After solidification of the top agar, the plates were inverted and incubated in the dark at 37.0 ± 1.0 °C for 48 ± 4 h.
CYTOTOXICITY:
- Cytotoxicity was examined by the reduction of the bacterial background lawn, the increase in the size of the microcolonies and the reduction of the revertant colonies
COLONY COUNTING:
The revertant colonies were counted automatically with the Sorcerer Colony Counter. Plates with sufficient test item precipitate to interfere with automated colony counting were counted manually. Evidence of test item precipitate on the plates and the condition of the bacterial background lawn were evaluated when considered necessary, macroscopically and/or microscopically by using a dissecting microscope. - Evaluation criteria:
- A test item is considered negative (not mutagenic) in the test if:
a) The total number of revertants in the tester strain TA100 or WP2uvrA is not greater than two (2) times the concurrent vehicle control, and the total number of revertants in tester strains TA1535, TA1537 or TA98 is not greater than three (3) times the concurrent vehicle control.
b) The negative response should be reproducible in at least one follow-up experiment.
A test item is considered positive (mutagenic) in the test if:
a) The total number of revertants in the tester strain TA100 or WP2uvrA is greater than two (2) times the concurrent vehicle control, or the total number of revertants in tester strains TA1535, TA1537, TA98 is greater than three (3) times the concurrent vehicle control.
b) In case a follow up experiment is performed when a positive response is observed in one of the tester strains, the positive response should be reproducible in at least one follow up experiment.
Acceptability criteria:
a) The vehicle control and positive control plates from each tester strain (with or without S9-mix) must exhibit a characteristic number of revertant colonies when compared against relevant historical control data generated at this laboratory.
b) The selected dose-range should include a clearly toxic concentration or should exhibit limited solubility as demonstrated by the preliminary toxicity range-finding test or should extend to 5 mg/plate.
c) No more than 5% of the plates are lost through contamination or some other unforeseen event. If the results are considered invalid due to contamination, the experiment will be repeated.
Results and discussion
Test resultsopen allclose all
- Key result
- Species / strain:
- other: all strains
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- at all test concentrations
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- with
- Genotoxicity:
- positive
- Remarks:
- at the dose levels of 86 and 154 μg/plate, resp. 2.9- and 6.2-fold increase.
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- at 275 μg/plate
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- at 154 μg/plate
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Key result
- Species / strain:
- other: TA1535, TA1537 and TA100.
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- at 154 μg/plate and above
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Key result
- Species / strain:
- E. coli WP2 uvr A
- Metabolic activation:
- without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- at 275 μg/plate and above
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Key result
- Species / strain:
- E. coli WP2 uvr A
- Metabolic activation:
- with
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- at 878 μg/plate and above
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- with
- Genotoxicity:
- positive
- Remarks:
- at the dose levels of 75 to 175 μg/plate; up to 7.6-fold
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- 200 μg/plate
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Key result
- Species / strain:
- E. coli WP2 uvr A
- Metabolic activation:
- without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- 878 μg/plate and upwards
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Additional information on results:
- DOSE-RANGE FINDING STUDY AND EXPERIMENT 1:
- Precipitation: yes, at the start of the incubation period at concentrations of 1600 and 5000 μg/plate and at 5000 μg/plate (with and without metabolic activation) at the end of the incubation period.
- Cytotoxicity: yes, as evidenced by a decrease in the number of revertants and a reduction of the bacterial background lawn, cytotoxicity was observed in all tester strains in the absence and presence of S9-mix.
- Mutagenicity: no, there was no increase in the number of revertants upon treatment with the test item under all conditions tested.
EXPERIMENT 2:
- Precipitation: yes, at the start of the incubation period at the concentration of 1568 μg/plate (with metabolic activation) and no precipitate was observed at the end of the incubation period.
- Cytotoxicity: yes, as evidenced by a decrease in the number of revertants and/or a reduction of the bacterial background lawn, cytotoxicity was observed in all tester strains in the absence and presence of S9-mix, except in tester strain WP2uvrA in the absence of S9-mix.
- Mutagenicity: yes, in the presence of S9-mix, the test item induced increases in the number of revertant colonies in the tester strain TA98. The increases observed were above the laboratory historical data range at the dose levels of 86 and 154 μg/plate and were respectively 2.9- and 6.2-fold.
EXPERIMENT 3
- Precipitation: yes, at the start of the incubation period at the concentrations of 1568 and 2800 μg/plate (for tester strain WP2uvrA). No precipitate was observed at the end of the incubation period.
- Cytotoxicity: yes, as evidenced by a decrease in the number of revertants and/or a reduction of the bacterial background lawn, cytotoxicity was observed in tester strain WP2uvrA at concentrations of 878 μg/plate (without metabolic activation) and upwards and in strain TA98 at the top dose of 200 μg/plate (with metabolic activation).
- Mutagenicity: yes, the test item induced increases in the number of revertant colonies in the tester strain TA98. The increases observed were above the laboratory historical data range at the dose levels of 75, 100, 125, 150 and 175 μg/plate (tested with metabolic activation) and were 3.8-, 5.5-, 7.6-, 6.2- and 5.3-fold respectively.
HISTORICAL CONTROL DATA (see table 2 in 'any other information on results incl. tables')
- The solvent and strain-specific positive control values were within the laboratory historical control data ranges. This indicated that the test conditions were adequate and the metabolic activation system functioned properly. - Remarks on result:
- other: Experiment 1 (5% S9-mix used)
Any other information on results incl. tables
Table 2 Historical data for the solvent control
|
TA1535 |
TA1537 |
TA98 |
TA100 |
WP2uvrA |
|||||
S9-mix |
- |
+ |
- |
+ |
- |
+ |
- |
+ |
- |
+ |
Range |
3 - 36 |
3 - 32 |
3 – 20 |
3 – 23 |
8 - 41 |
9 - 55 |
66 - 161 |
63 - 160 |
10 – 59 |
9 - 69 |
Mean |
11 |
11 |
6 |
7 |
16 |
23 |
105 |
105 |
25 |
31 |
SD |
4 |
4 |
3 |
3 |
5 |
7 |
19 |
20 |
7 |
8 |
n |
2057 |
2039 |
1950 |
1931 |
2023 |
2083 |
2027 |
2033 |
1739 |
1745 |
SD = Standard deviation; n = Number of observations
Historical control data from experiments performed between May 2015 and May 2017.
Table 3 Historical data for the positive control
|
TA1535 |
TA1537 |
TA98 |
|||
S9-mix |
- |
+ |
- |
+ |
- |
+ |
Range |
125 - 1381 |
78 - 1058 |
55 – 1324 |
55 – 1051 |
410 – 1995 |
250 - 1977 |
Mean |
839 |
220 |
736 |
382 |
1369 |
929 |
SD |
153 |
112 |
331 |
150 |
310 |
345 |
n |
2065 |
1967 |
1740 |
1933 |
1920 |
2014 |
|
TA100 |
WP2uvrA |
||
S9-mix |
- |
+ |
- |
+ |
Range |
537 – 1848 |
408 - 2651 |
93 – 1951 |
93 - 1359 |
Mean |
908 |
1330 |
1128 |
422 |
SD |
178 |
324 |
484 |
151 |
n |
2007 |
2020 |
1679 |
1728 |
SD = Standard deviation; n = Number of observations
Historical control data from experiments performed between May 2015 and May 2017.
Applicant's summary and conclusion
- Conclusions:
- An AMES test was performed according to OECD/EC guidelines and GLP principles. Based on the results of this Ames test it is concluded that Menadione is mutagenic in tester strain TA98 of the Salmonella typhimurium reverse mutation assay in the presence of S9-mix. The test item is not mutagenic in tester strain TA98 in the absence of S9-mix, in the other Salmonella typhimurium tester strains (TA1535, TA1537 or TA100) or the Escherichia coli reverse mutation assay using strain WP2uvrA.
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