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EC number: 257-471-2 | CAS number: 51850-20-5
Genetic toxicity: in vitro
Administrative data
- Endpoint:
- in vitro gene mutation study in bacteria
- Remarks:
- Type of genotoxicity: gene mutation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 30 July to 2 September 2013
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline study, performed to GLP.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
- Report date:
- 2013
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Deviations:
- yes
- Remarks:
- Minor deviations did not affect the overall interpretation of study findings or compromise integrity of the study
- GLP compliance:
- yes
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- Dihydrogen hexahydroxyplatinate
- EC Number:
- 257-471-2
- EC Name:
- Dihydrogen hexahydroxyplatinate
- Cas Number:
- 51850-20-5
- Molecular formula:
- H6O6Pt.2H
- IUPAC Name:
- hexahydroxyplatinate(2-)
- Test material form:
- solid - liquid: suspension
- Details on test material:
- - Name of test material (as cited in study report): dihydrogen hexahydroxyplatinate
- Substance type: no data
- Physical state: yellow powder
- Analytical purity: 99-100%
- Impurities (identity and concentrations) (ppm): carbon (795); (ppm with respect to metal): silver (137), aluminium (20), calcium (48), chromium (15), copper (20), iron (128), iridium (26), potassium (15), magnesium (6), manganese (3), molybdenum (8), sodium (714), nickel (28), osmium (29), palladium (74), rhodium (32), ruthenium (11), silicon (54), tellurium (2), zirconium (3)
- Composition of test material, percentage of components: 64.83% platinum
- Isomers composition: no data
- Purity test date: 28 May 2013
- Lot/batch No.: CZ0185
- Expiration date of the lot/batch: May 2018
- Stability under test conditions: no data
- Storage condition of test material: 15-25°C, protected from light
Constituent 1
Method
- Target gene:
- Histidine locus
Species / strainopen allclose all
- Species / strain / cell type:
- other: S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102 (main study (Experiments 1 and 2))
- Additional strain / cell type characteristics:
- other: histidine-requiring
- Species / strain / cell type:
- other: S. typhimurium TA 98, TA 100 and TA 102 (range-finding study)
- Additional strain / cell type characteristics:
- other: histidine-requiring
- Metabolic activation:
- with and without
- Metabolic activation system:
- Aroclor 1254-induced rat liver S-9
- Test concentrations with justification for top dose:
- Range-finding study: 0, 5, 15.8, 50, 158.1, 500, 1581 or 5000 µg/plate
Main study:
Experiment 1: 0, 5, 15.8, 50, 158.1, 500, 1581 or 5000 µg/plate
Experiment 2: 0, 156.3, 312.5, 625, 1250, 2500 or 5000 µg/plate - Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: dimethylformamide (DMF)
- Justification for choice of solvent/vehicle: preliminary solubility data indicated that dihydrogen hexahydroxyplatinate was insoluble in several commonly used solvents including water, acetone, anhydrous analytical grade dimethyl sulphoxide (DMSO), ethanol, tetrahydrofuran and dimethylformamide (DMF). The test article formed a homogenous suspension at approximately 50 mg/mL in water and at approximately 299 mg/mL in DMSO, DMF and acetone.
Controlsopen allclose all
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- Remarks:
- DMF
- True negative controls:
- no
- Positive controls:
- yes
- Remarks:
- 5 µg/plate
- Positive control substance:
- 2-nitrofluorene
- Remarks:
- TA98, without S-9
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- Remarks:
- DMF
- True negative controls:
- no
- Positive controls:
- yes
- Remarks:
- 2 µg/plate
- Positive control substance:
- sodium azide
- Remarks:
- TA100 and TA1535, without S-9
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- Remarks:
- DMF
- True negative controls:
- no
- Positive controls:
- yes
- Remarks:
- 50 µg/plate
- Positive control substance:
- 9-aminoacridine
- Remarks:
- TA1537, without S-9
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- Remarks:
- DMF
- True negative controls:
- no
- Positive controls:
- yes
- Remarks:
- 0.2 µg/plate
- Positive control substance:
- mitomycin C
- Remarks:
- TA102, without S-9
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- Remarks:
- DMF
- True negative controls:
- no
- Positive controls:
- yes
- Remarks:
- 10 µg/plate
- Positive control substance:
- benzo(a)pyrene
- Remarks:
- TA98, with S-9
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- Remarks:
- DMF
- True negative controls:
- no
- Positive controls:
- yes
- Remarks:
- 5 µg/plate (TA100, TA1535, TA1537), 20 µg/plate (TA102)
- Positive control substance:
- other: 2-aminoanthracene
- Remarks:
- TA100, TA102, TA1535 and TA1537, with S-9
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in agar (plate incorporation)
DURATION
- Preincubation period: 20 min (Experiment 2, TA1535 and TA1537 with S-9)
- Exposure duration: 3 days
- Fixation time (start of exposure up to fixation or harvest of cells): ~3 days
NUMBER OF REPLICATIONS: single test plates (range-finding study); triplicate (main study (Experiments 1 and 2))
SELECTION AGENT (mutation assays): histidine-free medium
DETERMINATION OF CYTOTOXICITY
- Method: other: background lawns examined for signs of toxicity (e.g. marked reduction in revertants compared to controls) - Evaluation criteria:
- For valid data, the test article was considered to be mutagenic if:
1. When assessed using Dunnett's test, an increase in revertant numbers gave a significant response (p≤0.01) which was concentration related.
2. The positive trend/effects described above were reproducible.
The test article was considered positive in this assay if all of the above criteria were met.
The test article was considered negative in this assay if none of the above criteria were met.
Results which only partially satisfied the above criteria were dealt with on a case-by-case basis. Biological relevance was taken into account, for example
consistency of response within and between concentrations and (where applicable) between experiments. - Statistics:
- Dunnett's test was used to assess the probability of the observed results arising by chance. Results were considered statistically significant when p≤0.01.
Results and discussion
Test resultsopen allclose all
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- with
- Genotoxicity:
- positive
- Remarks:
- in Experiments 1 and 2
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- without
- Genotoxicity:
- positive
- Remarks:
- in Experiments 1 and 2
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 100
- Metabolic activation:
- with
- Genotoxicity:
- positive
- Remarks:
- in Experiments 1 and 2
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 100
- Metabolic activation:
- without
- Genotoxicity:
- positive
- Remarks:
- in Experiments 1 and 2
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 102
- Metabolic activation:
- with
- Genotoxicity:
- positive
- Remarks:
- in Experiments 1 and 2
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- in Experiment 1 at 5000 µg/plate
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 102
- Metabolic activation:
- without
- Genotoxicity:
- ambiguous
- Remarks:
- statistically significant increase in revertants in Experiments 1 and 2, but not clearly concentration-related or reproducible
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 1535
- Metabolic activation:
- with
- Genotoxicity:
- positive
- Remarks:
- in Experiment 2, with pre-incubation
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- in Experiment 1 from 500 or 1581 µg/plate
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 1535
- Metabolic activation:
- without
- Genotoxicity:
- ambiguous
- Remarks:
- statistically significant increase in revertants in Experiment 2, but not clearly concentration-related or reproducible
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- in Experiment 1 from 500 or 1581 µg/plate
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 1537
- Metabolic activation:
- with
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 1537
- Metabolic activation:
- without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- in Experiment 2, at 5000 µg/plate
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Additional information on results:
- See tables 1 and 2 for revertant numbers/plate for experiments 1 and 2.
TEST-SPECIFIC CONFOUNDING FACTORS
- Effects of pH: no data
- Effects of osmolality: no data
- Evaporation from medium: no data
- Water solubility: no data
- Precipitation: noted in all strains treated with 5000 µg/plate, with and without S-9 (in Experiments 1 and 2)
- Other confounding effects: no data
RANGE-FINDING/SCREENING STUDIES: no evidence of cytotoxicity in tested strains (TA98, TA100 and TA102). Range-finding data were considered to be acceptable for cytotoxicity assessment only.
COMPARISON WITH HISTORICAL CONTROL DATA: results for vehicle controls were compared to historical control data from within the laboratory.
ADDITIONAL INFORMATION ON CYTOTOXICITY: cytotoxicity was observed as a slight thinning of the background bacterial lawn, a marked reduction in revertant numbers, or a complete killing of the test bacteria. - Remarks on result:
- other: all strains/cell types tested
- Remarks:
- Migrated from field 'Test system'.
Any other information on results incl. tables
Table 1: Number of revertants per plate (mean of 3 plates (5 for negative control)) – Experiment 1
|
TA98 |
TA100 |
TA102 |
TA1535 |
TA1537 |
|||||
Conc. |
-S-9 |
+S-9 |
-S-9 |
+S-9 |
-S-9 |
+S-9 |
-S-9 |
+S-9 |
-S-9 |
+S-9 |
0 (DMF) |
22.8 |
24.0 |
96.2 |
89.4 |
235.0 |
198.8 |
21.2 |
16.6 |
8.2 |
11.0 |
5 |
16.3 |
27.3 |
72.0 |
84.7 |
242.3 |
217.3 |
17.0 |
13.7 |
7.0 |
6.0 |
15.8 |
18.7 |
32.7 |
88.0 |
91.3 |
231.3 |
243.7 |
15.7 |
12.7 |
7.3 |
8.7 |
50 |
16.0 |
34.3 |
97.7 |
130.3** |
253.7 |
252.3* |
17.7 |
13.3 |
9.3 |
10.7 |
158.1 |
24.0 |
41.3 |
123.0* |
152.3** |
248.3 |
297.3** |
15.0 |
11.7 |
10.3 |
8.0 |
500 |
32.3* |
93.0** |
162.3** |
267.3** |
324.3** |
414.0** |
8.7 |
12.0 |
4.0 |
7.0 |
1581 |
54.7** |
118.0** |
164.3** |
272.7** |
184.7 |
483.3** |
9.0 |
5.7 |
6.7 |
5.3 |
5000 |
53.7** |
81.0** |
154.7** |
231.7** |
161.3 |
490.5** |
6.0 |
7.0 |
6.0 |
6.7 |
Positive control |
583.3 |
351.7 |
504.3 |
984.7 |
612.0 |
1169.0 |
416.0 |
175.7 |
180.0 |
151.0 |
*p≤0.05
**statistically significant, p≤0.01
Table 2: Number of revertants per plate (mean of 3 plates (5 for negative control)) – Experiment 2
TA98 |
TA100 |
TA102 |
TA1535 |
TA1537 |
||||||
Conc. |
-S-9 |
+S-9 |
-S-9 |
+S-9 |
-S-9 |
+S-9 |
-S-9 |
+S-9 |
-S-9 |
+S-9 |
0 (DMF) |
23.8 |
34.4 |
116.6 |
118.8 |
264.8 |
242.2 |
23.2 |
14.6 |
8.2 |
12.0 |
156.3 |
41.7** |
105.3** |
171.7** |
437.0** |
280.0 |
442.7** |
36.7 |
49.7** |
4.7 |
9.7 |
312.5 |
56.3** |
161.7** |
209.7** |
446.0** |
297.3 |
557.7** |
41.3* |
51.3** |
4.7 |
5.7 |
625 |
55.7** |
158.7** |
212.0** |
514.7** |
373.3** |
669.7** |
44.0** |
38.3** |
6.7 |
8.7 |
1250 |
63.0** |
210.3** |
205.7** |
612.7** |
361.3** |
662.7** |
34.7 |
45.3** |
4.3 |
9.7 |
2500 |
77.0** |
172.7** |
230.0** |
495.7** |
284.3 |
458.0** |
46.0** |
46.3** |
5.3 |
10.0 |
5000 |
66.7** |
159.7** |
190.0** |
423.0** |
203.3 |
278.7 |
27.3 |
45.7** |
3.0 |
7.7 |
Positive control |
923.7 |
384.7 |
665.7 |
1491.3 |
865.0 |
1520.0 |
580.0 |
302.7 |
104.0 |
173.7 |
*p≤0.05
**statistically significant, p≤0.01
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information):
positive
In a good-quality Ames assay, conducted according to GLP and OECD Test Guideline 471, dihydrogen hexahydroxyplatinate displayed evidence of mutagenicity when tested in five Salmonella typhimurium strains (TA98, TA100, TA102, TA1535 and TA1537), in the presence and absence of a rat liver metabolic activation (S9) system. - Executive summary:
Dihydrogen hexahydroxyplatinate was assessed for mutagenicity in a bacterial reverse mutation (Ames) assay performed to GLP, and according to OECD Guideline 471. Triplicate cultures of Salmonella typhimurium strains TA98, TA100, TA102, TA1535 and TA1537 were tested with and without the addition of a mammalian (rat liver) metabolic activation (S9) system in two separate experiments.
In the first experiment, agar containing the test substance at up to 5000 µg/plate was incubated with the bacterial strains for 3 days. The second experiment, also using concentrations of up to 5000 µg/plate, included an additional 20-minute pre-incubation step for cultures of TA1535 and TA1537 in the presence of S9.
There was significant evidence of mutagenicity in strains TA98 and TA100, with and without S9, and TA1535 and TA102 in the presence of S9 only. The lowest concentration producing a statistically significant increase in the number of revertant colonies was 50 µg/plate (for TA100, with S9). Cytotoxicity was observed at high concentrations in some of the test plates.Vehicle and positive controls performed as expected.
Under the conditions of this assay, dihydrogen hexahydroxyplatinate was mutagenic to S. typhimurium, with and without metabolic activation.
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