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EC number: 234-802-9 | CAS number: 12034-34-3
- 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
- Remarks:
- Type of genotoxicity: gene mutation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2010-04-14 to 2010-05-03
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study reliable without restrictions
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 010
- Report date:
- 2010
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Version / remarks:
- , 1997
- 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)
- Remarks:
- signed 2009-03-30
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- Disodium titanate
- EC Number:
- 234-802-9
- EC Name:
- Disodium titanate
- Cas Number:
- 12034-34-3
- Molecular formula:
- Na2O3Ti
- IUPAC Name:
- disodium oxotitaniumbis(olate)
- Details on test material:
- - Name of test material (as cited in study report): Disodium titanate
- Physical state: light yellow powder
- Storage condition of test material: At room temperature, in tightly closed container
No further information on the test material was stated.
Constituent 1
Method
- Target gene:
- the S. typhimurium histidine (his) system
- TA 1537: his C 3076; rfa-; uvrB-
- TA 98: his D 3052, rfa-, uvrB-; R-factor
- TA 1535: his G46; rfa-; uvrB-
- TA 102: his G 428; rfa-, uvrB+; R-factor
- TA 100: his G 46; rfa-, uvrB-, R-factor
The bacterial strains TA 1535, TA 1537, TA 98, TA 100, TA 102 were obtained from Trinova Biochem GmbH (35394 Gießen, Germany).
Species / strain
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
- Metabolic activation:
- with and without
- Metabolic activation system:
- S9 preparation with 34.3 mg/mL (Lot no. R 220110) in the pre-experiment/experiment I and experiment II.
- Test concentrations with justification for top dose:
- - experiment I: 3, 10, 33, 100, 333, 1000, 2500, and 5000 µg/plate
- experiment II: 3, 10, 33, 100, 333, 1000, 2500, and 5000 µg/plate - Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: on the day of the experiment, the test item was suspended in deionised water
- Justification for choice of solvent: the solvent was chosen because of its solubility properties
Controls
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: without metabolic activation: sodium azide (TA 1535, TA100); 4-nitro-o-phenylene-diamine (TA1537, TA98); methyl methane sulfonate (TA102). With metabolic activation: 2-aminoanthracene (TA1535, TA1537, TA98, TA100, TA102)
- Details on test system and experimental conditions:
- METHOD OF APPLICATION:
Experiment I was performed as a plate incorporation assay. Since a negative result was obtained in this experiment, experiment II was performed as a pre-incubation assay. The assay was performed in two independent experiments both with and without liver microsomal activation. Each concentration, including the controls, was tested in triplicate.
Precultures:
From the thawed ampoules of the strains 0.5 mL bacterial suspension was transferred into 250 mL Erlenmeyer flasks containing 20 mL nutrient medium. A solution of 20 μL ampicillin (25 μg/mL) was added to the strains TA 98, TA 100, and TA 102. This nutrient medium contains per litre 8 g Nutrient Broth (MERCK, D-64293 Darmstadt) and 5 g NaCl (MERCK, D-64293 Darmstadt). The bacterial cultures were incubated in a shaking water bath for 4 hours at 37° C. The optical density of the bacteria was determined by absorption measurement and the obtained values indicated that the bacteria were harvested at the late exponential or early stationary phase (10E8-10E9 cells/mL).
Agar:
The plates with the minimal agar were obtained from E. Merck, D-64293 Darmstadt. The overlay agar contains per litre 6.0 g Agar Agar, 6.0 g NaCl, 10.5 mg L-Histidine x HCl x H2O and 12.2 mg Biotin (MERCK, D-64293 Darmstadt). Sterilisations were performed at 121 °C in an autoclave.
MAMMALIAN MICROSOMAL FRACTION S9 MIX
The bacteria used in this assay do not possess the enzyme systems which, in mammals, are known to convert promutagens into active DNA damaging metabolites. In order to overcome this major drawback an exogenous metabolic system is added in form of mammalian microsome enzyme activation mixture.
S9 (Preparation by Harlan CCR):
Phenobarbital/β-Naphthoflavone induced rat liver S9 is used as the metabolic activation system. The S9 is prepared from 8 - 12 weeks old male Wistar rats (Hsd Cpb: WU, Harlan Laboratories GmbH, 33178 Borchen, Germany), weight approx. 220 - 320 g induced by applications of 80 mg/kg b.w. Phenobarbital i.p. (Desitin; D-22335 Hamburg) and β-Naphthoflavone p.o. (Aldrich, D-89555 Steinheim) each on three consecutive days. The livers are prepared 24 hours after the last treatment. The S9 fractions are produced by dilution of the liver homogenate with a KCl solution (1+3) followed by centrifugation at 9000 g. Aliquots of the supernatant are frozen and stored in ampoules at -80 °C. Small numbers of the ampoules can be kept at -20 °C for up to one week. Each batch of S9 mix is routinely tested with 2-aminoanthracene as well as benzo(a)pyrene. The protein concentration in the S9 preparation was 34.3 mg/mL (lot no. R 220110) in both experiments.
S9 Mix:
Before the experiment an appropriate quantity of S9 supernatant was thawed and mixed with S9 co-factor solution. The amount of S9 supernatant was 10% v/v in the S9 mix. Cofactors are added to the S9 mix to reach the following concentrations in the S9 mix:
- 8 mM MgCl2
- 33 mM KCl
- 5 mM Glucose-6-phosphate
- 4 mM NADP
in 100 mM sodium-ortho-phosphate-buffer, pH 7.4.
During the experiment the S9 mix was stored in an ice bath. The S9 mix preparation was performed according to Ames et al. (1977).
EXPERIMENTAL PERFORMANCE:
For each strain and dose level, including the controls three plates were used. The following materials were mixed in a test tube and poured onto the selective agar plates:
- 100 μL Test solution at each dose level (solvent or reference mutagen solution (positive control)),
- 500 μL S9 mix (for test with metabolic activation) or S9 mix substitution buffer (for test without metabolic activation),
- 100 μL Bacteria suspension (cf. test system, pre-culture of the strains),
- 2000 μL Overlay agar
In the pre-incubation assay 100 μL test solution (solvent or reference mutagen solution (positive control)), 500 μL S9 mix / S9 mix substitution buffer and 100 μL bacterial suspension were mixed in a test tube and incubated at 37 °C for 60 minutes. After pre-incubation 2.0 mL overlay agar (45 °C) was added to each tube. The mixture was poured on minimal agar plates. After solidification the plates were incubated upside down for at least 48 hours at 37 °C in the dark.
DATA RECORDING:
The colonies were counted using the Petri Viewer Mk2 (Perceptive Instruments Ltd, Suffolk CB9 7BN, UK) with the software program Ames Study Manager. The counter was connected to a PC running under Windows XP. The individual and mean values of the plates for each concentration together with standard deviations and enhancement factors as compared to the spontaneous reversion rates (see tables of results). Due to precipitation the plates were partly counted manually. - Evaluation criteria:
- The Salmonella typhimurium reverse mutation assay is considered acceptable if it meets the following criteria:
- regular background growth in the negative and solvent control
- the spontaneous reversion rates in the negative and solvent control are in the range of historical data
- the positive control substances should produce a significant increase in mutant colony frequencies
A test item is considered as a mutagen if a biologically relevant increase in the number of revertants exceeding the threshold of twice (strains TA98, TA100, and TA102) or thrice (strains TA1535 and TA1537) the colony count of the corresponding solvent control is observed.
A dose dependent increase is considered biologically relevant if the threshold is exceeded at more than one concentration.
An increase exceeding the threshold at only one concentration is judged as biologically relevant if reproduced in an independent second experiment.
A dose dependent increase in the number of revertant colonies below the threshold is regarded as an indication of a mutagenic potential if reproduced in an independent second experiment. However, whenever the colony counts remain within the historical range of negative and solvent controls such an increase is not considered biologically relevant. - Statistics:
- According to the OECD guideline 471, a statistical analysis of the data is not mandatory.
Results and discussion
Test resultsopen allclose all
- Species / strain:
- S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 102
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Precipitation: the test item precipitated in the overlay agar in the test tubes and on the incubated agar plates from 1000 up to 5000 μg/plate in both experiments. The undissolved particles of the test item had no influence on the data recording.
RANGE-FINDING/SCREENING STUDIES:
To evaluate the toxicity of the test item a pre-experiment was performed with all strains used. Eight concentrations were tested for toxicity and mutation induction with each 3 plates. The experimental conditions in this pre-experiment were the same as described for the experiment I (plate incorporation test). Toxicity of the test item can be evident as a reduction in the number of spontaneous revertants or a clearing of the bacterial background lawn. The pre-experiment is reported as main experiment I, since the criteria evaluable plates (>0 colonies) at five concentrations or more in all strains used are met. - Remarks on result:
- other: all strains/cell types tested
- Remarks:
- Migrated from field 'Test system'.
Any other information on results incl. tables
DISCUSSION OF RESULTS
- The plates incubated with the test item showed normal background growth up to 5000 µg/plate with and without S9 mix in all strains used.
- Toxic effects, evident as a reduction in the number of revertants (below the induction factor of 0.5), were observed at the following concentrations (μg/plate):
Strain |
Experiment I |
Experiment II |
||
|
without S9 mix |
with S9 mix |
without S9 mix |
with S9 mix |
TA 1535 |
/ |
2500 - 5000 |
2500 |
5000 |
TA 1537 |
5000 |
2500 - 5000 |
/ |
5000 |
TA 98 |
/ |
5000 |
/ |
5000 |
TA 100 |
/ |
5000 |
/ |
5000 |
TA 102 |
5000 |
2500 - 5000 |
5000 |
2500 - 5000 |
/ = no toxic effects evident as a reduction in the number of revertants (below the induction factor of 0.5)
- No substantial increase in revertant colony numbers of any of the five tester strains was observed following treatment with Disodium titanate at any concentration level, neither in the presence nor absence of metabolic activation (S9 mix). There was also no tendency of higher mutation rates with increasing concentrations in the range below the generally acknowledged border of biological relevance.
Summary of results of experiment I:
Metabolic activation |
Test group |
Dose level [µg/plate] |
Revertant colony counts (mean ± SD) |
||||
TA 1535 |
TA 1537 |
TA 98 |
TA 100 |
TA 102 |
|||
|
|||||||
Without activation |
Deionised water |
- |
16±5 |
11±1 |
28±6 |
139±12 |
382±24 |
Untreated |
- |
14±1 |
13±2 |
34±6 |
146±8 |
369±34 |
|
Disodium titanate |
3µg |
13±3 |
11±3 |
27±7 |
131±3 |
363±26 |
|
10 µg |
15±3 |
13±2 |
24±2 |
148±11 |
398±9 |
||
33 µg |
15±1 |
10±2 |
30±3 |
140±5 |
413±14 |
||
100 µg |
15±2 |
12±2 |
26±5 |
124±12 |
403±22 |
||
333 µg |
16±4 |
10±2 |
25±5 |
131±9 |
373±13 |
||
1000 µg |
11±4P |
09±1P |
28±5P |
132±4P |
398±29P |
||
2500 µg |
12±2P |
6±1P |
23±1P |
123±18P |
238±19P |
||
5000 µg |
11±1PM |
2±2PM |
24±3PM |
131±4PM |
75±10PM |
||
NaN3 |
10 µg |
1935±127 |
- |
- |
2012±67 |
- |
|
4-NOPD |
10 µg |
- |
- |
329±26 |
- |
- |
|
4-NOPD |
50 µg |
- |
70±5 |
- |
- |
- |
|
MMS |
3.0 µL |
- |
- |
- |
- |
3163±174 |
|
|
|||||||
With activation |
Deionised water |
- |
22±5 |
14±4 |
39±10 |
131±17 |
611±24 |
Untreated |
- |
22±2 |
13±3 |
51±4 |
137±7 |
559±19 |
|
Disodium titanate |
3 µg |
23±3 |
17±3 |
40±5 |
125±10 |
568±8 |
|
10 µg |
22±6 |
14±3 |
41±10 |
131±5 |
598±12 |
||
33 µg |
23±1 |
15±1 |
41±3 |
128±5 |
565±9 |
||
100 µg |
20±6 |
14±1 |
37±4 |
138±5 |
537±23 |
||
333 µg |
15±1 |
15±7 |
43±13 |
137±8 |
530±38 |
||
1000 µg |
14±1P |
14±3P |
41±10P |
118±13P |
421±37PM |
||
2500 µg |
8±2PM |
4±1PM |
22±6PM |
108±4PM |
25±4PM |
||
5000 µg |
2±2PM |
1±1PM |
11±1PM |
38±3PM |
5±2PM |
||
2-AA |
2.5 µg |
483±31 |
437±42 |
2941±199 |
3297±56 |
- |
|
2-AA |
10.0 µg |
- |
- |
- |
- |
3252±169 |
Summary of results of experiment II:
Metabolic activation |
Test group |
Dose level [µg/plate] |
Revertant colony counts (mean ± SD) |
||||
TA 1535 |
TA 1537 |
TA 98 |
TA 100 |
TA 102 |
|||
|
|||||||
Without activation |
Deionised water |
- |
15±2 |
25±1 |
29±1 |
145±10 |
409±9 |
Untreated |
- |
18±2 |
24±0 |
36±8 |
144±7 |
398±35 |
|
Disodium titanate |
3 |
16±6 |
28±3 |
26±3 |
139±10 |
385±6 |
|
10 |
17±2 |
27±3 |
30±4 |
147±16 |
386±6 |
||
33 |
16±4 |
24±9 |
30±3 |
137±4 |
394±4 |
||
100 |
19±2 |
26±1 |
30±2 |
150±4 |
370±9 |
||
333 |
14±6 |
25±3 |
27±4 |
134±10 |
371±3 |
||
1000 |
9±3P |
24±10P |
29±1P |
141±17P |
360±14P |
||
2500 |
5±3P |
21±7P |
25±2P |
118±14P |
334±10P |
||
5000 |
9±2PM |
18±4PM |
22±4PM |
124±10P |
53±9PM |
||
NaN3 |
10 |
1757±92 |
- |
- |
1997±58 |
- |
|
4-NOPD |
10 |
- |
- |
305±2 |
- |
- |
|
4-NOPD |
50 |
- |
80±9 |
- |
- |
- |
|
MMS |
3.0 µL |
- |
- |
- |
- |
3617±110 |
|
|
|||||||
With activation |
Deionised water |
- |
23±4 |
24±3 |
39±2 |
152±3 |
603±10 |
Untreated |
- |
21±4 |
27±2 |
46±1 |
154±19 |
517±60 |
|
Disodium titanate |
3 |
23±7 |
22±3 |
38±3 |
155±10 |
598±16 |
|
10 |
23±4 |
25±4 |
40±4 |
156±11 |
600±14 |
||
33 |
20±2 |
30±3 |
41±7 |
162±7 |
636±54 |
||
100 |
24±5 |
29±1 |
43±5 |
168±14 |
588±77 |
||
333 |
20±5 |
21±8 |
39±6 |
149±20 |
562±65 |
||
1000 |
16±4P |
19±4P |
38±6P |
141±7P |
427±20PM |
||
2500 |
14±4P |
13±0P |
31±10P |
97±16P |
63±9PM |
||
5000 |
3±1PM |
1±1PM |
16±4PM |
66±10PM |
6±2PM |
||
2-AA |
2.5 |
427±28 |
387±3 |
2644±148 |
2542±4 |
- |
|
2-AA |
10.0 |
- |
- |
- |
- |
2491±7 |
NaN3
|
sodium azide |
P
|
Precipitate
|
2-AA
|
2-aminoanthracene |
M |
Manual count |
MMS
|
methyl methane sulfonate |
|
|
4-NOPD |
4-nitro-o-phenylene-diamine |
|
|
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information):
negative
Disodium titanate is considered to be non-mutagenic in this Salmonella typhimurium reverse mutation assay. - Executive summary:
In conclusion, it can be stated that during the described mutagenicity test and under the experimental conditions reported, the test item did not induce gene mutations by base pair changes or frameshifts in the genome of the strains used.
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