potassium titanium oxide (K2Ti6O13)

Acute Toxicity: other routes

Administrative data

Endpoint:

acute toxicity: other routes

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Jan to June 2007

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP compliant study but study report available. The report contains limited experimental detail.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2007

Report date:

2007

Materials and methods

Test guideline

Qualifier:

no guideline available

Guideline:

other: Intratracheal instillation

Principles of method if other than guideline:

Research performed to quantify particle characteristics, perform quantitative analysis of the lung tissue samples to determine lung burden, examine biopersistance, and observe histopathological changes to evaluate inflammatory and fibrotic response.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

TOFIX-S

IUPAC Name:

TOFIX-S

Constituent 2

Reference substance name:

Reference substance 001

Test material form:

solid: fibres

Details on test material:

- Name of test material (as cited in study report): Potassium titanium oxide
- Molecular formula (if other than submission substance):
- Molecular weight (if other than submission substance):
- Smiles notation (if other than submission substance):
- InChl (if other than submission substance):
- Structural formula attached as image file (if other than submission substance): see Fig.
- Substance type:
- Physical state:Particle (fibre)
- Analytical purity:No data
- Impurities (identity and concentrations):No data
- Composition of test material, percentage of components:No data
- Isomers composition:No data
- Purity test date:No data
- Lot/batch No.:No data
- Expiration date of the lot/batch:No data
- Radiochemical purity (if radiolabelling):
- Specific activity (if radiolabelling):
- Locations of the label (if radiolabelling):
- Expiration date of radiochemical substance (if radiolabelling):
- Stability under test conditions:Stable
- Storage condition of test material:No data
- Other:Particle dimensions: Diameter Geometric Mean Diameter 1.4um; Geometric Standard Deviation 1.5; Geometric Mean Length 6.2 um; Geometric Standard Deviation 1.8. Approximately 15% of fibres were found to be less than 0.8um in diameter but were shorter than 20um. No fibres longer than 20um were found.

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

70 (nine week old) male Wistar rats were used.
The source of animals, diet, water, acclimatisation, weight and environmental conditions animals were maintained under was not documented.

Administration / exposure

Route of administration:

other: intratracheal instillation

Vehicle:

physiological saline

Details on exposure:

See report

Doses:

Single administration, 2 mg of TOFIX-S in 0.4ml of saline

No. of animals per sex per dose:

35 treated with Tofix-S via intratracheal Instillation with the remainder kept as control animals.

Control animals:

yes

Details on study design:

See attached report
- Duration of observation period following administration: 6 months
- Frequency of observations and weighing:Clinical observations, daily; body weights, weekly
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: Organ weights and histopathology at 3 days, 1 week, 1 month, 3 months and 6 months post-dose.

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

other: discriminating concentration

Effect level:

< 2 other: mg (total dose)

Based on:

test mat.

Mortality:

none

Clinical signs:

No effects of treatment reported

Body weight:

No effects of treatment reported

Gross pathology:

no details

Other findings:

Biological half life in the lungs is 2.2 months.
- Organ weights: No significant differences were found
- Histopathology: No significant differences were found
- Potential target organs: Lung
- Other observations: Lung burden of TOFIX-S was increased after treatment; Formation of 8-hydroxydeoxyguanosine, fibrosis related gene, TIMP-2 were not increased by treatment up to 6 months after dosing;

Applicant's summary and conclusion

Conclusions:

The substance is relatively harmless.
Tofix-S was predicted to have limited biological effect after a single intratracheal instillation. The biological half-life of TOFIX-S was determined to be 2.2 months. Measurements of indices for lung inflammation and fibrogenesis did not predict a fibrogenic response. No significant histopathological changes and no significant increase in the formation of 8-hydroxydeoxyguanosine (indicative of oxidative damage) was observed relative to the control.

Executive summary:

The biological effects of TOFIX-S in rats were investigated following a single intratracheal instillation in saline. Seventy male rats were divided into two groups of 35. One group was given a single intratracheal instillation of TOFIX-S in physiological saline and the other a single intratracheal instillation of physiological saline. Interim kills were carried out at 3 days, 1 week, 1 month, 3 months and 6 months. Histopathology, organ weights and indices of inflammation were investigated. No effects of TOFIX-S were reported. The lung burden of TOFIX-S was measured. The biological half-life of TOFIX-S was determined and estimated to be 2.2 months.

The acute toxicity of TOFIX-S via inhalation cannot be determined from this study since the route of administration is by intratracheal instillation. The study result should be used as supporting information.