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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
4.11.2014-3.12.2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
The study was performed by following the recommended method (OECD Guideline for Testing of Chemicals No 420 “Acute Oral Toxicity - Fixed Dose Method” (2001) and Method B1 bis Acute Toxicity (Oral) of Commission Regulation (EC) No. 440/2008 ) and GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015
Report date:
2015

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Version / remarks:
2001
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Version / remarks:
(EC) No. 440/2008
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
Certificate is as an attachment to the study report
Test type:
fixed dose procedure
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Tetrasodium enneatitanium icosaoxide hydrate
EC Number:
601-472-6
Cas Number:
117314-20-2
Molecular formula:
Sodium form: Na4Ti9O20 × n H2O Sodium/hydrogen form: 50 % Na4Ti9O20 × n H2O, 50 % Na2H2Ti9O20 × n H2O
IUPAC Name:
Tetrasodium enneatitanium icosaoxide hydrate
Test material form:
solid: particulate/powder
Remarks:
powder
Details on test material:
- Substance type: commercial product (pure active substance)
- Physical state: Solid powder
- Storage condition of test material: Ambient temperature, humidity and pressure. Stored in sealed containers in darkness.
- Stability under test conditions: Stable
- Purity: ca 100 %
- Particle size distribution: 2.92% <100μm
- Crystal structure: TiO6-octaedra
- Density: 2.83 x 10^3 kg/m3
- pH value: the pH value of the substance in an aqueous solution is appr. 11

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories UK Ltd., Oxon, UK.
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: 157 - 186 g
- Fasting period before study: Overnight
- Housing: The animals were housed in groups of up to four in suspended solid-floor polypropylene cages furnished with woodflakes.
- Diet (e.g. ad libitum): 2014C Teklad Global Rodent diet supplied by Harlan Laboratories UK Ltd., Oxon, UK
- Water (e.g. ad libitum): tap water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25 °C
- Humidity (%): 30 to 70%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Remarks:
Arachis oil BP was used because the test item did not dissolve/suspend in distilled water.
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 30 mg/ml or 200 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg
- Justification for choice of vehicle: Arachis oil BP was used because the test item did not dissolve/suspend in distilled water.

MAXIMUM DOSE VOLUME APPLIED: 10 ml
Doses:
In the absence of data regarding the toxicity of the test item, 300 mg/kg was chosen as the starting dose
- Dose level (mg/kg: 300 mg/kg
- Concentration (mg/ml): 30
- Dose volume (ml/kg): 10

In the absence of toxicity at a dose level of 300 mg/kg, five additional animals was treated as follows:
- Dose level (mg/kg): 2000
- Concentration (mg/ml): 200
- Dose Volume (ml/kg): 10

No. of animals per sex per dose:
Dose 300 mg/kg: 1 female
Dose 2000 mg/kg: 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were made half, 1, 2, and 4 hours after dosing and then daily for fourteen days. Morbidity and mortality checks were made twice daily. Individual body weights were recorded on Day 0 (the day of dosing) and on Days 7 and 14.
- Necropsy of survivors performed: yes.
- Other examinations performed: Clinical signs and body weight. Gross necropsy, including external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded.
Statistics:
The test item was classified according to Annex 3 of the OECD Guidelines for Testing of Chemicals No. 420 "Acute Oral Toxicity - Fixed Dose Method" (adopted 17 December 2001)

Evaluation of data included identification of the number of animals that died during the study (or that were killed for humane reasons), and determination of the nature, severity, onset and duration of the toxic effects. If possible, the signs of evident toxicity were described. Evident toxicity refers to the toxic effects of sufficient severity that administration of the next higher dose level could result in development of severe signs of toxicity and probable mortality. Effects on body weights and abnormalities noted at necropsy were also identified.
Using the mortality data obtained, an estimate of the acute oral median lethal dose (LD50) of the test item was made.

Results and discussion

Preliminary study:
The sighting study included administering a dose of 300 mg/kg of test item to a female. At the absence of any signs of toxicity, a female was dosed with 2000 mg/kg of test item. At the absence of any signs of toxicity, four females were administered 2000 mg/kg test item.
Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There was no mortality (see table 1, Any other information on results incl. tables).
Clinical signs:
No signs of systemic toxicity were noted during the observation period (see table 1, Any other information on results incl. tables).
Body weight:
All animals showed expected gains in body weight over the observation period (see table 2, Any other information on results incl. tables).
Gross pathology:
No abnormalities detected at necropsy (see table 3, Any other information on results incl. tables.)
Other findings:
No effects were noted.

Any other information on results incl. tables

Table 1. Individual Clinical Observations and Mortality Data

Dose level (mg/kg Animal number
and sex
Effects Noted After Dosing (Hours) Effects Noted During Period After Dosing (Days)
0.5 1 2 4 1 2 3 4 5 6 7 8 9 10 11 12 13 14
300 1-0 F 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
2000 2-0 F 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
3-0 F 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
3-1 F 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
3-2 F 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
3-3 F  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

Table 2. Individual Body Weights and Body Weight Changes

Dose level (mg/kg Animal number
and sex
Body weight (g) a Day Body Weight Gain (g) During Week
0 7 14 1 2
300 1-0 F 170 189 197 19 8
2000 2-0 F 166 185 205 19 20
3-0 F 167 186 198 19 12
3-1 F 157 174 193 17 19
3-2 F 176 184 189 8 5
3-3 F  186 199 206 13 7

Table 3. Individual Necropsy Findings.

Dose level (mg/kg Animal number
and sex
Time of Death Macroscopic Observations
300 1-0 F Killed day 14 No abnormalities detected
2000 2-0 F Killed day 14 No abnormalities detected
3-0 F Killed day 14 No abnormalities detected
3-1 F Killed day 14 No abnormalities detected
3-2 F Killed day 14 No abnormalities detected
3-3 F  Killed day 14 No abnormalities detected

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Remarks:
According to GHS, the substance is unclassified.
Conclusions:
The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2000 mg/kg body weight (Globally Harmonized Classification System - Unclassified).
Executive summary:

The toxicity of the test item was studied through a sighting test on one Wistar Rat with a starting dose of 300 mg/kg. As the starting dose induced no signs of toxicity, the dose was increased to 2000 mg/kg. As the Wistar Rat showed no signs of toxicity, four more rats were administered 2000 mg/kg of test item. After a 14 day observation period the lives of the rats were terminated.

There were no deaths and no signs of systemic toxicity were noted during the observation period. All animals showed expected gains in body weight over the observation period. No abnormalities were noted at necropsy.

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2000 mg/kg body weight (Globally Harmonized Classification System - Unclassified).