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Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
20.4.2015-4.5.2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
The test was performed according to recommended test Guidelines (OECD Guideline for the Testing of Chemicals No. 402 “Acute Dermal Toxicity” (adopted 24 February 1987) and Method B3 Acute Toxicity (Dermal) 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 402 (Acute Dermal Toxicity)
Version / remarks:
Adopted 24.2.1987
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
(EC) No. 440/2008
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
The 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:
male/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 to 12 weeks
- Weight at study initiation: males 251 - 274 g, females 208-224 g
- Fasting period before study: No
- Housing: The animals were housed 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
- Humidity (%): 30 to 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
arachis oil
Remarks:
arachis oil BP,
Details on dermal exposure:
TEST SITE
- Area of exposure: Back and flanks
- % coverage: 10% of the total body surface area
- Type of wrap if used: A piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): After the 24-Hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with arachis oil BP to remove any residual test item.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg
- Constant volume or concentration used: yes
- For solids, paste formed: yes

VEHICLE
- Amount(s) applied (volume or weight with unit): The test item was moistened with Arachis oil BP
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 females and 5 males
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed for deaths or overt signs of toxicity 30 minutes, 1, 2 and 4 hours after dosing and subsequently once daily for 14 days.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, dermal reactions, mortality
Statistics:
Data evaluations included the relationship, if any, between the exposure of the animal to the test item and the incidence and severity of all abnormalities including behavioral and clinical observations, gross lesions, body weight changes, mortality and any other toxicological effects.

Using the mortality data obtained, an estimate of the acute dermal median lethal dose (LD50) of the test item was made.

Results and discussion

Preliminary study:
Five female and five male rats were treated with 2000 mg/kq bw test item moistened with Arachis Oil BP. The treatment lasted 24 h. The observation period was 14 days.

There were no deaths, signs of systemic toxicity or dermal irritation.
Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths (see Table 1, Any other infromation on results incl. tables).
Clinical signs:
There were no signs of systemic toxicity (see Table 1, Any other infromation on results incl. tables).
Body weight:
Four females showed body weight loss or no gain in body weight during the first week with expected gain in body weight during the second week. The remaining animals showed expected gains in body weight over the study period (see Table 2, Any other infromation on results incl. tables).
Gross pathology:
No abnormalities were noted at necropsy (see Table 3, Any other infromation on results incl. tables).
Other findings:
Dermal Reactions:
Very slight erythema and very slight edema were observed on days three and four in one female. There were no signs of dermal irritation in the remaining animals (see Tables 4 and 5, Any other infromation on results incl. tables).

Any other information on results incl. tables

Table 1 Individual Clinical Observations and Mortality Data

Dose level (mg/kg) Animal number Effects Noted After Dosing (Hours) Effects Noted During Period After Dosing (Days)
and sex 0.5 1 2 4 1 2 3 4 5 6 7 8 9 10 11 12 13 14
2000               1-0 M 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0  0
1 -1 M 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0
1 -2 M 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0
1 -3 M 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0
1 - 4 M 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0
2 - 0 F 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0
 2 - 1 F  0 0  0  0  0  0  0  0
 2 - 2 F  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0
 2 - 3 F  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0
 2 - 4 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) at Day  Weight Change (g) During Week
0 7 14 1 2
2000 1-0 Male 263 279 304 16 25
1-1 Male 274 293 326 19 33
1-2 Male 255 273 293 18 20
1-3 Male 264 282 309 18 27
1-4 Male 251 258 281 7 23
2-0 Female 224 227 232 3 5
2-1 Female 213 213 216 0 3
2-2 Female 212 207 213 -5 6
2-3 Female 211 210 215 -1 5
2-4 Female 208 207 217 -1 10

Table 3 Individual Necropsy Findings

Dose Level mg/kg Animal Number and Sex Time of Death  Macroscopic Observations
2000 1-0 Male Killed Day 14 No abnormalities detected
1-1 Male Killed Day 14 No abnormalities detected
1-2 Male Killed Day 14 No abnormalities detected
1-3 Male Killed Day 14 No abnormalities detected
1-4 Male Killed Day 14 No abnormalities detected
2-0 Female Killed Day 14 No abnormalities detected
2-1 Female Killed Day 14 No abnormalities detected
2-2 Female Killed Day 14 No abnormalities detected
2-3 Female Killed Day 14 No abnormalities detected
2-4 Female Killed Day 14 No abnormalities detected

Table 4 Individual Dermal Reactions - Males

Dose level (mg/kg) Animal number Observation Effects Noted After Initiation of Exposure (Days)
and sex 1 2 3 4 5 6 7 8 9 10 11 12 13 14
2000               1-0 M Erythema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Edema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Other 0 0 0 0 0 0 0 0 0 0 0 0 0 0
1 - 1 M Erythema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Edema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Other 0 0 0 0 0 0 0 0 0 0 0 0 0 0
 1 - 2 M Erythema
Edema  0  0  0  0  0  0  0  0  0  0  0  0  0  0
Other  0  0  0  0  0  0  0  0  0  0  0  0  0  0
1 - 3 M Erythema  0  0  0  0  0  0  0  0  0  0  0  0  0  0
Edema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Other 0 0 0 0 0 0 0 0 0 0 0 0 0 0
1 - 4 M Erythema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Edema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Other 0 0 0 0 0 0 0 0 0 0 0 0 0 0

Table 5 Individual Dermal Reactions - Females

Dose level (mg/kg) Animal number Observation Effects Noted After Initiation of Exposure (Days)
and sex 1 2 3 4 5 6 7 8 9 10 11 12 13 14
2000               2-0 F Erythema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Edema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Other 0 0 0 0 0 0 0 0 0 0 0 0 0 0
2 - 1 F Erythema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Edema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Other 0 0 0 0 0 0 0 0 0 0 0 0 0 0
 2 - 2 F Erythema
Edema  0  0  0  0  0  0  0  0  0  0  0  0  0  0
Other  0  0  0  0  0  0  0  0  0  0  0  0  0  0
2 - 3 F Erythema  0  0  0  0  0  0  0  0  0  0  0  0  0  0
Edema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Other 0 0 0 0 0 0 0 0 0 0 0 0 0 0
2 - 4 F Erythema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Edema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Other 0 0 0 0 0 0 0 0 0 0 0 0 0 0

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Remarks:
According to GHS, the substance is unclassified.
Conclusions:
The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight. Therefore the test item is not classified as acutely toxic via the skin.
Executive summary:

The study was performed to assess the acute dermal toxicity of the test item in the Wistar strain rat.

A group of ten animals (five males and five females) was given a single, 24 hour, semi-occluded dermal application of the test item to intact skin at a dose level of 2000 mg/kg body weight. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy.

Mortality. There were no deaths.

Clinical Observations. There were no signs of systemic toxicity.

Dermal Irritation. Very slight erythema and very slight edema were observed on days three and four in one female. There were no signs of dermal irritation in the remaining animals.

Body Weight. Four females showed body weight loss or no gain in body weight during the first week with expected gain in body weight during the second week. The remaining animals showed expected gains in body weight over the study period.

Necropsy. No abnormalities were noted at necropsy.

The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight.

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