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Administrative data

Description of key information

Skin irritation: Not-irritating (rabbits)
Eye irritation: Irritating (rabbits)

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
June 14, 1993 - August 19, 1993
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study predates and contains a few minor deviations from the current guideline study. However, the study is similar to a OECD 404 study and it is performed according to EPA TSCA Good Laboratory Practice Standards (40 CFR 792).
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
The exposure period of test substance. Reversibility of skin ractions were not recorded. Age of animals and their weight at the end of study missing. Two other test substances were tested concurrently on separate test sites on these rabbits
Principles of method if other than guideline:
Exposure time of the test substance was 24 hours (OECD 404; 4 hours) and the test sites were evaluated for erythema, edema and other evidence of dermal effects at 24, 48 and 72 hours (OECD 404; 1, 24, 48, 72 hours after patch removal) after application of the test substance. Two other test substances were tested concurrently on separate test sites on these rabbits. Age of the animals were not mentioned at start of the study and weight of the animals were not measured at conclusion of the study. Furthermore, clinical signs were not reported and the reversibility of skin reactions were not observed up to 14 days after removal of the patches.
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hare Marland, Hewitt, New Jersey
- Weight at study initiation: 2638 - 3293g
- Housing: singly in suspended, stainless steel, wire-mesh cages
- Diet (e.g. ad libitum): conventional laboratory diet ad libitum. During exposure period of 24hours animals did not have access to food.
- Water (e.g. ad libitum): drinking water ad libitum. During exposure period of 24hours animals did not have access to food.
- Acclimation period: two weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C +/- 2°C
- Humidity (%): 50% +/- 10%
- Photoperiod (hrs dark / hrs light): 12/12

Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5ml
- Concentration (if solution): 100%
Duration of treatment / exposure:
24 hours
Observation period:
72 hours
Number of animals:
6
Details on study design:
TEST SITE
- Area of exposure: 2-inch gauze square
- % coverage
- Type of wrap if used: piece of rubber sheeting

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with water and soap
- Time after start of exposure: 24 hours

SCORING SYSTEM:
The application site was examined for erythema and oedema according to the Draize technique.

Erythema and eschar formation:
No erythema 0
Very slight erythema (barely perceptible) 1 (slight)
Well-defined erythema 2 (mild)
Moderate to severe erythema 3 (moderate)
Severe erythema (beet redness) to slight eschar formation (injuries in depth) 4 (severe)

Edema formation:
No edema 0
Very slight edema (barely perceptible) 1 (slight)
Slight edema (edges of area well defined by definite raising) 2 (mild)
Moderate edema (raised approximately 1.0 mm) 3 (moderate)
Severe edema (raised more than 1.0 mm extending beyond the area of exposure) 4 (severe)
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 24 h
Score:
1
Max. score:
8
Reversibility:
no data
Remarks on result:
other: The scores are the sum of mean erythema and edema scores
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 48 h
Score:
1.2
Max. score:
8
Reversibility:
no data
Remarks on result:
other: The scores are the sum of mean erythema and edema scores
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 72 h
Score:
1.5
Max. score:
8
Reversibility:
no data
Remarks on result:
other: The scores are the sum of mean erythema and edema scores
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24 h
Score:
1
Max. score:
4
Reversibility:
no data
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 48 h
Score:
1.2
Max. score:
4
Reversibility:
no data
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 72 h
Score:
1.5
Max. score:
4
Reversibility:
no data
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24 h
Score:
0
Max. score:
4
Reversibility:
no data
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 48 h
Score:
0
Max. score:
4
Reversibility:
no data
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 72 h
Score:
0
Max. score:
4
Reversibility:
no data
Irritant / corrosive response data:
Table 1 Individual skin irritation scores

Skin responses observed in test rabbits following topical exposure to H-20206
Rabbit Erythema Edema
Number 24 hr 48 hr 72 hr 24 hr 48 hr 72 hr
28096 1 2 2 0 0 0
28223 1 1 2 0 0 0
28179 1 1 1 0 0 0
28100 1 1 1 0 0 0
28101 1 1 1 0 0 0
28184 1 1 2 0 0 0
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
The primary dermal irritation/corrosion potential of Titanium tetra(octanolate), branched and linear was evaluated when applied to the skin of rabbits for 24 hours. By the study report, the test substance was a mild skin irritant under conditions of this study.
Executive summary:

This study was regarded reliable with restrictions since there was a few minor deviations from current guideline study (two other test substances were tested concurrently on separate test sites on these rabbits, clinical signs were not reported, test substance exposure time was 24h, animals were not observed to determine reversibility of skin reactions and there was not available physicochemical properties of test material).

Slight erythema was observed in all six rabbits by 24 hours following application. By 48 hours, slight erythema was observed in 5 rabbits and mild erythema in 1. By 72 hours, 3 rabbits exhibited mild erythema. No edema was observed throughout this study. By the study report the test substance is evaluated a mild skin irritant. The result of this study is used as a key value in hazard assessment.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
June 17, 1993 - August 27, 1993
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study predates current guideline. However, the study is similar to a current OECD 405 guideline study and it is performed according to EPA TSCA Good Laboratory Practice Standards (40 CFR 792).
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
The eye of one rabbit was washed after 20 seconds and 0,01ml of the test material was introduced into the eye
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Hare Marland, Hewitt, New Jersey
- Age at study initiation: Young adults
- Weight at study initiation: 2649g and 2563g at the day of treatment
- Housing: singly in suspended, stainless steel, wire-mesh cages
- Diet (e.g. ad libitum): 125 grams of Purina Certified High Fiber Rabbit Chow #5323 daily
- Water (e.g. ad libitum): ad libitum
- Acclimation period: approximately 2 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C +/- 2°C
- Humidity (%): 50% +/- 10%
- Photoperiod (hrs dark / hrs light): 12-hour light/12-hour dark cycle
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.01 ml
Duration of treatment / exposure:
0.01 ml placed into the lower conjunctival sac of each right eye. After 20 seconds both eyes of one rabbit were rinsed for 1 minute with room temperature water. The treated and control eyes of the remaining rabbit were not washed. Observations were made up to day 3 for the washed rabbit eye and up to day 21 for the unwashed rabbit eye.
Observation period (in vivo):
21 days
Number of animals or in vitro replicates:
2
Details on study design:
0.01 ml of undiluted test material was placed into the right conjunctival sac of each of 2 female New Zealand White rabbits. After 20 seconds, both eyes of one rabbit were washed with water. The treated and control eyes of the other rabbit were not washed. Observations of the cornea, iris and conjunctiva were made using illumination and magnification and scored according to Draize scale. Observations were made at 1 and 4 hours, and at 1, 2, 3 days for the washed rabbit eye and at 1 and 4 hours, and at 1, 2, 3, 7, 14, and 21 days for the unwashed rabbit eye. Treated eyes were also observed for any responses to treatment such as pannus, blistering of the conjunctiva, ulceration, or other effects indicative of corrosive action. Hemastix reagent strip® were used to detect occult blood in discharge from the eye.
Irritation parameter:
cornea opacity score
Remarks:
opacity
Basis:
mean
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 24 hours
Irritation parameter:
cornea opacity score
Remarks:
area
Basis:
mean
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 24 hours
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24-72 hours
Score:
0.2
Max. score:
2
Reversibility:
fully reversible within: 2 days
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
mean
Time point:
other: 24-72 hours
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 21 days
Irritant / corrosive response data:
The test substance produced slight corneal opacity, moderate iritis, mild chemosis, and blistering of the conjunctiva and nictitating membrane in both treated eyes. Severe conjunctival redness and copious blood-tinged discharge were observed in the treated unwashed eye. Moderate conjuctival redness and moderate blood-tinged discharge were observed in the treated washed eye. The washed and unwashed eyes were normal by 3 and 21 days, respectively, following treatment.

Rabbit 28203unwashed eye  1 hour 4 hour  1 day   2 days  3 days  7 days  14 days  21 days
 Cornea                
  Opacity  1 1  0  0   0  0  0  0
  Area  4  4  0  0  0  0  0  0
 Iris  0  1  1  0  0  0  0  0

 Conjuctiva

                
  Redness 2B   2B  3  3  2  2  1  0
  Chemosis  2  2  2  1  1  1  1  0
  Discharge  3H+  3H+  3H+  0  0  0  0  0

 Rabbit 28220washed eye  1 hour 4 hour  1 day   2 days  3 days     
 Cornea                
  Opacity  1 1  0  0   0      
  Area  4  4  0  0  0      
 Iris  1  1  0  0  0      
 Conjuctiva                
  Redness 2B   2B  2  2  0      
  Chemosis  2  2  1  1  0      
  Discharge  1H+  2H+  0  0  0      

B+ = Hemastix evaluations positive for blood

B = Blistering of the conjunctiva and nictitating membrane

Interpretation of results:
highly irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The eye irritation potential of Titanium tetra(octanolate), branched and linear was evaluated when introduced to the eyes of rabbits. The test material is considered a severe eye irritant. The study predates current guideline study, but is perfomed in similar way than OECD 405 study.
Executive summary:

Titanium tetra(octanolate), branched and linear was applied undiluted into the eyes of two rabbits. After 20 seconds, both eyes of one rabbit were washed with water. The treated and control eyes of the other rabbit were not washed. Observations were made at 1 and 4 hours, and at 1, 2, 3 days for the washed rabbit eye and at 1 and 4 hours, and at 1, 2, 3, 7, 14, and 21 days for the unwashed rabbit eye. The test material caused slight to severe, but reversible, ocular lesions in the eyes of rabbits.

By the study report the test material is considered a severe eye irritant. This study was regarded reliable with restrictions, since there is few minor deviations from the current guideline (0.01ml test material was introduced into the rabbit eye and the eye of the one rabbit was washed at 20 seconds after treatment). The result of this study is used as a key value in hazard assessment.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation

There is one study available on titanium tetra(octanolate), branched and linear to evaluate the skin irritation of the substance. Further evidence on the potential of this substance to cause skin irritation is evaluated based on the read-across data from the decomposition products. The target substance is hydrolytically unstable having the half-life less than 10 minutes (Brekelmans, M. J. C., 2013). Thus, the supporting irritation information for this endpoint was collected from the decomposition products, Exxal 8; alcohols, C7 -C9 -iso, C8 -rich and titanium dioxide (TiO2).

There is evidence of skin irritancy of this substance only in one animal study. A good quality study by Sarwer (1993) was conducted using method similar to OECD 404 standards. The test substance was applied on the skin of six rabbits for 24 hours. Skin reactions were observed at 24, 48 and 72 hours following application. Slight erythema was observed in all six rabbits by 24 hours. By 48 hours, slight erythema was observed in 5 rabbits and mild erythema in one rabbit. By 72 hours, 3 rabbits exhibited mild erythema. No edema was observed throughout this study. Mean value for erythema in tested animals from readings at 24, 48 and 72 hours was 1.2. Thus, no classification for skin irritation is warranted for titanium tetra(octanolate), branched and linear. This study was selected as a key study.

Supporting evidence on skin irritation comes from the study performed using degradation product of the target substance. Topical application of Exxal 8 produced only signs of mild irritation in the rabbit following a 4 hour semi-occluded dermal patch exposure. Dermal observations were conducted 45 minutes, 24, 48 and 72 hours and 7 days after exposure. All animals survived the exposure. Well defined erythema was noted in 1 animal at the 45 minute point while the other animals had very slight erythema. Erythema increased after the 45 minute interval. Five animals were noted with well-defined erythema at the 24 and 48 hour intervals. At the 72 hour interval, all animals were noted with well-defined erythema. Erythema increased again at the Day 7 interval; two animals were noted with severe erythema and four animals were noted with well-defined erythema. The mean skin irritation scores between 24 and 72 hours were: erythema 1.89 and edema 1.22.

Read-across data from the other decomposition product, TiO2, indicates that the substance is shown to lack irritation properties. Titanium dioxide has been used in various dermatological and cosmetic formulations, without any known adverse effects (WHO, 1982).

As a conclusion, the skin irritation data on titanium tetra(octanolate), branched and linear and on the decomposition products is considered reliable. These results do not indicate this substance to be classified as irritating to skin.

Eye irritation

There is one study available on titanium tetra(octanolate), branched and linear to evaluate the eye irritation of the substance. Further evidence on the potential of this substance to cause eye irritation is evaluated based on the read-across data from the decomposition products. The target substance is hydrolytically unstable having the half-life less than 10 minutes (Brekelmans, M. J. C., 2013). Thus, the supporting eye irritation information was collected from the decomposition products, Exxal 8; alcohols, C7 -C9 -iso, C8 -rich and titanium dioxide (TiO2).

There is evidence of eye irritancy of the target substance only in one animal study. A good quality study, except only two rabbits were used, was conducted using method similar to OECD 404 standards (Sarwer, J.W., 1993). Titanium tetra(octanolate), branched and linear was applied undiluted into the eyes of two rabbits. After 20 seconds, both eyes of one rabbit were washed with water. The treated and control eyes of the other rabbit were not washed. Observations were made at 1 and 4 hours, and at 1, 2, 3 days for the washed rabbit eye and at 1 and 4 hours, and at 1, 2, 3, 7, 14, and 21 days for the unwashed rabbit eye. Eyes were scored for irritation in accordance with the Draize Eye Test.  Mean eye irritation scores between 24 and 72 hours were: cornea score 0, iris score 0.2, and conjunctival redness 2.0. In summary, this result would lead to the classification as eye irritant cat 2. This study was selected as a key study.

Supporting evidence on eye irritation comes from the study performed using the organic degradation product of the target substance, Exxal 8. Rabbits were administered Exxal 8 at a dose of 0.1 ml solution in the eye. Observations were made at 1, 4, 24, 48, and 72 h and 4 and 7 days post instillation. Eyes were scored for irritation in accordance with the Draize Eye Test. Signs of mild irritation were observed within 1 h post instillation, but resolved to unremarkable by Day 7. There were no signs of corneal damage in any of the test animals.  Mean eye irritation scores between 24 and 72 hours were: cornea score 0.5, iris score 0.9, and conjunctival redness 1.5.

Another decomposition product of titanium tetra(octanolate), branched and linear is non-hazardous titanium dioxide. Possible risk of eye irritation is related only to the titanium dioxide dust. However, after hydrolysis of the target substance, TiO2 does not cause any relevant eye irritation hazard for humans as it exists as a hydrated solid precipitate.

In conclusion of the irritation properties, the known irritation properties of titanium tetra(octanolate), branched and linear and the main decomposition products indicate this substance is not irritating to the skin, but is irritating to the eyes.


Justification for selection of skin irritation / corrosion endpoint:
This study predates and contains a few minor deviations from the current guideline study. However, the study is similar to OECD 404 study and it is performed according to EPA TSCA Good Laboratory Practice Standards (40 CFR 792).

Justification for selection of eye irritation endpoint:
This study predates current guideline. However, the study is similar to a current OECD 405 guideline study and it is performed according to EPA TSCA Good Laboratory Practice Standards (40 CFR 792).

Effects on eye irritation: irritating

Justification for classification or non-classification

Based on the skin irritation information on titanium tetra(octanolate), branched and linear, the substance has not to be classified according to CLP Regulation 1272/2008 and Directive 67/548/EEC.

Based on the eye irritation information on titanium tetra(octanolate), branched and linear, the substance has to be classified to hazard class Eye Irrit. 2 according to CLP Regulation 1272/2008 and as Xi; R36 according to Directive 67/548/EEC.

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