Registration Dossier

Administrative data

Description of key information

Skin irritation:
Not irritating (rabbits)
Eye irritation:
Moderately 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:
weight of evidence
Study period:
No study period reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Pre-dates GLP and pre-dates current guideline. Similar to OECD 404 but reversibility not fully investigated.
Qualifier:
according to
Guideline:
other: Federal Register No. 38. 187 § 1500.41 (skin) side of 27 27 019 Sept. 1973 evaluation key to Draize, J.H. (1959) DERMAL TOXICITY
Deviations:
not specified
Principles of method if other than guideline:
Study method was similar to OECD 404, Acute Dermal Irritation/Corrosion. Testing was performed on 6 New Zealand White rabbits on both abraded and unabraded skin sites with occlusive dressings. Treatment was for 24 hours. Following removal of the patches the animals were scored for erythema and eschar formation and oedema according to the grading system in OECD 404 at 24 and 72 hours post dose. The animals were killed 7 days post dose and a necropsy examination of the skin performed.
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
Six male and female NZW rabbits were acclimatised for more than 3 days before the start of the study. The animals weighed 3 to 4 kg. They were housed in a permanent building, fully air-conditioned with filtered air. There was a 12 hour light/dark light cycle from 07:00 am to 19:00 pm. The temperature was 22+/- 1 degree C and the humidity was 55 +/- 10%. The animals were housed in stainless steel cages without litter. Standard laboratory pelleted diet and tap water were available ad-libitum.
Type of coverage:
occlusive
Preparation of test site:
other: Test site was shaved and both abraded and non-abraded skin tested.
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated skin on test animals
Amount / concentration applied:
0.5 ml
Duration of treatment / exposure:
24 hours
Observation period:
graded up to 72 h post dose. Animals killed at 7 d post dose and necropsy examination of skin performed.
Number of animals:
6
Details on study design:
Hair was shaved on both sides of the spine using electric hair clippers, approximately 16 hours before application. The application site was ca. 2.5 cm x 2.5 cm = 6.25 cm2. Untreated skin was used as a negative control.
The left side was abraded over an area of ca. 6.25 cm2, with 5 vertical lines.
A tuberculin syringe was used for the application of 0.5 ml of unchanged test material. Following application to the skin the site was covered with 2 layers of gauze (2.5 cm x 2.5 cm in size). These were held onto the skin with elastic bandage. This was held in place with PVC film and adhesive tape. The exposure time was 24 hours.
Scoring of the test sites was performed according to the Draize method (see table below).
The test sites were scored at 24 and 72 h post dose. After 7 days post dose the animals were killed and a necropsy examination of the skin was performed for the assessment of the intact and abraded skin, subcutaneous tissues and musculature at the application sites.
Irritation parameter:
overall irritation score
Basis:
mean
Score:
0.54
Reversibility:
other: necropsy examination performed at 7 days post dose.
Remarks on result:
other: necropsy examination of intact and abraded skin, subcutaneous tissue and underlying muscle were without findings for all animals.
Irritant / corrosive response data:
Overall mean was 0.54. Classified as not irritating.
Other effects:
A yellowish discolouration of the skin at the application sites was reported - this was possibly the test material.

Assessment levels and calculated irritation index – irritation grades

 

 

Rabbit number

 

 

 

Time after application

(h)

1

2

3

4

5

6

Aggregate value

Mean

Erythema and Eschar formation

Intact skin

24

 

 

0

0

0

0

0

0

0

0

72

1

1

1

0

1

0

4

0.67

Erythema and Eschar formation

Abraded skin

24

 

 

0

0

1

1

0

1

3

0.5

72

1

1

1

1

1

1

6

1.0

Oedema formation

Intact skin

24

 

0

0

0

0

0

0

0

0

72

0

0

0

0

0

0

0

0

Oedema formation

Abraded skin

24

 

0

0

0

0

0

0

0

0

72

0

0

0

0

0

0

0

0

Necropsy findings

Rabbit 1

intact and scarified skin:

Subcutaneous tissue and underlying muscles without findings

Rabbit 2

Findings as for rabbit 1

Rabbit 3

Findings as for rabbit 1

Rabbit 4

Findings as for rabbit 1

Rabbit 5

Findings as for rabbit 1

Rabbit 6

Findings as for rabbit 1

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
The primary dermal irritation/corrosion potential of titanium tetraisopropanolate was evaluated when applied to the skin of rabbits. The test substance was a non-irritant under conditions of this study.
Executive summary:

This study was regarded reliable with restrictions since the study was performed according to OECD 404 guideline except reversibility of skin reactions was not fully investigated.

By the study report, titanium tetraisopropanolate was classified not irritating. Since titanium tetraisopropanolate is hydrolytically unstable, the intrinsic properties are related to the main degradation product, propan-2 -ol. Propan-2 -ol is neither classified for skin irritation/corrosion according to EU regulation No. 1272/2008 (CLP).

Thus, the overall conclusion of the study would be that titanium tetraisopropanolate is not irritating to skin.
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:
There is no study period reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The test procedure predates current guideline, but it is comparable with OECD 405.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
Final score at 7 days rather than 21 days. No irritation results presented at 1hour after test item application and at 7 days.
Principles of method if other than guideline:
Test item was applied in the conjuctival sac of one eye. The second, untreated eye, served as a control. Irritation of eyes were observed at 1, 24, 48, 72 hours and 7 days after test item application.
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 3-4 kg
- Housing: stainless steel cage without litter
- Diet (e.g. ad libitum): standard pellet for rabbit ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: >3 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 1 °C
- Humidity (%): 55 ± 10%
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.1 ml was placed into the conjunctival sac of one eye by means of a tuberculin syringe (without a needle).
Duration of treatment / exposure:
Single treatment followed by 7 day observation period.
Observation period (in vivo):
7 days.
Number of animals or in vitro replicates:
6
Details on study design:
For each animal there was a comparison of treated and untreated eye and classification of findings according to Draize scale. Recordings were made at 1 h, 24 h, 48 h and 72 h after instillation. In case, irritation was observed at 72 hours observation was performed at 7 days.

SCORING SYSTEM:
Irritation parameter:
overall irritation score
Basis:
mean
Remarks:
18 animals
Time point:
other: 24, 48, 72 hrs
Score:
30.3
Max. score:
110
Reversibility:
not specified
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
18 animals
Time point:
other: 24, 48, 72 hrs
Score:
16.6
Max. score:
80
Reversibility:
not specified
Irritation parameter:
iris score
Basis:
mean
Remarks:
18 animals
Time point:
other: 24, 48, 72 hrs
Score:
0.9
Max. score:
10
Reversibility:
not specified
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
18 animals
Time point:
other: 24, 48, 72 hrs
Score:
9.8
Max. score:
20
Reversibility:
not specified
Irritant / corrosive response data:
The irritation index for the titanium tetrapropanolate was 30.3
Other effects:
1 h after application: Redness and swelling of the conjunctiva and strong secretion were recorded. Also recorded was a white-yellowish, sliding pad on the cornea; this was tentatively considered to be the test item
24 h to 72 h after application: Purulent surface in five rabbits was recorded.
7 d after application: No significant change from the 72 h findings was reported.

 

24 hours

48 hours

72 hours

Rabbit numbers

1

2

3

4

5

6

1

2

3

4

5

6

1

2

3

4

5

6

Cornea opacity (a)

0

1

0

1

1

1

0

1

0

1

1

1

0

2

0

2

2

1

Area of cornea (b)

0

4

0

4

4

4

0

4

0

4

4

4

0

4

0

4

4

4

1: a x b x 5 (max 80)

0

20

0

20

20

20

0

20

0

20

20

20

0

40

0

40

40

20

Iris score

1

1

1

1

1

1

0

1

0

1

1

1

0

1

0

1

1

1

2: Iris score x 5

5

5

5

5

5

5

0

5

0

5

5

5

0

5

0

5

5

5

Conjunctivae redness (a)

2

2

1

2

1

1

1

1

1

2

2

2

1

1

1

2

2

2

Conjunctivae chemosis (b)

2

2

1

3

4

2

1

2

1

1

3

1

1

2

1

1

1

2

Conjunctivae discharge (c)

3

3

2

3

3

3

1

2

0

3

3

1

0

2

0

0

0

1

3: a x b x c x 2 (max 20)

14

14

8

16

16

12

6

10

4

12

16

8

4

10

4

6

6

10

Score 1 + 2 + 3 (max 110)

19

39

13

41

41

37

6

35

4

37

41

33

4

55

4

51

51

35

Interpretation of results:
moderately irritating
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
Eye irritation properties of titanium tetraisopropanolate was evaluated after test item administration to rabbit eye. The test substance was classified as moderately irritating.
Executive summary:

Eye irritation potential of titanium tetraisopropanolate was evaluated by administering test substance into eye of six rabbits. Eye responses were recorded at 1h, 24h, 48h, 72h and 7 days after test item application and the responses were evaluated according to Draize scale.

The study is considered reliable with restrictions, since the test procedure predates current guideline, but it is comparable with OECD 405 guideline study. Although the assessment of reversibility of eye responses finished at 7 days after application it was noted that at 7 days there was no significant change from the findings at 72 hours.

By the study report, titanium tetraisopropanolate was classified moderately irritating.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Three reports were available on skin irritation properties of titanium tetraisopropanolate with rabbits and guinea pigs. McAlack, J. (1976) reported that 100% titanium tetraisopropanolate was not irritating when applied to the skin of rabbits for 4 hours in a study broadly comparable to OECD 404 guideline study. Ferenz, K. L. (1978) reported that the test substance in a concentration of 7.5% in vehicle (dimethyl phtalate) caused mild to no irritation and as a 75% concentration in the same vehicle caused moderate to no irritation after 24 or 48h exposure. The study report by Billmeier, J. (1978) showed no skin irritation potential of undiluted test substance in rabbits after 24h exposure in a study conducted in a similar way than OECD 404 guideline.

The potential of this substance to cause skin irritation is also evaluated based on the read-across data on skin irritation of the decomposition products, because the target substance is hydrolytically unstable having the half-life less than 3 minutes (Scholz, T. 2010). The weight of evidence approach is used to evaluate the skin irritation of titanium tetraisopropanolate as the studies on the substance itself are unreliable and lacking some important information on skin irritation effects of the decomposition products. After hydrolysis no significant reaction products other than isopropyl alcohol (IPA) and non-hazardous hydrated titanium dioxide (TiO2) exist. Thus, it is considered relevant to evaluate the information on the skin irritation of the decomposition products, IPA and TiO2 together with the substance itself.

Publication by Nixon G. et al. (1975) evaluated the dermal irritation/corrosion potential of IPA by administering the substance on the intact and abrated skin of rabbits for 4 hours. Based on skin reactions recorded for 48 hours IPA was concluded to be non-irritant. Equally, IPA has no harmonized classification entry as Skin Irritant/Corrosive in the Annex VI of CLP regulation 1272/2008 and EU Directive 67/548/EEC.

The 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 weight of evidence of the skin irritation on titanium tetraisopropanolate and on IPA is considered reliable. These results do not indicate this substance to be classified as irritating to skin.

Eye irritation

Four studies are available for titanium tetraisopropanolate on eye irritation with rabbits. Billmeier J. (1978) reported that the test material applied non-diluted into rabbit eye caused moderate irritation in reliable klimisch score 2 study. Britelli, M. (1976) reported moderate to severe eye irritation after application of non-diluted test material into rabbit eye, although the treated eyes were washed after 20 sec. Titanium tetraisopropanolate was considered eye irritant in the study by Dashiel, O. L. (1980) where undiluted test item was placed into eye of two rabbits. Eye of one rabbit was washed and the eye of other rabbit was not. Washing of the eye did not have effect on eye responses. In a similar study Ferenz, R. L. (1978) reported that the undiluted test material was highly irritating to the eyes of rabbits.

The results of the titanium tetraisopropanolate are similar to the properties of the main decomposition product, isopropyl alcohol (IPA). The intrinsic properties of titanium tetraisopropanolate, after rapid hydrolysis (half-life < 3 minutes) when it comes in contact with water or moisture, can be concluded to be caused by IPA. Eye irritation information for IPA is evaluated by OECD SIDS concluding the substance as eye irritant (Morgan, R.Let al. (1987), Marzulli, F.N.et al. (1973), Griffith, J.F. et al. (1980) cited in OECD (2004). IPA has also harmonized classification to eye irritation hazard (Eye Irrit. 2, H319) in the Annex VI of CLP regulation 1272/2008 and (Xi, R36) according to EU Directive 67/548/EEC.

The study of Billmeier, J. (1978) was broadly comparable to the current OECD 405 guideline and the study report contains sufficiently data for assessment. Therefore, the result of this study, irritating to eyes, is used as a key value for hazard assessment and classification and labeling. In addition, the known eye irritation properties of the main decomposition product of titanium tetraisopropanolate indicate this substance to be classified as eye irritant.

In conclusion of the irritation properties, although the studies are not reported in great detail and are not performed in strict compliance with current guidelines, they indicate that the substance is not irritating to the skin, but is irritating to the eyes.


Justification for selection of skin irritation / corrosion endpoint:
This study is regarded the most reliable among the three studies performed for the target substance.

Justification for selection of eye irritation endpoint:
This study is regarded the most reliable among the four studies performed for the target substance.

Effects on eye irritation: irritating

Justification for classification or non-classification

Based on the skin irritation information on titanium tetraisopropanolate and on the decomposition products, the substance has not to be classified according to CLP Regulation 1272/2008 and Directive 67/548/EC.

Based on the eye irritation information on titanium tetraisopropanolate and on the decomposition products, 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/EC.