Registration Dossier

Administrative data

Description of key information

Skin irritation:
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:
weight of evidence
Study period:
October 23, 1978 - January 12, 1979
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Study pre-dates GLP and performed according to a non-guideline method. Insufficient data is provided on study methods and results
Reason / purpose:
reference to same study
Qualifier:
no guideline followed
Principles of method if other than guideline:
0,05ml of a 5% and a 50% suspension (vol/vol) of the test material in dimethyl phtalate (DMP) was applied on shaved, shoulder intact skin of 10 guinea pigs. Skin reaction was observed and recorded at 24h and at 48h after test material application.
GLP compliance:
no
Species:
guinea pig
Strain:
other: albino
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 451g
Type of coverage:
not specified
Preparation of test site:
shaved
Vehicle:
other: dimethyl phtalate
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0,05ml
- Concentration (if solution): 5% and 50% (vol/vol)
Duration of treatment / exposure:
24 hours and 48 hours
Observation period:
At 24 hours and 48 hours after test material application skin reactions were recorded
Number of animals:
10 animals
Details on study design:

A range-finding study was conducted with 3 male albino guinea pigs to test for skin Irritation potential. This test material was a skin irritant as 50% suspension in dimethyl phthalate (DMP); it did not irritate the skin at 5%.
The primary irritation test was conducted on ten unexposed guinea pigs by applying and lightly rubbing in 0.05 ml of a 50% and a 5% suspension of the test material in dimethyl phthalate (DMP) on shaved, intact shoulder skin.

Reaction codes are as follows:
+ mild erythema
++ moderate erythema
+++ strong erythema
++++ erythema plus oedema
+++++ necrosis
Irritant / corrosive response data:
Titanic acid, tetrakis(2-ethylhexyl) ester caused moderate to no irritation when tested as a 50% suspension in dimethyl phtalate on the shaved, intact skin of guinea pigs and mild to no irritation when tested as a 5% suspension.

Reactions on intact guinea pig skin

 

Test group

(10 animals)

Test group

(10 animals)

Concentration in DMP

50%

5%

Primary irritation test - 24 hours

7+,

3 negative

1+,

9 negative

Primary irritation test - 48 hours

4+,

6 negative

10 negative

Reaction codes are as follows: + mild erythema ++moderate erythema +++ strong erythema ++++ erythema plus oedema +++++necrosis

Interpretation of results:
moderately irritating
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
The primary dermal irritation potential of titaniumtetrakis(2-ethylhexanolate) was evaluated when applied to the skin of guinea pigs. The test material caused moderate to no irritation when tested as a 50% suspension.

Executive summary:

This study was regarded not reliable since the study pre-dates GLP and it is non-guideline study. Furthermore, the study report includes insufficient details on study methods and results. Clinical signs were not reported during the study nor were autopsy at the termination.

Based on the study report, the test material (50%suspension) is considered moderately irritating to the skin of guinea pigs. This study does not satisfy the guideline requirements for the skin irritation study and thus, the result of this study is used as a weight of evidence in hazard assessment.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Skin irritation

There is one study available on titanium tetrakis(2-ethylhexanolate) 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 weight of evidence approach is used to determine the skin irritation of this substance evaluating relevant data also from the decomposition products, 2-ethylhexanol (2-EH) and titanium dioxide (TiO2).

A skin irritation study by Ferenz, R.L. (1978) was conducted for 5% and 50% solution of titanium tetrakis(2-ethylhexanolate). The test substance was applied on the skin of six rabbits for 24 hours. Skin reactions were observed at 24 and 48 hours following application. Based on the study report, the test material in 50% suspension was considered moderately irritating and in 5% suspension not irritating to the skin of guinea pigs.

2 -ethylhexanol (2 –EH), the decomposition product of the target substance, was tested in a valid non-GLP OECD 404 study using 3 rabbits (Mürmann, P., 1987). Severe erythema and edema was noted in all treated animals at 24 hours after treatment which persisted until 72 hours. The skin reactions caused irreversible changes and resulted in scab formation, desquamation, formation of new skin in all animals during days 6 through 14 after patch removal. Scars and peeling scabs were observed on day 14 in all animals. The observed effects including the late scarification are consistent with a strong irritant, but not a corrosive agent.

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). Overall, the results indicate that titanium dioxide has a low potential to irritate the skin of humans under anything other than extreme and unrealistic exposure conditions.

As a conclusion, the weight of evidence of the skin irritation on titanium tetrakis(2-ethylhexanolate) and on the decomposition products is considered reliable. These results indicate this substance should be classified as irritating to skin.

Eye irritation

The weight of evidence approach is used to determine the eye irritation hazard of titanium tetrakis(2-ethylhexanolate) evaluating relevant data from the substance itself but also from the decomposition products, 2-ethylhexanol (2-EH) and titanium dioxide (TiO2). Read-across data from the decomposition products is used for assessment, because the target substance is hydrolytically unstable having the half-life less than 10 minutes (Brekelmans, M. J. C., 2013).

There are two eye irritation studies available on Titanium tetrakis(2-ethylhexanolate). In the pre-guideline eye irritation study by Gargus, J.L. 1983, Titanium tetrakis(2-ethylhexanolate) was applied undiluted into the eyes of rabbits. Observations were made at 1 and 4 hours, and at 1, 2, 3, 7, 14, and 21 days for the treated eyes. The test substance irritated the cornea and conjunctiva of rabbit eyes. In the other pre-guideline study by Ferenz, R.L. 1978 titanium tetrakis(2 -ethylhexanolate) was applied undiluted into the eyes of two rabbits. After 20 seconds, treated eye of one rabbit was washed with water. The treated eye of the other rabbit was not washed. Observations were made at 1 and 4 hours, and at 1, 2, 3, 7, 14, and 21 days for the treated eyes. Titanium tetrakis(2-ethylhexanolate) severely irritated the cornea and conjunctiva and moderately irritated the iris of both the washed and unwashed rabbit eyes. At 21 days, the unwashed eye had slight corneal opacity and the washed eye had mild to moderate corneal irritation.

Further evidence on eye irritation comes from the studies where eye irritation potential of 2 -ethylhexanol (2 -EH), the decomposition product of target substance, was investigated (Mürmann, P., 1987). 2-EH was markedly irritant to the rabbit's eye in a valid OECD 405 test using 3 animals. 2-EH caused moderate eye irritation in all 3 treated animals. The effects were fully reversible within 21 days. The MMAS (Mean Modified Average Score) according to Draize was 28.59. The mean conjunctivae score (reddening) was 2.56 and exceeded slightly the EU criterion for classification. In the other study by ECETOC (1998) the eye irritating properties of 2-EH were examined in 4 New Zealand White rabbits according to the OECD 405 test guideline and under GLP. The eye reactions were examined until day 14 after the instillation of 0.1 ml into the conjunctival sac. For comparison with the EU classification criteria the means of the eye reactions of all animals at the examinations at 24, 48, and 72 hours after treatment were calculated. The eye reactions observed were slightly below the EU classification criteria in this study.

Another decomposition product of titanium tetrakis(2-ethylhexanolate) is non-hazardous titanium dioxide. Possible risk of eye irritation is related only to the titanium dioxide dust. After hydrolysis of titanium tetrakis( 2-ethylhexanolate), TiO2 does not cause any relevant eye irritation hazard for humans as the substance exists as hydrated solid precipitate.

Respiratory irritation

Irritating effects of 2 -ethylhexanol (2 -EH) on eyes and the respiratory tract were investigated in controlled experimental human studies. In these studies by Kiesswetter et al. (2005) and van Thriel et al. (2005) volunteers were exposed for 4 h to mean exposure levels of 1.5, 10 and 20 ppm. The studies revealed strong dose–response relationships between airborne 2-EH concentrations and blink rates and nasal irritation. In the course of 4 h exposure, blink rates increased significantly showing no adaptation and nasal irritation remained unchanged across.

Because of rapid hydrolysis of the target substance the intrinsic properties are related to the main decomposition product, 2-EH. As this alcohol causes irritation of the respiratory tract after during 4-hour exposure, and has been proposed the classification to hazard class STOT SE 3 H335, titanium tetrakis(2-ethylhexanolate) will be classified accordingly.

In conclusion of the irritation properties, the known skin irritation properties of the titanium tetrakis(2-ethylhexanolate) and of the main decomposition products indicate this substance is irritating to the skin. Based on the eye irritation data of the substance itself and on the decomposition products, titanium tetrakis(2-ethylhexanolate) is irritating to the eyes. Based on respiratory irritation data of 2-EH in humans, titanium tetrakis(2-ethylhexanolate) has to be classified into specific target organ toxicity category 3 (STOT SE3, H335).


Justification for selection of skin irritation / corrosion endpoint:
One study available for the substance.

Justification for selection of eye irritation endpoint:
Conclusion is based on WoE from two pre-guideline klimisch score 3 studies.

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: irritating

Effects on respiratory irritation: irritating

Justification for classification or non-classification

Based on the skin irritation information on the substance itself and on the decomposition products, the substance has to be classified to hazard class Skin Irrit. 2 according to CLP Regulation 1272/2008 and as Xi; R38 according to Directive 67/548/EEC.

Based on the eye irritation information on the substance itself 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/EEC.

Titanium tetrakis(2-ethylhexanolate) decomposes rapidly to 2 -ethylhexanol (2 -EH). 2 -EH has been shown to cause irritation of the respiratory tract in the experimental human studies. As the intrinsic properties of the substance are related to the decomposition product, the substance has to be classified to hazard class STOT SE 3H335 according to CLP Regulation 1272/2008 and as Xi; R37 according to Directive 67/548/EEC.