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Description of key information

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
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: Non-GLP study that predates current guideline. There is no positive control and no use of Freund's complete adjuvant.
Reason / purpose for cross-reference:
reference to same study
Principles of method if other than guideline:
Two days after the primary irritation test (see chapter 7.3.1 Skin irritation/corrosion.weight_of_evidence.001), induction phase for sensitisation test was started. A series of four intradermal injections of 0.1ml of a 1% test substance solution in acetone/dimethyl phthalate (DMP) 1:9 was given to ten guinea pigs, one each week over three-week period. Following two-week rest period, the test animals were challenged for sensitization by applying 0.05ml of a 50% and 5% suspension of test material in DMP on shaved shoulder skin. At the same time a control group of 10 previously unexposed guinea pigs received similair applications to provide a direct comparison of the challenge reactions.
The skin at the challenge site was evaluated for irritation at 24 and 48 hours after application. Sensitization was defined as a significant score increase at challenge over the response expected from the same amount applied initially or on the concurrent controls.

GLP compliance:
not specified
Type of study:
intracutaneous test
Justification for non-LLNA method:
Provided study is a non-GLP study that predates current guidelines and requirements.
Species:
guinea pig
Strain:
not specified
Details on test animals and environmental conditions:
Albino guinea pigs were used. Initial average weight of animals was 451g and final average weight was 696g. No details on environmental conditions were reported.
Route:
intradermal
Vehicle:
other: acetone/dimethyl phthalate
Concentration / amount:
1.0%
Day(s)/duration:
At weekly intervals for 4 weeks.
Route:
epicutaneous, open
Vehicle:
other: dimethyl phthalate
Concentration / amount:
50% or 5%
Day(s)/duration:
Following a 2 week rest period after the last induction treatment.
No. of animals per dose:
10
Details on study design:
RANGE FINDING TESTS: a skin irritation study was initially conducted (this is reported in IUCLID chapter 7.3.1).

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 4
- Exposure period: 4 weeks
- Test groups: 10 per group
- Control group: 10 animals
- Site: intradermal
- Frequency of applications: at weekly intervals
- Duration: for 4 weeks
- Concentrations: 1.0% in acetone/ dimethyl phthalate

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: following a 2 week rest period after the last induction treatment
- Exposure period: test item was lightly rubbed into skin. No information was supplied regarding duration of exposure.
- Test groups: 2
- Control group: yes
- Site: shoulder skin
- Concentrations: 50% and 5% in dimethyl phthalate
- Evaluation (hr after challenge): 24 and 48 hours

CONTROLS
At the challenge test, 10 unexposed guinea pigs of the same age received identical topical applications to the 50% and 5% test item groups. Therefore these animals had not been treated during the induction phase but were similarly treated during the challenge phase.
Challenge controls:
10 animals at 50% and 10 animals at 5% test item in vehicle.
Reading:
1st reading
Group:
negative control
Remarks on result:
not measured/tested
Reading:
2nd reading
Group:
negative control
Remarks on result:
not measured/tested
Reading:
1st reading
Group:
positive control
Remarks on result:
not measured/tested
Reading:
2nd reading
Group:
positive control
Remarks on result:
not measured/tested
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
50% in vehicle
No. with + reactions:
8
Total no. in group:
10
Clinical observations:
2++, 6+, 2 negative for sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
5% in vehicle
No. with + reactions:
3
Total no. in group:
10
Clinical observations:
3+, 7 negative for sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
50% in vehicle
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
1++,9+, 0 negative for sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
5% in vehicle
No. with + reactions:
2
Total no. in group:
10
Clinical observations:
2+, 8 negative for sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
other: challenge control
Dose level:
50% in vehicle
No. with + reactions:
7
Total no. in group:
10
Clinical observations:
7+, 3 negative for sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
other: challenge control
Dose level:
5% in vehicle
No. with + reactions:
1
Total no. in group:
10
Clinical observations:
1+, 9 negative for sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
other: challenge control for 50%
Dose level:
50% in vehicle
No. with + reactions:
7
Total no. in group:
10
Clinical observations:
7+, 3 negative for sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
other: challenge control for 5%
Dose level:
5% in vehicle
No. with + reactions:
1
Total no. in group:
10
Clinical observations:
1+, 9 negative for irritation
Interpretation of results:
not sensitising
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
The potential sensitisation properties of titanium tetrakis(2-ethylhexanolate) were tested using primary sensitization test on guinea pigs. Based on the study results test substance is considered as not skin sensitizer. No guideline was followed in this study.
Executive summary:

The test substance was administrated 1% solution (vol/vol) in acetone/DMP 1:9 in a series of four sacral intradermal injections (10 animals). At the time of challenge 0.05ml 5% and 50% test substance (vol/vol) in DMP was applied and lightly rubbed to the shaved intact shoulder skin. A control group of 10 previously unexposed guinea pigs received similair applications at the same time to provide a direct comparison of the challenge reactions. At challenge no sensitization response was observed.

This study was regarded not reliable since the study report contains insufficient details on study methods and results. This study does not satisfy the guideline requirements for the sensitization study, but the result is used as a weight of evidence in hazard assessment.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

The weight of evidence approach is used to determine the sensitization 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).

The potential sensitization properties of titanium tetrakis(2-ethylhexanolate) were tested in non-guideline primary sensitization test on guinea pigs. The test substance was administrated as 1 % solution (vol/vol) in a series of four sacral intradermal injections (10 animals). At the time of challenge 0.05 ml 5 % and 50 % test substance (vol/vol) was applied and lightly rubbed to the shaved intact shoulder skin. A control group of 10 previously unexposed guinea pigs received similar applications at the same time to provide a direct comparison of the challenge reactions. At challenge no sensitization response was observed. Based on the study results test substance is considered as not skin sensitizer.

There is only limited amount of information available of 2 -ethylhexanol (2 -EH), the degradation product of the target substance. Based on the REACH registration data from 2010 no skin sensitizing potential was observed for 2-EH.

Published information on titanium and TiO2 confirmed that there was no human evidence of skin sensitization, contact dermatitis or appreciable dermal absorption (Clayton & Clayton (eds.), 1981). There is also evidence of a lack of titanium compound toxicity to the skin demonstrated by its use in the therapy of skin disorders and as a biocompatible implant material (West & Wyzan, 1963 cited in WHO, 1982)

As a conclusion on skin sensitization, there is available enough reliable information to support the conclusion that titanium tetrakis(2-ethylhexanolate) is not skin sensitizer. Furthermore, decomposition products of titanium tetrakis(2-ethylhexanolate) are not classified as skin sensitizers according to EU regulation No. 1272/2008 (CLP).


Migrated from Short description of key information:
Primary sensitization study in guinea pigs: negative

Justification for selection of skin sensitisation endpoint:
One study available for the substance.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Titanium tetrakis(2-ethylhexanolate) is not classified for skin sensitization in accordance to the CLP Regulation No. 1272/2008 and EU Directive 67/548/EEC.