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Diss Factsheets

Toxicological information

Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
migrated information: read-across based on grouping of substances (category approach)
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.
Justification for type of information:
The substance is hydrolytically unstable. When it comes in contact with water or moisture complete hydrolysis will take place with no significant reaction products other than alcohols, ethyl acetoacetate and hydrated titanium dioxide. Because of the rapid hydrolysis, the influence of the mode of administration through inhalation, dermal and oral is related to the organic degradation products released from the substance. Based on the toxicological properties of these degradation products the hazard assessment concentrates on the most hazardous degradation product (alcohols). The testing conducted with analogue substances of the category (category 1 and 2) proves that the toxicity is similar to the toxicity of alcohol released when the target substance comes in contact with moisture. The identification of degradation products from the hydrolysis study conducted for the target substance verifies that there are no impurities released from the target substance which might change the toxicity of the target substance compared to the toxicity of the pure alcohol or ethyl acetoacetate. The read-across approach from analogue category members are used to justify that the mode of administration through oral, inhalation and/or dermal is similar to the adverse effects of the degradation products and therefore the read-across from the most hazardous degradation products can be used to evaluate the toxicological effects of the target substance. In addition, as all the titanates in category 1 and 2 have similar hydrolyzing behavior, the test results of analogue category members releasing same alcohols can be used to read-across the short-term and long-term toxicity, skin and eye irritation, sensitization, and genotoxicity of the target substance.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1979
Report date:
1979

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Two days after the primary irritation test, 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 acetone 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:
no
Type of study:
not specified
Justification for non-LLNA method:
Non-GLP study that predates current guideline. There is no positive control and no use of Freund's complete adjuvant.

Test material

Constituent 1
Chemical structure
Reference substance name:
Titanium tetrabutanolate
EC Number:
227-006-8
EC Name:
Titanium tetrabutanolate
Cas Number:
5593-70-4
Molecular formula:
C16H36O4Ti
IUPAC Name:
titanium tetrakis(butan-1-olato)
Details on test material:
- Name of test material (as cited in study report): Titanic acid, tetrabutyl ester; Haskell No. 12,678
- Substance type: organometallic
- Physical state: liquid
- Analytical purity: 95%
- Lot/batch No.: 12,678

In vivo test system

Test animals

Species:
guinea pig
Strain:
other: albino
Sex:
not specified
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 480g
- Weigh at study conclusion: 726g
CONTROL ANIMALS
- Weight at study initiation: 540g
- Weigh at study conclusion: 799g

Study design: in vivo (non-LLNA)

Induction
Route:
intradermal
Vehicle:
other: acetone/DMP 1:9
Concentration / amount:
0.1ml of a 1% solution (vol/vol) of test material in acetone/DMP 1:9
Day(s)/duration:
Day 0, 7, 14, 21
Challengeopen allclose all
Route:
epicutaneous, open
Vehicle:
other: acetone/DMP 1:9
Route:
epicutaneous, open
Vehicle:
other: acetone
Concentration / amount:
5% and 50% solution (0.05ml)
Day(s)/duration:
Two weeks after induction
No. of animals per dose:
10 animals in test group
10 animals in control group
Details on study design:
RANGE FINDING TEST:
A range finding test was conducted with the test material using three guinea pigs. Results showed that 100% concentration of the test material is a moderate skin irritant and 50% suspension in acetone did not irritate the skin.

MAIN STUDY:
A. INDUCTION EXPOSURE
- No. of exposures: 4
- Exposure period: 3 weeks
- Test groups: Test substance in acetone/DMP 1:9
- Control group: no exposure
- Site: sacral intradermal injections
- Frequency of applications: every 7th day
- Duration: 0-21 d
- Concentrations: 1% test substance

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: 35
- Exposure period: 24, 48 h
- Test groups: 5% and 50% test substance in acetone
- Control group: 5% and 50% test substance in acetone
- Site: shoulder skin
- Concentrations: two different
- Evaluation (hr after challenge): 24, 48
Challenge controls:
A control group of 10 previously unexposed guinea pigs received similair applications than the test group at the time of challenge to provide a direct comparison of the challenge reactions.
Positive control substance(s):
no

Results and discussion

In vivo (non-LLNA)

Resultsopen allclose all
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% suspension
No. with + reactions:
7
Total no. in group:
10
Clinical observations:
1++, 6+, 3 neg
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 50% suspension. No with. + reactions: 7.0. Total no. in groups: 10.0. Clinical observations: 1++, 6+, 3 neg.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
50% suspension in acetone
No. with + reactions:
8
Total no. in group:
10
Clinical observations:
8+, 2 neg
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 50% suspension in acetone. No with. + reactions: 8.0. Total no. in groups: 10.0. Clinical observations: 8+, 2 neg.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
50% suspension in acetone
No. with + reactions:
7
Total no. in group:
10
Clinical observations:
1++, 6+, 3neg
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 50% suspension in acetone. No with. + reactions: 7.0. Total no. in groups: 10.0. Clinical observations: 1++, 6+, 3neg.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
50% suspension in acetone
No. with + reactions:
8
Total no. in group:
10
Clinical observations:
8+, 2neg
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 50% suspension in acetone. No with. + reactions: 8.0. Total no. in groups: 10.0. Clinical observations: 8+, 2neg.
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
5% suspension in acetone
No. with + reactions:
2
Total no. in group:
10
Clinical observations:
2+, 8neg
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 5% suspension in acetone. No with. + reactions: 2.0. Total no. in groups: 10.0. Clinical observations: 2+, 8neg.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
5% suspension in acetone
No. with + reactions:
2
Total no. in group:
10
Clinical observations:
2+, 8neg
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 5% suspension in acetone. No with. + reactions: 2.0. Total no. in groups: 10.0. Clinical observations: 2+, 8neg.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
5% suspension in acetone
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
10 neg
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 5% suspension in acetone. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: 10 neg.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
5% suspension in acetone
No. with + reactions:
1
Total no. in group:
10
Clinical observations:
1+, 9 neg
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 5% suspension in acetone. No with. + reactions: 1.0. Total no. in groups: 10.0. Clinical observations: 1+, 9 neg.

Any other information on results incl. tables

Read-across justifications and data matrices are presented in IUCLID section 13.

Applicant's summary and conclusion

Interpretation of results:
not sensitising
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
The potential sensitisation properties of titanium tetrabutanolate 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:

This study was conducted for titanium tetrabutanolate, the analogue of the target substance. 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 acetone 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.