Tetra-n-butyl titanate, polymer with water

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Remarks:

Test on guinea pigs, no positive control, no use of Freund's adjuvant.

Type of information:

read-across from supporting substance (structural analogue or surrogate)

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 the particular alcohol and hydrated titanium dioxide. This rapid hydrolysis (hydrolysis half-life < 3 minutes to < 2 hours) is the driving force for toxicokinetics of the target substance. Because of the rapid hydrolysis the influence of the mode of administration through inhalation, dermal and/or oral is related to the most hazardous degradation product (alcohol) released from the substance. The testing conducted with analogue substances of the category proves that the toxicity is similar to the toxicity of alcohol released from the target substance in contact with moisture. The identification of degradation products from the hydrolysis study conducted for the target substance verifies that there are no impurities in the alcohol released from the target substance which might change the toxicity of the target substance compared to the toxicity of the pure alcohol. 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. In addition, the test results of analogue category members releasing same alcohols are used to evaluate the short term and long-term toxicity, skin and eye irritation and sensitization, and mutagenic properties of the target substance.

Qualifier:

no guideline followed

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 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.

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

Route:

intradermal

Vehicle:

other: acetone/DMP 1:9

Concentration / amount:

Day 0: 0.1ml of a 1% solution (vol/vol) of test material in acetone/DMP 1:9
Day 7: 0.1ml of a 1% solution (vol/vol) of test material in acetone/DMP 1:9
Day 14: 0.1ml of a 1% solution (vol/vol) of test material in acetone/DMP 1:9
Day 21: 0.1ml of a 1% solution (vol/vol) of test material in acetone/DMP 1:9

Day(s)/duration:

Day 0, 7, 14, 21

Adequacy of induction:

not specified

Route:

epicutaneous, open

Vehicle:

other: acetone/DMP 1:9

Concentration / amount:

5% and 50% solution (0.05ml) of test material in acetone

Day(s)/duration:

Challenge after two-week rest period after induction.

Adequacy of challenge:

not specified

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

Group:

positive control

Remarks on result:

other: No positive controls used in the study.

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.

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

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:

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.

This toxicity study from this analogue category member (Titanium tetrabutanolate) is used for the weight of evidence to justify that the skin sensitization of Tetra-n-butyl titanate, polymer with water. Skin sensitization result of the Tetra-n-butyl titanate and the use of read-across data from Titanium tetrabutanolate is justified.

The result of this study is used as a weight of evidence in hazard assessment.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

There is no skin sensitisation data available for tetra-n-butyl titanate, polymer with water. The weight of evidence approach is used to determine the skin sensitisation potential of the target substance evaluating relevant data from the analogue substance and from the decomposition products.

The analogue substance (titanium tetrabutanolate) of category of highly reactive titanates hydrolyses rapidly (half-life < 5 min) in aqueous test media releasing n-butanol with the hydrated titanium oxide precipitating out of the test solution. Due to the rapid hydrolysis, it was considered that any toxicity would be due to the presence of n-butanol and not the parent test item. The category justification is presented in the Annex I of this CSR.

The potential sensitization properties of titanium tetrabutanolate were investigated 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 in any dose level tested. Based on the study results test substance is considered as not skin sensitizer.

Read-across data from the decomposition products (n-butanol and titanium dioxide) is used for assessment, because the target substance is hydrolytically unstable having the half-life less than 2 hours (Brekelmans, M. J. C., 2013).n-Butanol, the degradation product of the target substance, is not likely to be a skin sensitizer since the substance has no classification as skin sensitizer according to EU regulation No. 1272/2008 (CLP).

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 information from the analogue category member and from the degradation products to support the conclusion that tetra-n-butyl titanate, polymer with water is not skin sensitizer.

Migrated from Short description of key information:
Primary sensitization study in guinea pigs: negative (conducted for the analogue substance)

Justification for selection of skin sensitisation endpoint:
There is not available sensitisation study for the target substance. This primary sensitisation study in guinea pigs was conducted for the analogue category member. Both the analogue substance and the target substance hydrolyze rapidly in aqueous solutions releasing n-butanol.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Tetra-n-butyl titanate, polymer with water is not classified for skin sensitization in accordance to the CLP Regulation No. 1272/2008 and EU Directive 67/548/EEC.