Bis(ethyl acetoacetato-O1',O3)bis(2-methylpropan-1-olato)titanium

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

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.

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.

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:

0.1ml of a 1% solution (vol/vol) of test material in acetone/DMP 1:9

Day(s)/duration:

Day 0, 7, 14, 21

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

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.

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:

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

The weight of evidence approach is used to address the sensitization potential of bis(ethylacetoacetato‐O1',O3")bis(2-methyl propan-1-olato)titanium. Since no key studies were available for the substance itself the sensitisation data from relevant read-across data from the analogue category member and from the degradation products is used for hazard assessment. The target substance is hydrolytically unstable having the half-life less than 10 minutes (Brekelmans, M. J. C., 2013). Thus, it is justified to use sensitization data from the decomposition product, 2-methylpropanol, titanium dioxide (TiO2) and ethyl acetoacetate (EAA).

To assess the sensitizing potential of this titanate, information on the skin sensitization study conducted for the analogue category member of the target substance, titanium tetrabutanolate is evaluated. All titanates in this category behave similar way when in contact with water. The category and the read-across justifications are presented in the Annexes of the CSR.

The potential sensitization properties of titanium tetrabutanolate were tested in a non-guideline primary sensitization test on guinea pigs (Ferenz, R.L., 1979). 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.

 

2-methylpropanol, the most hazardous 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).

Ethyl acetoacetate (EAA), the other decomposition product of the target substance, is not supposed to exhibit skin sensitizing properties either since there are no reports on contact allergy taking into account the long experience with human exposure to the substance as an ingredient in cosmetics (European Chemicals Bureau, 2002).

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 and titanium salt 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 sensitisation, there is available enough information to conclude that bis(ethylacetoacetato‐O1',O3")bis(2-methyl propan-1-olato)titanium is not skin sensitizer. Decomposition products of bis(ethylacetoacetato‐O1',O3")bis(2-methyl propan-1-olato)titanium are not classified as skin sensitizers according to EU regulation No. 1272/2008 (CLP) Annex VI. Furthermore, there is available read-across data from analogue category members to support this conclusion.

Migrated from Short description of key information:
Bis(ethylacetoacetato‐O1',O3")bis(2-methyl propan-1-olato)titanium is not a skin sensitizer based on the studies conducted for the analogue category member, titanium tetrabutanolate. Furthermore, the available data and the current classification of the degradation products support this conclusion.

Justification for selection of skin sensitisation endpoint:
No study available for the substance itself. The selected study is performed using the category member of the target substance.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Bis(ethylacetoacetato-O1',O3")bis(2-methyl propan-1-olato)titanium is not classified for skin sensitization in accordance to the CLP Regulation No. 1272/2008 and EU Directive 67/548/EEC.