Titanium tetrabutanolate

Endpoint summary

Description of key information

Skin irritation:
Irritating (rabbits)
Eye irritation:
Serious eye damage due to irreversible effects (rabbits)
Respiratory irritation:
The following result is from n-butanol, the degradation product of the target substance.
Irritating due to the decrease in the respiration rate (mice)

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 3, 1984 - November 16, 1984

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study pre-dates GLP and performed according to a non-guideline method. Insufficient data is provided on study methods and results. However, the test material contained only 25 % titanium tetrabutanolate. The main component of the test material was kerosene (75 %).

Qualifier:

no guideline followed

Principles of method if other than guideline:

The test material was evaluated for primary skin irritation potential in male and female rabbits. Prior treatment, the dorsal area of each rabbit was clipped free of hair. 0,5ml aliquot of the test material was applied under a one by one square gauze patch which was secured in place with adhesive tape. The trunk of each rabbit was wrapped with impervious rubber damming and the rabbits were then immobilized in stocks for 24hours. Twenty-four hours following application, the test substance was removed and the exposure sites were wiped with propylene glycol. Dermal responses were graded and scored at 24. 48. 72 and 96 hours and 7 days.

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hazleton Dutchland. Inc., Denver, Pennsylvania
- Housing: individually in elevated wire-mesh cages
- Diet (e.g. ad libitum): commercial rabbit ration (Purina Lab Rabbit Chow #5321) ad libitum except during 24 hours immobilization period
- Water (e.g. ad libitum): tap water ad libitum except during 24 hours immobilization period
- Acclimation period: minimum of seven days

After observation period of 7 days all rabbits were sacrificed with T61 euthanasia solution and discarded without necropsy

Type of coverage:

not specified

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0,5ml
- Concentration (if solution): 100%

Duration of treatment / exposure:

24 hours

Observation period:

At 24, 48, 72 and 96 hours and 7 days after test material application the skin responses were recorded

Number of animals:

6

Details on study design:

TEST SITE
The dorsal area of each rabbit was clipped free of hair. Test material was applied under a one by one square gauze patch which was secured in place with adhesive tape. The trunk of each rabbit was wrapped with impervious rubber damming and the rabbits were then immobilized in stocks for 24hours.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): exposure sites were wiped with propylene glycol
- Time after start of exposure: 24h

SCORING SYSTEM:
Draize scale for scoring primary skin irritation

Irritation parameter:

edema score

Basis:

animal #6

Time point:

24/48/72 h

Score:

1.7

Max. score:

4

Remarks on result:

positive indication of irritation

Irritation parameter:

edema score

Basis:

animal #5

Time point:

24/48/72 h

Score:

1.7

Max. score:

4

Remarks on result:

positive indication of irritation

Irritation parameter:

edema score

Basis:

animal #4

Time point:

24/48/72 h

Score:

1.7

Max. score:

4

Remarks on result:

positive indication of irritation

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1.3

Max. score:

4

Remarks on result:

positive indication of irritation

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1.7

Max. score:

4

Remarks on result:

positive indication of irritation

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1.3

Max. score:

4

Remarks on result:

positive indication of irritation

Irritation parameter:

erythema score

Basis:

animal #6

Time point:

24/48/72 h

Score:

1.3

Max. score:

4

Remarks on result:

positive indication of irritation

Irritation parameter:

erythema score

Basis:

animal #5

Time point:

24/48/72 h

Score:

2.3

Max. score:

4

Remarks on result:

positive indication of irritation

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

24/48/72 h

Score:

2

Max. score:

4

Remarks on result:

positive indication of irritation

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

2

Max. score:

4

Remarks on result:

positive indication of irritation

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

4

Remarks on result:

positive indication of irritation

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

2

Max. score:

4

Remarks on result:

positive indication of irritation

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

24/48/72 h

Score:

1.74

Reversibility:

not reversible

Remarks on result:

other: Skin blanching, thickening, fissuring and necrosis was observed

Irritant / corrosive response data:

Titanium tetrabutanolate produced well-defined erythema (Grade 2) in five animals and moderate to severe erythema (Grade 3) in one animal at 24 hours. Well-defined erythema (Grade2) was noted also in five animals at 48 hours, in all animals at 72 hours, and in only one animal at 96 hours. Very slight erythema (Grade 1) was noted in one animal at 48 hours and in five animals at 96 hours. Moderate to severe edema (Grades 3 or 4) was noted in all animals at 24 hours, subsiding to very slight edema in all animals at 48 hours and in three animals at 72 hours. Other dermal effects noted during this study were skin blanching, thickening, fissuring, and necrosis. No mortality occurred during the study.

Other effects:

Animal Other dermal effects
Number Sex 24h 48h 72h 96h 7d
E36661 M B BT TN N N
E36662 M B BT BT N N
E36663 M B BTF TN N N
E36702 F B BTF BTF TNF N
E36103 F B BTF BTF NF NF
E36704 F B TF BTF N N

B-Blanching
T-Thickening
F-Fissuring
N-Necrosis

Animal		Erythema score							Edema score
Number	Sex	24h	48h	72h	96h	7d	avg 24/48/72		24h	48h	72h	96h	7d	avg 24/48/72
E36661	M	2	2	2	1	0	2,0		3	1	0	0	0	1,3
E36662	M	2	2	2	1	0	2,0		3	1	1	0	0	1,7
E36663	M	2	2	2	1	0	2,0		3	1	0	0	0	1,3
E36702	F	2	2	2	2	0	2,0		4	1	0	0	0	1,7
E36103	F	3	2	2	1	0	2,3		3	1	1	0	0	1,7
E36704	F	1	1	2	1	0	1,3		3	1	1	0	0	1,7

Interpretation of results:

highly irritating

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

The primary dermal irritation/corrosion potential of the test substane (25 % titanium tetrabutanolate, 75 % kerosene) was evaluated when applied to the skin of rabbits for 24 hour. By the study report, the test substance is considered to be severely irritating.

Executive summary:

This study was regarded not reliable, since the study pre-dates GLP and performed according to a non-guideline method. Insufficient data is provided on study methods and results. By the study report, the test substance is severe skin irritant.

The result of this study cannot be used to evaluate the skin irritation of titanium tetrabutanolate, since the composition of the tested material was 25 % titanium tetrabutanolate and 75% kerosene. Thus, the result is used as a weight of evidence in hazard assessment.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

October 23, 1978 - December 22, 1978

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: This study predates current guideline and the study report does not include details on test substance, test animals and test procedure

Qualifier:

no guideline followed

Principles of method if other than guideline:

0.1 ml of the undiluted test substance was placed into the right conjunctival sac of two albino rabbit. After 20 seconds treated eye was washed with tap water for one minute. The treated eye of the other rabbit was not washed. Observations of the cornea, iris and conjunctiva were made at one and four hours, and at one, two, three, seven, fourteen and twenty-one days.

GLP compliance:

no

Species:

rabbit

Strain:

not specified

Details on test animals or tissues and environmental conditions:

Rabbits were described albino rabbits. There were no details on environmental conditions.

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

0.1 ml

Duration of treatment / exposure:

Test substance was placed into the right conjunctival sac. Observations were made at 1, 4, 24, 48, 72 hours, and at days 7, 14, and/or 21.

Observation period (in vivo):

21 days

Number of animals or in vitro replicates:

24

Details on study design:

0.1 ml test substance was placed into the right conjunctival sac. Total of 2 animals were treated. After 20 seconds treated eye of the one rabbit was washed with tap water for one minute. The treated eye of the other rabbit was not washed. Observations of the cornea, iris and conjunctiva were made with hand-slit lamp at 1, 4, 24, 48, 72 hours, and at days 7, 14, and 21. Fluor-i-strip stain and a biomicroscope were used at examinations after the day of treatment.

Irritation parameter:

other:

Basis:

animal #1

Remarks:

not washed

Time point:

21 d

Reversibility:

fully reversible within: 21 days

Irritation parameter:

other:

Basis:

animal #2

Remarks:

washed

Time point:

21 d

Reversibility:

not fully reversible within: 21 days

Animal/treatment	Cornea	Iris	Conjunctiva
0.1 ml undiluted liquid, Eye not washed	Cornea not seen 1 -4 hrs. due to conjunctival swelling. Generalized moderate opacity with severe corneal swelling 1 -14 days. Moderate area of moderate opacity with moderate to severe swelling at 21 days.	Iris not seen 1 -4 hrs. due to conjunctival swelling. Moderate to severe irritis with a flare 1 -3 days; moderate at 7 days; slight injection at 14 days.	Redness: Severe 1 hr.-7 days with blanching at 1 hr. - 1 day; moderate at 14 days. Swelling:. Severe 1 - 4hrs.; moderate 1 -4 days; mild at 7 days; slight at 14 days Discharge: Copious Hemastix -Positive 1hr-2 days; moderate Hemastix-Positive at 3 days; mild at 7 days
0.1 ml undiluted liquid, Eye washed after 20 seconds	Generalized mild opacity 1 hr.-3 days with severe corneal swelling 1 -2 days and moderate to severe swelling at 3 days; Moderate area of slight opacity with mild to moderate swelling at 7 days; Small area of slight opacity with mild corneal swelling 14 -21 days	Moderate iritis 1hr.-3 days with a flare 1 -2 days	Redness: Severe 1 hr-3 days with blanching at 1 hr-1 day. Swelling: Moderate at 1 hr.; moderate to severe at 4hrs.; moderate 1 -2 days; mild at 3 days Discharge: Copious Hemastix-Positive 1 hr.-1 day; moderate at 2 days; mild at 3 days

Interpretation of results:

Category 1 (irreversible effects on the eye)

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

The eye irritation potential of Titanium tetrabutanolate was evaluated when introduced to the eyes of rabbits. The test material caused persistent lesions which were not fully reversible within an observation period of 21 days and is thus classified in Category 1 eye irritant by the applicant.

Executive summary:

Titanium tetrabutanolate 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 tetrabutanolate severely irritated the cornea and conjunctiva and moderately to severily irritated the iris of both the washed and unwashed rabbit eyes. At 21 days, the unwashed eye had moderate to severe corneal irritation and the washed eye had mild corneal irritation.

This study was regarded as non reliable, since the study report does not include details on test material and test procedure. Furthermore, tabulation of irritant/corrosive response data for each animal at each observation time point is missing.

This study does not satisfy the guideline requirements for the eye irritation study and thus the result of this study is used as a supporting evidence for hazard assessment

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

Skin irritation

There are two low quality skin irritation studies available for titanium tetrabutanolate. 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 5 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, n-butanol and titanium dioxide (TiO2).

A skin irritation study by Ferenz, R. L. (1978) was conducted for 5% and 50% solution of titanium tetrabutanolate in acetone. 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 mildly irritating to the skin of guinea pigs.

In the other study by Cargus, J. L. (1984) mixture of titanium tetrabutanolate was investigated. Because the tested item contained 25 % of titanium tetrabutanolate and 75 % kerosene the study result cannot be used for evaluation of skin irritation caused by the target substance. In the study six rabbits were exposed to test item for 24 hours and skin responses were recorded at 24, 48, 72 and 96 hours and 7 days after test item application. The test substance is considered to be severely irritating.

Skin irritation of n-butanol, the decomposition product of the target substance, has been studied in experimental animals. The results from most of the experiments indicate that n-butanol was irritating to skin (UNEP, 2004). n-Butanol has also the harmonized classification to Skin Irrit. 2.

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 data from the skin irritation of titanium tetrabutanolate and from the decomposition products is considered reliable. These results indicate this substance to be classified as irritating to skin.

Eye irritation

The weight of evidence approach is used to determine the eye irritation hazard of titanium tetrabutanolate evaluating relevant data from the substance itself but also from the decomposition products, n-butanol 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 5 minutes (Brekelmans, M. J. C., 2013).

In an eye irritation study by Ferenz, R. L. (1978), 0.1 ml of the undiluted test substance was placed into the right conjunctival sac of two albino rabbit. After 20 seconds treated eye was washed with tap water for one minute. The treated eye of the other rabbit was not washed. Observations of the cornea, iris and conjunctiva were made at one and four hours, and at one, two, three, seven, fourteen and twenty-one days. Titanium tetrabutanolate severely irritated the cornea and conjunctiva and moderately to severely irritated the iris of both the washed and unwashed rabbit eyes. At 21 days, the unwashed eye had moderate to severe corneal irritation and the washed eye had mild corneal irritation. Results of this study indicate the irreversible effects on cornea in rabbits.

In the other study by Cargus, J.L (1984), mixture of titanium tetrabutanolate was investigated. Because the tested item contained 25 % of titanium tetrabutanolate and 75 % kerosene the study result cannot be used for evaluation of eye irritation caused by the target substance. 0.01 ml of the undiluted test substance was placed into the right conjunctival sac of two albino rabbit. After 20 seconds treated eye was washed with 25 % propylene glycol in distilled water for one minute. The treated eye of the other rabbit was not washed. Observations of the cornea, iris and conjunctiva were made at one and four hours, and at one, two and three days. The test material caused conjunctival irritation (redness, grade 2) in the washed eye at 1 and 4 hours but subsided to grade 1 at 24 and 48 hours. Chemosis (grade 1) was noted in the unwashed and washed eyes at 1 and 4 hours. A discharge (grade 1) was observed in both the unwashed and washed eye at 1 and 4 hours only. No opacity or iritis was observed in either eye at any observation interval throughout the study. All observed effects were reversible within 72 hours.

Eye irritation of n-butanol, the decomposition product of the target substance, has been studied in experimental animals. The results from these studies indicate that n-butanol was severe irritant (UNEP, 2004). n-Butanol has also the harmonized classification to Eye Dam. 1.

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

Respiratory irritation

There is no respiratory irritation data available for the target substance. Thus, read-across data from n-butanol, the most hazardous degradation product of the target substance, is evaluated here.

The effect of n-butanol on the respiratory rate in mice (six mice per dose level) was investigated by Ceaurriz et al. (1981). Animals were exposed for 5 minutes and the RD 50 was determined to be 1268 ppm. The RD50 is the concentration of an irritant that causes a 50 % decrease in breathing rate. Based on the study results it was predicted that 40 mg/m³ (13 ppm) in air would have a minimal or no effect on humans, 390.9 mg/m³ (127 ppm) would be uncomfortable, and 3 909 mg/m³ (1 268 ppm) would be intolerable.

Because of rapid hydrolysis of the target substance the intrinsic properties are related to the most hazardous decomposition product, n-butanol. As this alcohol causes irritation of the respiratory tract during 5 min exposure, and has the harmonized classification to hazard class STOT SE 3 H335, titanium tetrabutanolate will be classified accordingly.

In conclusion, the known skin irritation properties of titanium tetrabutanolate and of the hazardous decomposition product (n-butanol) indicate this substance is irritating to the skin. Based on the eye irritation data of the substance itself and on the decomposition product (n-butanol), titanium tetrabutanolate produces serious eye damage. Based on respiratory irritation data of n-butanol in experimental animals, titanium tetrabutanolate has to be classified into specific target organ toxicity category 3 (STOT SE3, H335).

Justification for selection of skin irritation / corrosion endpoint:
The most reliable study.

Justification for selection of eye irritation endpoint:
Undiluted target substance was investigated.

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: corrosive

Effects on respiratory irritation: irritating

Justification for classification or non-classification

Based on the skin irritation information on the substance itself and on the hazardous decomposition product, 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 hazardous decomposition product, the substance has to be classified to hazard class Eye Dam. 1 according to CLP Regulation 1272/2008 and as Xi; R41 according to Directive 67/548/EEC.

Titanium tetrabutanolate decomposes rapidly to n-butanol. n-Butanol has been shown to cause irritation of the respiratory tract in the experimental animal studies. As the intrinsic properties of the target substance are related to the decomposition product, the target 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.