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

Endpoint summary

Description of key information

Skin irritation: Irritating (guinea pigs)
Eye irritation: corrosive (guinea pigs)
Respiratory irritation:
The following result is from 2-methylpropanol, the degradation product of the target substance.
Irritating due to the decrease in the respiration rate (rats and rabbits)

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

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:

significant methodological deficiencies

Remarks:

Study pre-dates GLP and performed according to a non-guideline method. Insufficient data is provided on study methods and results.

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.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

One drop (~0,05ml) 5% and 50% solution (vol/vol) of the test material in acetone was applied on shaved, shoulder intact skin of 10 guinea pigs. Skin reaction was observed and recorded at 24h and at 48h after test material application.

GLP compliance:

no

Species:

guinea pig

Strain:

other: albino

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 480g

Type of coverage:

not specified

Preparation of test site:

shaved

Vehicle:

other: acetone

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount applied: One drop (~0,05ml)
- Concentration (if solution): 5% and 50% (vol/vol)

VEHICLE
- Amount(s) applied (volume or weight with unit):
- Concentration (if solution):
- Lot/batch no. (if required):
- Purity:

Duration of treatment / exposure:

24 hours and 48 hours

Observation period:

At 24 hours and 48 hours after test material application skin reactions were recorded

Number of animals:

10 animals

Details on study design:

TEST SITE
-shoulder skin of the animal

REMOVAL OF TEST SUBSTANCE
-washing of the test substance was not done

SCORING SYSTEM:
+ mild erythema
++ moderate erythema
+++ strong erythema
++++ erythema plus edema
+++++ necrosis

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritant / corrosive response data:

Titanic acid, tetrabutyl ester caused moderate to no irritation when tested as a 50% suspension in acetone on the shaved, intact skin of guinea pigs and mild to no irritation when tested as a 5% suspension.

Reactions on intact guinea pig skin

	Test group (10 animals)	Test group (10 animals)
Concentration in acetone	50%	5%
Primary irritation test - 24 hours	1+, 9 negative	1+, 9 negative
Primary irritation test - 48 hours	1 +, 9 negative	1+, 9 negative

Reaction codes are as follows: + mild erythema ++moderate erythema +++ strong erythema ++++ erythema plus oedema +++++necrosis

Interpretation of results:

slightly irritating

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

The primary dermal irritation potential of titanium tetrabutanolate was evaluated when applied to the skin of guinea pigs for 24 hour and for 48 hour. The test substance is considered to be mild skin irritant according to this study.

Executive summary:

Titanium tetrabutanolate was applied in two concentrations (5% and 50% vol/vol in acetone) to two separate test areas on the intact skin on each animal´s back. By the study report the test material is considered to be mild irritant to the skin of guinea pigs.

This study was regarded not reliable since the study pre-dates GLP and it is non-guideline study. Furthermore, the study report includes insufficient details on study methods and results. This study does not satisfy the guideline requirements for the skin irritation study. 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:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

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.

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:

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:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable

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

Weight of evidence approach is used to evaluate the skin irritation of bis(ethylacetoacetato‐O1',O3")bis(2-methyl propan-1-olato)titanium. No key study is available for the skin irritation for the substance itself so relevant read-across data from the analogue category member 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, the supporting irritation information for this endpoint was also collected from the decomposition products, 2 -methylpropanol, ethyl acetoacetate (EAA) and titanium dioxide (TiO2).

Further evidence on the skin irritation comes from the analogue category member of the target substance, titanium tetrabutanolate. All these titanates in this category behave similar way when in contact with water. Furthermore, 2-methylpropanol is released from the target substance and butanol from titanium tetrabutanolate when the substances are in contact with water. The category justification and the read-across justifications are presented in the Annexes of the CSR.

A skin irritation study by Ferenz, R. L. (1979) 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.

Publication by Smyth, H.F. et al. (1954) evaluated the dermal irritation/corrosion potential of 2 -methylpropanol by administering the substance on the intact and abrated skin of rabbits for 24 hours. Based on skin reactions recorded within 24 hours of application of 0.01 ml of undiluted sample the substance was concluded to be slightly irritant.

Further information on skin irritation of the target substance comes from two studies conducted for EAA, another decomposition product of the target substance. Though very limited amount of information is available, the one study demonstrates that EAA has no irritating and the other study that EAA has mild irritating properties to skin (European Chemicals Bureau, 2002).

The read-across data from the third decomposition product, TiO2, indicates that the substance is shown to lack skin irritation properties. Titanium dioxide has been used in various dermatological and cosmetic formulations, without any known adverse effects (WHO, 1982).

Based on the weight of evidence approach, the data on the skin irritation properties of the analogue category member (titanium tetrabutanolate) and on the decomposition products is considered reliable. It is concluded that these results indicate this titanate to be classified as irritating to skin.

Eye irritation

Weight of evidence approach is used to evaluate the eye irritation of bis(ethylacetoacetato‐O1',O3")bis(2-methyl propan-1-olato)titanium. Since there is no key eye irritation study available for the substance itself relevant read-across data from the analogue category member is used for hazard assessment. Since the target substance is hydrolytically unstable having the half-life less than 10 minutes (Brekelmans, M. J. C., 2013) it is also justified to use the relevant irritation information from the decomposition products, 2-methylpropanol, ethyl acetoacetate (EAA) and titanium dioxide (TiO2).

Further evidence on the eye irritation comes from the analogue category member of the target substance, titanium tetrabutanolate. All these titanates in this category behave similar way when in contact with water. Furthermore, 2-methylpropanol is released from the target substance and butanol from titanium tetrabutanolate when the substances are in contact with water. The category justification and the read-across justifications are presented in the Annexes of the CSR.

In an eye irritation study by Ferenz, R. L. (1978), 0.1 ml of undiluted titanium tetrabutanolate 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.

Publication by Spielmann H et al. (1993) evaluated the eye irritation potential of potential of 2-methylbutanol by applying the substance on hen's egg chorioallantoic membrane for the duration of 5 min. According to the results of HET-CAM study, 2-methylpropanol is classified as group-4 (R-41) irritating with irreversible effect compound.

Further information on eye irritation of the target substance comes from two studies conducted for EAA, the decomposition product of the target substance (European Chemicals Bureau, 2002). These studies demonstrated mild to moderate eye irritating effects that were fully reversible in three days.

TiO2 is non-hazardous decomposition product of bis(ethylacetoacetato‐O1',O3")bis(2-methyl propan-1-olato)titanium. Possible risk of eye irritation caused by this substance is related only to the TiO2 dust. However, after hydrolysis of the target substance, TiO2 is not expected to cause any relevant eye irritation hazard for humans as it exists as a hydrated solid precipitate.

Although the eye irritation studies of the analogue category member and the decomposition products are not reported in great detail and are not performed in strict compliance with current guidelines, they indicate that the target substance is corrosive to the eyes.

Respiratory irritation

Rats and rabbits were exposed, by inhalation, for a period of 4 h to various concentrations of 2-methylpropanol. At a concentration of 15700 mg/m3, there was irritation of the airways. Three days later, symptoms included central nervous depression, a decreased number of lymphocytes in bone marrow, a decreased blood-lactate level, delay in elimination of bromophthalein from blood, and morphological changes including dystrophia of hepatocytes and olfactory neurons in the brain. After exposure to 8000 mg/m3, symptoms were similar but less severe (Kushneva et al., 1983).

Because of rapid hydrolysis of the target substance the intrinsic properties are related to the most hazardous decomposition product, 2-methylpropanol. As this alcohol causes irritation of the respiratory tract during 4 hours exposure, and has the harmonized classification to hazard class STOT SE 3 H335, this titanate will be classified accordingly.

Justification for selection of skin irritation / corrosion endpoint:
The study is performed using the analogue category member.

Justification for selection of eye irritation endpoint:
The study is performed using the analogue category member.

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 from the analogue category member of bis(ethylacetoacetato‐O1',O3")bis(2-methyl propan-1-olato)titanium and its decomposition products, the substance is classified as Skin irritant 2 according to CLP Regulation 1272/2008 and Directive 67/548/EEC.

Based on the eye irritation information from the analogue category member of bis(ethylacetoacetato‐O1',O3")bis(2-methyl propan-1-olato)titanium and its decomposition products, 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.

This titanate decomposes rapidly to 2-methylpropanol. 2-methylpropanol 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 products, 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.