Titanium tetrakis(2-ethylhexanolate)

Endpoint summary

Description of key information

Oral:
The oral LD50 (rat; male) is 7500 mg/kg bw
The oral LD50 (rat; male) for 2-ethylhexanol, the degradation product, is 3 290 mg/kg bw
Inhalation:
There is no valid data available for acute inhalation toxicity for the target substance.
The LC50 (rat; male, female) for 2-ethylhexanol, the degradation product, is > 1.4 mg/l (vapor saturation concentration)
Dermal:
There is no valid data available for acute oral toxicity for the target substance.
The oral LD50 (rat; male, female) for the 2-ethylhexanol, the degradation product, is > 3 000 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Data from Handbook or collection of data. Restrictions: number of animals per dose, number of dose levels, and dose levels are not reported. Read-across justification: 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 alcohol and hydrated titanium dioxide. This rapid hydrolysis (hydrolysis half-life < 3 minutes to < 2 hours) is the driving force for the toxicokinetics of target substance. Because of the rapid hydrolysis, the influence of the mode of administration through inhalation, dermal and oral is related to the hazardous degradation product (alcohol) released from the target substance. 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 hazardous properties of the target substance compared to the properties of the pure alcohol. As there is a mechanistic reasoning to the read-across, the unnecessary animal testing is avoided by using the read-across data from the degradation product (relevant alcohol) to evaluate irritation, sensitization and the short term and long-term toxicological effects and mutagenicity of the target substance.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

dose levels, number of animals per dose level not reported

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: own breeding facility
- Age at study initiation:
- Weight at study initiation: 150 - 180 g
- Fasting period before study: 18 hrs
- Housing:
- Diet (e.g. ad libitum): standard diet pellets type K; Staatliche Zentralstelle für Versuchstierzucht unnd -versorgung, Berlin -Lichtenberg, GDR
- Water (e.g. ad libitum): tap water
- Acclimation period: n.a.


ENVIRONMENTAL CONDITIONS
no data

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

Dose levels not reported. Doses were geometrically spaced.

No. of animals per sex per dose:

not reported

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: animals were daily observed and weekly weighed.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: no.

Statistics:

LD50 was calculated according to Litchfield and Wilcoxon (1949) J. Pharmacol. Exp. Therap. 96: 2.

Sex:

male

Dose descriptor:

LD50

Effect level:

3 290 mg/kg bw

95% CL:

2 870 - 3 790

Clinical signs:

other: Narcosis.

The oral LD50 was 3290 mg/kg (range p=0.05: 2870-3790 mg/kg). Deaths occurred
within 2 days after dosing. Animals died in narcosis with no other findings.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral toxicity of undiluted 2-EH was examined in a protocol that is similar to OECD test guideline 401.The LD50 value was 3290 mg/kg bw in fasted male rats.

Executive summary:

The acute oral toxicity of technical grade 2 -EH was examined in a protocol that was similar to the recently retracted OECD test guideline 401. 36 fasted male rats received the unchanged test material by oral gavage; the doses were geometrically spaced. The dose levels and the number of animals per dose level were not reported. The study is therefore regarded to be valid with restrictions.

The LD50 was 3290 mg/kg bw [range (p=0.05): 2870 – 3790 mg/kg bw] in fasted male rats receiving the undiluted 2-EH by oral gavage. Deaths occurred within 2 days, and the animals died in narcosis without any other signs of toxicity (Schmidt P, Gohlke R, and Rothe R, 1973).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 290 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

1989-03-30 through 1989-04-12

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Acceptable, well-documented study report which meets basic scientific principles. Original report available as copy. Restriction: low number of animals, short observation period. Only 2 dose levels tested. Restriction acceptable because of low test substance volatility. No data on gross pathology. Read-across justification: 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 alcohol and hydrated titanium dioxide. This rapid hydrolysis (hydrolysis half-life < 3 minutes to < 2 hours) is the driving force for the toxicokinetics of target substance. Because of the rapid hydrolysis, the influence of the mode of administration through inhalation, dermal and oral is related to the hazardous degradation product (alcohol) released from the target substance. 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 hazardous properties of the target substance compared to the properties of the pure alcohol. As there is a mechanistic reasoning to the read-across, the unnecessary animal testing is avoided by using the read-across data from the degradation product (relevant alcohol) to evaluate irritation, sensitization and the short term and long-term toxicological effects and mutagenicity of the target substance.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

yes

Remarks:

only 2 dose levels; low animal numbers; 7 day observation period

Principles of method if other than guideline:

Method: similar to OECD 403 with restrictions: 2 dose levels tested. 3 animals per sex and dose level were tested. Test atmosphere concentration and particle size was determined. Observation period was 7 days.

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Raleigh, North Carolina
- Age at study initiation: Group I Group II
Males 8 weeks 9 weeks
Males 9 weeks 11 weeks

- Weight at study initiation: Group I Group II
Males: range: 230-238 g; 350-335 g
mean: 235g 353g
Females: range: 221-228 g; 250-265 g
mean: 225g 258g



- Fasting period before study:
- Housing: in stainless steel wire mesh cages; in groups of 2 during the first week of acclimatisation; singly thereafter
- Diet (e.g. ad libitum): standard laboratory diet (Purina Rodent laboratory Chow Brand Animal Diet #5001)
- Water (e.g. ad libitum): automated watering system
- Acclimation period: 1 week (Group I) and 3 weeks (Group II)


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 67-76°F
- Humidity (%): 40-70%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12hrs dark/12 hrs light

Route of administration:

other: Group I: vapour + aerosol; Group II: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Plexigla / glass exposure chamber
- Exposure chamber volume: 100 L
- Method of holding animals in test chamber: animals were caged
- Source and rate of air: house-supply air
- System of generating particulates/aerosols:
Group I: the test material was placed into a 250 mL Erlenmeyer flask from where it was delivered by a fluid metering pump into the fluid inlet of an air atomizing nozzle. House-supply air was delivered through the air inlet to the atomizer to generate the aerosol which was directed into the exposure chamber.
Group II: air was drawn through 2 glass bubblers, place in water bath in tandem, which contained the test material. The air was heated to 50°C in the first and 30°C in the second bubbler; the air was then directed to a 3-neck flask containing glass wool before the filtered air was directed to the exposure chamber.

- Method of particle size determination:
Group I: once during exposure using a Delron DCI-6 Cascade Impactor.
Group II: hourly during exposure using a TSI Aerodynamic Particle Sizer (Model 3300)



TEST ATMOSPHERE
- Brief description of analytical method used:
Group I: gravimetric determination of test material drawn from the breathing zone onto glass microfibre filter paper followed by a charcoal tube. The gravimetric concentration (aerosol/vapour/total) was calculated by dividing the weight difference in mg by the volume of air sampled in L.

Group II: hourly samples were drawn and directed to a IRAN 1A Ambient Air Analyzer. The exposure level was determined from the absorbance using a calibration curve constructed using the same equipment.

- Samples taken from breathing zone: yes


VEHICLE
- Composition of vehicle (if applicable): air
- Concentration of test material in vehicle (if applicable): none


TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: Group I: 81% of particles < 10 microns
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): Group I: 5.6 microns (geometric st. dev. 1.9)
Group II: no aerosol formation was considered, due to very low levels of particulates (0.015 mg/m³)

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

0.89 mg/L (vapour) and 5.3 mg/L (mixed vapour and aerosol)

No. of animals per sex per dose:

3

Control animals:

other: historical controls

Details on study design:

- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: viability was assessed twice daily. Body weights were determined on days 1 (immediately prior to exposure) and on day 8 (prior to sacrifice).
- Necropsy of survivors performed: no

Statistics:

none

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 0.89 - <= 5.3 mg/L air

Exp. duration:

4 h

Remarks on result:

other: 0.89 mg/L (vapour); 5.3 mg/L (mixed vapour and aerosol)

Mortality:

Group I: all animals died (6/6)
Group II: no animals died (0/6)

Clinical signs:

other: Group I: 4 animals died during the exposure period or shortly thereafter. Observations included laboured breathing, nasal discharge, prostration, and closed eyes.

Body weight:

Group I: 4 animals died during the exposure period or shortly thereafter.
Group II: decreased activity was noted during exposure; after the exposure the animals were unremarkable, and most gained weight during the following week.

Gross pathology:

No data

The proportion of inspirable aerosol was high in the first experiment with Group I, and there was a large discrepancy between the measured and the nominal concentration which was calculated from the amount of test material consumed during the exposure.

Group	Concentration (mg/L)
	aerosol	vapour	total	nominal
I	4.3	1.1	5.3	43
II	-	0.89	0.89	2.5

The vapour saturation concentration was calculated to be 1.4 mg/L at 20°C, based on the vapour pressure of 0.2 mm Hg.

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The LC50 was > 890 mg/m3. The complete mortality in the first experiment was attributed to the high proportion of respirable aerosol.

Executive summary:

Following the 4 hour inhalation exposure to 0.89 mg 2-EH/ L no mortalities or clinical signs of toxicity were noted in male and female Sprague-Dawley rats within the 7-day observation period.

In contrast, all animals of the 5 mg/L target concentration group died, 4 of them during the exposure or shortly thereafter. It was, however, demonstrated that only 20% of the measured concentration was attributable to vapour whereas 80% was represented by particulates. The majority of the particulates (81%) had a mean aerodynamic diameter of 10 µm and were thus respirable by rats. The measured concentration was only 12.3% compared to the nominal concentration which was calculated from the consumed test material.

Based on the above it is concluded that the 4 -hour LC50 in rats was > 0.89 mg/L. The vapour saturation concentration was calculated to be 1.4 mg/L at 20°C, based on the vapour pressure of 0.2 mm Hg (BioDynamics, 1989).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

1987-09-15 to 1987-09-29

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Non-GLP guideline study. Read-across justification: 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 alcohol and hydrated titanium dioxide. This rapid hydrolysis (hydrolysis half-life < 3 minutes to < 2 hours) is the driving force for the toxicokinetics of target substance. Because of the rapid hydrolysis, the influence of the mode of administration through inhalation, dermal and oral is related to the hazardous degradation product (alcohol) released from the target substance. 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 hazardous properties of the target substance compared to the properties of the pure alcohol. As there is a mechanistic reasoning to the read-across, the unnecessary animal testing is avoided by using the read-across data from the degradation product (relevant alcohol) to evaluate irritation, sensitization and the short term and long-term toxicological effects and mutagenicity of the target substance.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

no

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

other: WISW (SPF TNO)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: F. Winkelmann, Borchen, Germany
- Age at study initiation: no data
- Weight at study initiation: 173.1 g (mean)
- Fasting period before study: no data
- Housing: Macrolon cages Type III, in groups of 1 to 5 animals
- Diet (e.g. ad libitum): R10 rat diet; Ssniff Spezialfutter GmbH, Soest, Germany
- Water (e.g. ad libitum): tap water
- Acclimation period: 4 to 8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 1 °C
- Humidity (%): 60 +/- 5
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12 hours


IN-LIFE DATES: From: day -1 To:day 14 after initiation

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: >10% of the body surface; clipped 24 h before initiation
- % coverage: >10
- Type of wrap if used: the test site was covered with a gauze patch (5x7cm) and fixed with a cotton wrap.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): no
- Time after start of exposure: 24 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 3.604 ml/ kg bw, i.e. 3000 mg/kg bw
- Concentration (if solution): neat

Duration of exposure:

24 hours

Doses:

3000 mg/kg bw

No. of animals per sex per dose:

5 per sex

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: days -1, 1, 7, and 14 after initiation
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other:

Statistics:

The LD50 was calculated according to Litchfield and Wilcoxon (1949). Pharmacol. Exp. Ther. 96: 99

Preliminary study:

There was no mortality neither in male nor female rats. The dermal LD50 was >3000 mg/kg body weight in rats.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 3 000 mg/kg bw

Mortality:

There was no mortality neither in male nor female rats.

Clinical signs:

other: Animals were excited until 1 hour after test substance application, and free of symptoms thereafter.

Gross pathology:

Mucosa of the small intestine was hyperaemic in 2 animals; red coloured urine was noted in one rat, associated with changes in the kidney.

Body weight development in treated rats (combined males and females):

Day after initiation	Mean body weight [g]
0 before treatment	173.1
1	171.4
7	186.5
14	201.8

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The dermal LD50 was >3000 mg/kg body weight in rats.

Executive summary:

The acute dermal toxicity of 2-ethylhexanol was tested in rats according to OECD 402. 5 animals of either sex were exposed to 3000 mg/kg bw for 24 hours under a semiocclusive dressing. There were no mortalities within the 14 days observation period. The body weight development was not affected, and there were no clear clinical signs or observations during necropsy which could be related to the treatment. Therefore, the dermal rat LD₅₀ was >3000 mg/kg bw in this study (Hüls AG, 1987).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 000 mg/kg bw

Additional information

Acute toxicity oral

There is one low quality study available on titanium tetrakis(2-ethylhexanolate) to evaluate the acute oral toxicity. As the target substance is hydrolytically unstable having the half-life less than 10 minutes (Brekelmans, M. J. C., 2013), information from degradation products are also used to evaluate the lethality and non-lethality of this substance after oral administration. Weight of evidence approach is used to assess the acute oral toxicity of the target substance based on the data from substance itself and from the hazardous degradation product.

In a non-reliable study by Sherman, H. (1961) the approximate lethal dose of the titanium tetrakis(2-ethylhexanolate) was assessed in several rats, one animal per dose. Following administration test animals were observed for clinical signs and mortality for 10 days. Clinical signs of toxicity were observed in animals received dose of 3 500 mg/kg bw or higher. The animals administered using the dose of 7500 mg/kg bw or higher were found dead within 48 hours. Thus, the ALD was concluded to be 7500 mg/kg bw.

The additional data to evaluate acute oral toxicity of target substance come from acute oral study conducted using degradation product, 2-ethylhexanol. The acute oral toxicity of 2 -EH was examined in a protocol that was similar to the recent OECD test guideline 401. 36 fasted male rats received the unchanged test material by oral gavage; the doses were geometrically spaced. The dose levels and the number of animals per dose level were not reported. The study is therefore regarded to be valid with restrictions. The LD50 was 3290 mg/kg bw in fasted male rats. Thus, it can be concluded that 2-ethylhexanol has low order of acute toxicity after oral route of exposure.

Based on the read-across data on the other decomposition product, TiO2, the lowest dose reported to produce any toxic effect in rats by oral route is determined to be 60 g/kg (US EPA, 1994). In other study, a group of 10 male and 10 female rats was given titanium dioxide in the diet at 100 g/kg/bw for 30-34 days. All animals remained healthy and behaved normally. Weight gain and food intake were comparable for the control group and no relevant gross pathology was observed at autopsy (WHO, 1982).

As a conclusion, the LD50-value on titanium tetrakis(2-ethylhexanolate) and the LD50-values on the decomposition products (2-ethylhexanol and hydrated titanium dioxide) are considered reliable. These results do not indicate this substance to be classified as causing evident acute oral toxicity in accordance with the criteria set out in the CLP Regulation 1272/2008 and Directive 67/548/EEC.

Acute toxicity inhalation

There is no study available for titanium tetrakis(2 -ethylhexanolate) itself to evaluate the acute inhalation toxicity. However, there is one non reliable study for 2 -EH, the decomposition product of the target substance, showing LC50 value > 0.89 mg/l. Following the 4 hour inhalation exposure to 0.89 mg 2-EH/l no mortalities or clinical signs of toxicity were noted in male and female Sprague-Dawley rats within the 7-day observation period (Hoffman, 1989). In contrast, all animals of the 5 mg/L target concentration group died, 4 of them during the exposure or shortly thereafter. It was, however, demonstrated that only 20% of the measured concentration was attributable to vapour whereas 80% was represented by particulates. The majority of the particulates (81%) had a mean aerodynamic diameter of 10 µm and were thus respirable by rats. The measured concentration was only 12.3% compared to the nominal concentration which was calculated from the consumed test material. Based on the above it is concluded that the 4-hour LC50 in rats was > 0.89 mg/L. The vapour saturation concentration was calculated to be 1.4 mg/L at 20°C.

Because of the instability of the target substance the intrinsic properties are most likely related to the 2-EH. However, inhalation exposure route of 2-EH is unlikely as it has low fugacity level (ECHA guidance R14, page 28) based on the vapor pressure of 0.1 kPa at 20 deg. Celsius. In addition, 2 -EH has not demonstrated any acute hazards in oral (LD50 3250 mg/kg bw/day) or dermal (LD50 > 3000 mg/kg bw/day) toxicity tests. Furthermore, exposure estimate and risk characterisation indicates low hazard via inhalation (see ES&RC in CSR sections 9&10).

TiO2 is non-hazardous substance and has very low acute and long-term toxicity (US EPA, 1994; WHO, 1982). Furthermore, it is a solid precipitate of the target substance after hydrolysis, and present in hydrated form in the solution after the degradation. Thus, it is not relevant to be considered for this endpoint.

Based on the low bioavailability of 2 -EH via inhalation from the target substance it is regarded not to cause any inhalation hazard. According to the weight of evidence approach CSA does not indicate the target substance to be classified for acute inhalation hazard.

Acute toxicity dermal

There is no valid data available for acute dermal toxicity for the target substance. Furthermore, dermal route is not considered to be relevant exposure route, as skin contact is not likely during the production and use of the test substance because of adequate RMMs in use (see sections 9&10 of CSR). Furthermore, this substance decomposes very rapidly (half-life < 10 minutes) releasing 2-ethylhexanol (2-EH) and hydrated titanium dioxide (TiO2) which has no adsorption potential through skin.

There is available one acute dermal toxicity study for 2-ethylhexanol, the degradation product of titanium tetrakis(2-ethylhexanolate) (Mürmann, 1987). 2-EH was tested in rats according to OECD 402. Five animals of either sex were exposed to 3000 mg/kg bw for 24 hours under a semiocclusive dressing. There were no mortalities within the 14 days observation period. The body weight development was not affected, and there were no clear clinical signs or observations during necropsy which could be related to the treatment. Therefore, the dermal rat LD50 was > 3000 mg/kg bw in this study.

Thus, the chemical safety assessment does not indicate the need to investigate further the acute dermal toxicity.

Justification for selection of acute toxicity – oral endpoint
No reliable study available for the substance itself. Based on the read-across data from the main decomposition product as the target substance is highly reactive (hydrolytically unstable with half-life of < 10 minutes (Brekelmans, M. J. C, 2013).

Justification for selection of acute toxicity – inhalation endpoint
Based on the read-across data from the main decomposition product as the target substance is highly reactive (hydrolytically unstable with half-life of < 10 minutes (Brekelmans, M. J. C, 2013). It is concluded that the 4-hour LC50 in rats was > 0.89 mg/m3. The vapour saturation concentration was calculated to be 1.4 mg/L at 20°C. Because of low fugasity (vapour pressure of 2-ethylhexanol 0.1 kPa), exposure assessment and risk characterisation indicates low hazard via inhalation (see ES&RC in CSR sections 9&10).

Justification for selection of acute toxicity – dermal endpoint
Exposure unlikely as approriate RMMs in use. Based on the read-across data from the main decomposition product as the target substance is highly reactive (hydrolytically unstable with half-life of < 10 minutes (Brekelmans, M. J. C, 2013).

Justification for classification or non-classification

Lethality:

The available data for titanium tetrakis(2 -ethylhexanolate) indicate low potential for acute toxicity. Based on the lethal effects of titanium tetrakis(2 -ethylhexanolate)and the decomposition products, the substance has not to be classified according to CLP Regulation 1272/2008 and Directive 67/548/EEC.