Titanium(4+) ethanolate

Endpoint summary

Description of key information

Oral:
The oral LD50 (rat; female) > 2 000 mg/kg bw
Inhalation:
There is no valid data available for acute inhalation toxicity for the target substance. LC50 for the ethanol, the degradation product, is > 60 000 ppm (114mg/l).
Dermal:
There is no valid data available for acute dermal toxicity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

04 July 2012 - 23 January 2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study is carried out based on the OECD No. 423 Acute Oral Toxicity, Acute Toxic Class Method and in compliance with OECD principles of Good Laboratory Paractice (GLP)

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Qualifier:

according to guideline

Guideline:

other: JMAFF guidelines (2011)

GLP compliance:

yes

Test type:

acute toxic class method

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approx. 8 weeks old
- Weight at study initiation: first group 161, 160, 165 grams, second group 168, 181, 170
- Fasting period before study: Animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test substance.
- Housing: 3 animals per cage in labeled Makrolon cages (MIV type; height 18 cm.) containing sterilized sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom).
- Diet (e.g. ad libitum):Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water (e.g. ad libitum):Free access to tap water.
- Acclimation period:at least 5 days before start of treatment under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C):18 to 24°C
- Humidity (%):40 to 70%
- Air changes (per hr):approximately 15 room air changes/hour
- Photoperiod (hrs dark / hrs light):12-hour light/12-hour dark cycle

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 2000mg/kg (1,805 ml/kg) body weight

Doses:

2000mg/kg bw

No. of animals per sex per dose:

six females (2 groups of three females)

Details on study design:

The toxicity of the test substance was assessed in a limit test by treatment of six females (2 groups of three females in a stepwise manner) at a dose level of 2000 mg/kg body weight.
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality twice daily, clinical signs at 0, 2 and 4 hours on the day of dosing (Day 1) and once daily there after, until Day 15. Body weights at Day 1, 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, necropsy

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred. See attached results, table 1.

Clinical signs:

other: Hunched posture was noted in three animals on Day 1. See attached results, table 2.

Gross pathology:

No abnormalities were found at macroscopic post mortem examination of the animals. See attached results, table 4

Other findings:

no findings noted

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The oral LD50 value of Titanium(4+) ethanolate in Wistar rats was established to exceed 2000 mg/kg body weight. This study was conducted according to the OECD 423 method and in compliance with GLP.

Executive summary:

The objective of this study was to assess the toxicity of the titanium(4 +) ethanolate when administered in a single oral dose (2000 mg/kg bw) to female rats. The oral route was selected as it is a possible route of human exposure during manufacture, handling or use of the test substance. No mortalities was observed at the tested dose level. According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.

The study is considered reliable without restrictions since the study is carried out based on the OECD No. 423 guideline and in compliance with principles of Good Laboratory Paractice (GLP).

Based on these results, Titanium(4 +) ethanolate does not have to be classified and has no obligatory labeling requirement for acute oral toxicity according to CLP Regulation 1272/2008 and Directive 67/548/EEC.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 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:

1985

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The study is reasonably well reported but there are deviations from an guideline protocol. It can be considered sufficiently well reported to be an acceptable study with sufficient basic documentation to demonstrate that it meets basic scientific principles and contains enough detail to be able to judge the results reliable. 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:

, Exposure period only 60 minutes. Species mouse rather than preferred rat. Observations reported for only 3 days rather than 14. Volume of chamber 29 litres (above 20 litres) . No detailed observations of effects. No pathology.

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

mouse

Strain:

CD-1

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, WIlmington, MA
- Age at study initiation: Not stated
- Weight at study initiation: 25 - 30 g
- Housing: standard mouse cages with wood chip bedding in groups of 6
- Diet at libitum (Rodent lab chow 5001, Ralston Purina Mills, St Louis, MO)
- Water ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature: 22 - 24°C
- Photoperiod (hrs dark / hrs light): 12 hour light/12 hour dark cycle

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: glass chambers
- Exposure chamber volume: 29 litre
- Method of holding animals in test chamber: not restrained
- System of generating vapour: Solvent placed on a filter paper in the chamber which was suspended beneath a fan.

TEST ATMOSPHERE
- Brief description of analytical method used: verified using a single wavelength infrared spectrometer through a closed loop re-circulating pump
- Samples taken from breathing zone: no. Samples taken from different parts of the chamber prior to the study to ensure homogenous atmosphere so sampling could be done with confidence from the top of the chamber during the study.

Duration of exposure:

60 min

Concentrations:

40,000, 50,000 and 60,000 ppm for different exposure duration.
- One exposure period per exposure level.
- Exposure duration: 60, 30, and 10 minutes.

No. of animals per sex per dose:

6

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 72 days.
- Necropsy and target organs: not applicable.

Statistics:

Analysis by the probit analysis of Bliss (Quart J Pharmac, 11, 192, 1938) after log transformation and LC50 plus confidence limits calculated.

Sex:

male

Dose descriptor:

LC50

Effect level:

> 60 000 ppm

Exp. duration:

60 min

Sex:

male

Dose descriptor:

other: EC50

Effect level:

49 570 ppm

95% CL:

> 47 000 - < 52 600

Exp. duration:

10 min

Remarks on result:

other: based on motor performance test.

Sex:

male

Dose descriptor:

other: EC50

Effect level:

32 500 ppm

95% CL:

> 27 800 - < 37 750

Exp. duration:

30 min

Remarks on result:

other: based on motor performance test.

Sex:

male

Dose descriptor:

other: EC50

Effect level:

30 300

95% CL:

> 28 000 - < 32 750

Exp. duration:

60 min

Remarks on result:

other: based on motor performance test.

Mortality:

No LC50 was determined as no deaths occurred at any of the exposure concentrations.

Clinical signs:

other: Slight to moderate ataxia was observed and recovery from this exceeded 4 hours at all exposure levels.

Body weight:

no data

Gross pathology:

not performed

Recovery from the exposure as assessed using the motor performance test was slow. There was incomplete recovery up to 4 hours after exposure for all exposure period cohorts.

All of the reported EC50 values are above the lower explosive limit reported in chapter 4. Based on the vapour pressure in chapter 5, the saturated vapour concentration would be 55,000ppm, therefore the maximum exposure in this study must be saturated vapour.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

In an acute toxicity inhalation study, mice were exposed to ethanol for different periods of time up to 1 hour. An LC50 could not be obtained; no deaths were reported for exposures up to 60,000ppm (114mg/l).

Executive summary:

In an acute toxicity inhalation study, mice were exposed to ethanol for different periods of time up to 1 hour in order to determine the LC50 and the EC50 for motor performance. An LC50 could not be obtained for inhalation exposure; no deaths were reported for exposures up to 60,000ppm (114mg/l), which can be considered the saturated vapour concentration. In the motor performance test, an EC50 60 min value of 30,300ppm was established, with a slope for the dose effect curve of 12.6. This result differered only slightly from the EC50 30 min. Whilst exposures were only for 1 hour, the evidence suggests that exposures for 4 hours would not have significantly reduced the motor performance results or the LC50. It should be noted that all of the reported EC50 values are above the lower explosive limit reported in chapter 4. On this basis and based on the result in mice, inhalation exposure poses little hazard at any feasible exposure concentration.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

114 000 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Clinical signs:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute toxicity oral

There is one key study available on titanium(4+) ethanolate to evaluate the acute oral toxicity. As the target substance is hydrolytically unstable having the half-life less than 5 minutes (Brekelmans, M.J.C., 2013), supporting information from degradation products are also used to evaluate the lethality and non-lethality of this substance after oral administration.

In a reliable guideline compliant study by Beerens-Heijnen, C.G.M. (2012) the toxicity of the titanium(4+) ethanolate was assessed in a limit test by treatment of six females at a dose level of 2000 mg/kg body weight. Following administration test animals were observed for clinical signs and mortality for 14 days. No mortality occurred and no other clinical signs were observed than hunched posture in three animals on Day 1. Body weight gain was normal and no abnormalities were found post mortem examination of animals. The oral LD50 value of titanium(4+) ethanolate in Wistar rats was established to exceed 2000 mg/kg body weight.

The supporting read-across data on acute oral toxicity of ethanol proves that after the hydrolysis these decomposition products released from the substance do not cause evident lethality. In an acute toxicity study ethanol was administered in female rats using a relatively large number of animals over 7 closely spaced doses, an LD50 value of 14500 -15500 mg/kg was obtained (Youssef, A, et al., 1992). Lowest robust reported oral LD50 value for ethanol is 8300 mg/kg/bw (mouse) (OECD, 2005). Thus, it can be concluded that ethanol 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(4+) ethanolate and the LD50-values on the decomposition products (ethanol 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.

The key value for CSA was selected based on the study of Beerens-Heijnen, C.G.M. (2012) as this LD50-value (>2000 mg/kg body weight) is presenting the only available acute toxicity value of titanium(4+) ethanolate conducted in compliance with OECD guidelines.

Acute toxicity inhalation

There are no studies available on titanium(4+) ethanolate itself to evaluate the acute inhalation toxicity of the substance. The potential of this substance to cause acute effects is evaluated based on the read-across data on acute toxicity of the decomposition products, because the target substance is hydrolytically unstable having the half-life less than 5 minutes (Brekelmans, M.J.C., 2013). The weight of evidence approach is used to determine the lethality and non-lethality of this substance evaluating relevant data also from the decomposition products, ethanol and titanium dioxide (TiO₂).

In an acute inhalation studies, ethanol has shown a low order of acute toxicity. An LC50 value was not achieved at exposures of up to 60 000 ppm (114mg/l) for 60 minutes in study in CD-1 mice (Moser, 1985). Mice in this study experienced moderate ataxia, which reversed after more than 4 hours recovery period at all exposure levels. To put this result into context, it is worth noting that the lower explosive limit (LEL) for ethanol is around 50mg/l. Furthermore,it should be noted that all of the reported EC50 values are above.

Another decomposition product of titanium(4+) ethanolate is non-hazardous hydrated titanium dioxide. TiO₂does not cause any relevant exposure hazard for humans as it is non-volatile solid precipitate after hydrolysis of the target substance.

Based on the results available, inhalation exposure poses no hazard at any feasible exposure concentration.These results do not indicate this substance to be classified as causing evident acute inhalation toxicity in accordance with the criteria set out in the CLP Regulation 1272/2008 and Directive 67/548/EEC.

Acute toxicity dermal

There is no valid data available for acute dermal toxicity. However, 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 < 5 minutes) releasing ethanol and hydrated titanium dioxide which has no adsorption potential through skin.

There is available one acute dermal toxicity study for ethanol (OECD, 2005), the degradation product of titanium(4+) ethanolate. This document cites an unreferenced result indicating that LDLo for ethanol is 20 000 mg/kg bw. Based on this fact, ethanol can be considered practically non-toxic via dermal route. Furthermore, dermal uptake of ethanol is very low, since the half life for the evaporation of ethanol from skin is 11.7 seconds (Pendlington, 2001) which implies that continuous immersion would be required for there to be any potential for dermal absorption . 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
OECD guideline study without deviations performed in accordance with GLP.

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 < 5 minutes (Brekelmans, M.J.C, 2013).

Justification for classification or non-classification

The available data for titanium (4+) ethanolate indicate relatively low potential for acute toxicity.

Based on the acute effects of titanium (4+) ethanolate and the decomposition products, the substance has not to be classified for acute toxicity according to CLP Regulation 1272/2008 and Directive 67/548/EEC.