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

Endpoint summary

Description of key information

Oral:
The oral LD50 (rat; female) > 2000 mg/kg bw.
Inhalation:
There is no data available for acute inhalation toxicity for the target substance. The LC50 value for the most hazardous degradation product, 2-methylpropanol is > 18180 mg/m3.
Dermal:
There is no data available for acute dermal toxicity for the target substance. The LD50 value for the most hazardous degradation product, 2-methylpropanol is > 2000 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:

experimental study

Adequacy of study:

key study

Study period:

June 4, 2012 - July 9, 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted in accordance with OECD No. 423 guideline and in compliance with GLP.

Qualifier:

according to guideline

Guideline:

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

Qualifier:

according to guideline

Guideline:

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

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nohsan, Notification No. 8147, April 2011; including the most recent partial revisions.

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

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: Young adult animals (approx. 10-11 weeks old) were selected
- Weight at study initiation: Body weight variation did not exceed +/- 20% of the sex mean.
- Fasting period before study: Animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test substance. Water was available ad libitum
- Housing: Group housing of 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: Acclimatization period was 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:2000 mg/kg (1.802 ml/kg) body weight

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations daily, weighing weekly
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

No statistical analysis was performed

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

no mortality occurred (Table 1 in attached background material).

Clinical signs:

other: On day 1 hunched posture was noted in three females, and lethargy and uncoordinated movements were noted in one other female. (Table 2 in attached background material).

Gross pathology:

Reddish foci on the thymus was found in one animal at macroscopic post mortem examination. Macroscopic post mortem examination of the other animals did not reveal any abnormalities (Table 4 in attached background material).

Interpretation of results:

relatively harmless

Remarks:

Migrated information Criteria used for interpretation of results: OECD GHS

Conclusions:

Acute toxicity of Bis(ethylacetoacetato-O1', O3") bis(2-methyl propan-1-olato)titanium, was evaluated using OECD 423 Acute toxic class method. The LD50 value in rats was established to exceed 2 000 mg/kg of body weight measured by administering test substance as a single oral dose to female animals.

Executive summary:

Bis(ethylacetoacetato-O1', O3") bis(2-methyl propan-1-olato)titanium was administered as an oral gavage in female rats to evaluate acute toxicity. The test substance did not cause any deaths during the study period and thus the LD50 value was concluded to be > 2 000mg/kg body weight under the conditions of this study.

Based on these results, Bis(ethylacetoacetato-O1', O3") bis(2-methyl propan-1-olato)titanium does not have to be classified according to Regulation (EC) No 1272/2008 (CLP) for acute oral toxicity. This study was regarded reliable without restrictions since the study was conducted in accordance with OECD No. 423 guideline and in compliance with GLP.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

18 180 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 adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

Acute toxicity oral

There is one key study available on bis(ethylacetoacetato-O1’,O3”) bis(2-methyl propan-1-olato)titanium 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), 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. (2013) the toxicity of the bis(ethylacetoacetato-O1’,O3”) bis(2-methyl propan-1-olato)titanium 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, and lethargy and uncoordinated movements were noted in one other female on Day 1. Body weight gain was normal. Reddish foci on the thymus were found in one animal at post mortem examination. The oral LD50 value of bis(ethylacetoacetato-O1’,O3”) bis(2-methyl propan-1-olato)titanium in Wistar rats was established to exceed 2000 mg/kg body weight.

The supporting read-across data on acute oral toxicity of ethyl acetoacetate (EAA) proves that after the hydrolysis this decomposition product released from the substance does not cause evident lethality. In an acute toxicity study where EAA was administered in rats an LD50 value of 3980 mg/kg was obtained (O'Neil M.J. et al. 2006).

Further supporting evidence for the acute toxicity of the target substance comes from the study conducted for 2-methylpropanol, the most hazardous degradation product of the target substance (O'Neil, M.J. 2006). After single oral gavage in rats the LD50 value was concluded to be 2460 mg/kg bw. Thus, the substance is considered practically non-toxic.

Based on the read-across data on the 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).

Lethality:

The key LD50-value for bis(ethylacetoacetato-O1’,O3”) bis(2-methyl propan-1-olato)titanium and the supporting LD50 values for the decomposition products (2-methylpropanol, EAA and TiO2) 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/EC. The key value for CSA was selected based on the study of Beerens-Heijnen (2013) as this LD50-value (> 2000 mg/kg bw) is presenting the reliable toxicity value for the target substance.

Non-lethality:

Because of rapid hydrolysis (half-life < 10 minutes) the intrinsic properties of the target substance are related to the most hazardous decomposition product 2-methylpropanol. Exposure to high inhalation or oral doses of isobutanol can cause transient, acute decreases in central nervous system function (reduced responsiveness to external stimuli, ataxia, hypoactivity) (UNEP, 2004). As there is evidence of neurotoxicity caused by 2-methylpropanol after single oral and also after inhalation exposure, this substance has been classified to hazard class STOT SE 3 H336. Due to rapid hydrolysis of bis(ethylacetoacetato-O1’, O3”) bis(2 -methyl propan-1 -olato) titanium, this leads also to the classification of the target substance for hazard class STOT SE 3 H336.

Inhalation

There are no studies available on bis(ethylacetoacetato-O1’,O3”) bis(2-methyl propan-1-olato)titanium itself to evaluate the acute inhalation toxicity of the substance. The target substance is hydrolytically unstable. When it comes in contact with water or moisture, a complete hydrolysis will take place with no significant reaction products other than 2-methylpropanol, ethyl acetoacetate (EAA) and titanium dioxide (TiO2). Because of rapid hydrolysis, read-across data on the acute inhalation toxicity of these reaction products is used to evaluate the lethality and non-lethality of the target substance.

The read-across data on acute inhalation toxicity of 2-methylpropanol proves that this substance do not cause evident lethality, since LC50 values measured for the substance varies between 15500 - 26250 mg/m3 ) (UNEP, 2004).

In the study by Li, et al. 1994 cited in UNEP, 2004 male and female rats were exposed to atmospheric vapor levels of 0, 1500, 3000, or 6000 ppm (0, 4,550, 9090, 18120 mg/m3) for six hours. The exposed rats were evaluated in a neurobehavioral battery (motor activity determination and a functional observational battery) within two hours post-exposure. Hypoactivity and diminished response to a startle reflex (during the inhalation exposure) was observed during exposure for the 3000 and 6000 ppm (9090 and 18180 mg/m3) exposures. Decreases in motor activity were noted post-exposure in the 6000 ppm (18180 mg/m3 ) groups but not the 3000 or 1500 ppm (9090 or 4550 mg/m3 )groups. No effect on motor activity was detected at the 7 and 14 -day time points. No exposure-related effects were noted in the FOB assessment. Since no mortality was observed at the highest concentration level tested, the LC50 value is determined to be > 18180 mg/m3.

Further information on non-toxicity of the target substance comes from inhalation studies conducted for EAA. Though only two summaries of acute inhalation tests are available both studies report that no mortalities in rats were observed when animals were exposed to a saturated atmosphere of EAA over a test period of 7 and 8 hours (registration data 2010 and European Chemicals Bureau, 2002).

The third decomposition product of bis(ethylacetoacetato-O1’,O3”) bis(2-methyl propan-1-olato)titanium is TiO2. TiO2 does not cause any relevant exposure hazard for humans as it is non-volatile solid precipitate after hydrolysis of the target substance.

Lethality:

Based on the weight of evidence on the decomposition of the target substance and on the inhalation study results of the decomposition products it is concluded that this substance is not classified for acute inhalation toxicity in accordance with the criteria set out in the CLP Regulation 1272/2008 and Directive 67/548/EEC.

Non-lethality:

Because of rapid hydrolysis (half-life < 10 minutes) the intrinsic properties of the target substance are related to the most hazardous decomposition product 2-methylpropanol. As this alcohol causes defects indicative for CNS depression after single application (UNEP, 2004) and has a harmonized classification to hazard class STOT SE 3H336, the weight of evidence approach suggests bis(ethylacetoacetato-O1’,O3”) bis(2-methyl propan-1-olato)titanium to possess similar properties than 2-methylpropanol. Thus, this leads to the classification of this substance for hazard class STOT SE3 H336.

Dermal

There is no valid data available for acute dermal toxicity. Furthermore, dermal route is not considered to be relevant exposure route as skin contact is not likely during the production and use of the substance since the adequate RMMs are in use (CSR sections 9 & 10). Furthermore, bis(ethylacetoacetato-O1’,O3”) bis(2 -methyl propan-1 -olato)titanium decomposes very rapidly (half-life < 10 minutes) releasing 2-methylpropanol and non-hazardous ethyl acetoacetate (EAA) and titanium dioxide (TiO2).

2-methylpropanol can be considered practically non-toxic via dermal route, since dermal LD50 value for the substance is > 2000 mg/kg bw (UNEP, 2004).

Also EAA is concluded to be non-toxic, since the dermal LD50 exceeds 10 300 mg/kg bw (European Chemicals Bureau, 2002).

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
Key study performed for the substance itself.

Justification for selection of acute toxicity – inhalation endpoint
Based on the read-across data from the most hazardous decomposition product as the target substance is hydrolytically unstable with half-life of < 10 minutes (Brekelmans, M. J. C, 2013).

Justification for selection of acute toxicity – dermal endpoint
Based on the read-across data from the most hazardous decomposition product as the target substance is hydrolytically unstable with half-life of < 10 minutes (Brekelmans, M. J. C, 2013).

Justification for classification or non-classification

Lethality:

 

The available data for bis(ethylacetoacetato-O1’,O3”) bis(2 -methyl propan-1-olato)titanium indicate low potential for acute toxicity. Based on the lethal effects of this titanate and the decomposition products, the substance has not to be classified according to CLP Regulation 1272/2008 and Directive 67/548/EEC.

 

Toxicity to a specific organ:

Bis(ethylacetoacetato-O1’,O3”) bis(2 -methyl propan-1-olato)titanium decomposes rapidly to 2-methylpropanol, EAA and TiO₂. 2-methylpropanol has been shown to cause transient depression of the central nervous system after exposure via oral and inhalation routes. As the intrinsic properties of the target substance are related to the decomposition products, this titanate has to be classified for hazard class STOT SE 3 H336 according to CLP Regulation 1272/2008 and as R67 according to Directive 67/548/EEC.