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

Endpoint summary

Description of key information

Oral:
The oral LD50 (rat; male) 23 020 mg/kg bw
Inhalation:
There is no valid data available for acute inhalation toxicity for the substance. LC50 value is for the hazardous degradation product (IPA) 24 600 mg/m3.
Dermal:
Not relevant route of exposure. There is no valid data available for acute dermal toxicity for the substance. Information for IPA indicated the LD50 value of 12 870 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:

January 11, 1978 - April 28, 1978

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The test procedure is not based on guideline, but it is comparable with OECD Guideline 401. Though the detailed description of method and the discussion of the result is missing, the study was performed in consistent way and it is scientifically acceptable.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

The study report do not include details on test procedure and test substance. Only male rats were used in the study.

Principles of method if other than guideline:

LD50 test; 4 groups of ten male rats received a single oral gavage of the test substance. Survivors were sacrificed 14 days later. LD50 value was calculated from the mortality data using the method of D.J. Finney. Probit analysis, 2nd Ed., 1952, Cambridge University Press.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: Chr:CD

Sex:

male

Details on test animals or test system and environmental conditions:

No details on test animals and environmental conditions available

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

VEHICLE
no vehicle was used

MAXIMUM DOSE VOLUME APPLIED:
Dose (mg/kg) Average dose (ml)
29 000 6,52
25 000 5,58
20 000 4,68
17 000 3,96

DOSAGE PREPARATION (if unusual): Test material was administered, as received, without any preparation

Doses:

17 000, 20 000, 25 000, 29 000 mg/bw

No. of animals per sex per dose:

10 males / dose

Control animals:

no

Details on study design:

The test material, as received, was administered by intragastric intubation to four groups of ten young adult male rats in single dose.
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:Animals were weighed at the initiation of the study
- Necropsy of survivors performed: no
- Other examinations performed: clinical signs and body weight

Sex:

male

Dose descriptor:

LD50

Effect level:

23 020 mg/kg bw

Based on:

test mat.

Mortality:

Dose (mg/kg) Mortality ratio
29 000 10/10
25 000 5/10
20 000 1/10
17 000 2/10

Clinical signs:

other: Dose (mg/kg) Clinical signs 29 000 Ataxia, lethargy, rapid and labored respiration, gasping, prostration, salivation, lacriation, stained mouth and weight loss after dosing at 29 000 mg/kg 25 000 Ataxia, lethargy, belly-to-cage posture, rapid and labo

Gross pathology:

not done

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

Acute toxicity of bis(ethyl acetoacetato-O1',O3)bis(propan-2-olato)titanium was determined by using test method equal to OECD 401. LD50 value was 23 020mg/kg of body weight measured by administering test substance as a single oral dose to male rats.

Executive summary:

This study was regarded reliable with restrictions since only male rats were used in this study. Furthermore, the study report does not contain all details of test animals and the study do not include all details on test substance, test method and results. However, the study was performed in a consistent way and it is scientifically acceptable.

In this study, Bis(ethyl acetoacetato-O1',O3)bis(propan-2 -olato)titanium was administered as a single oral dose by intragastric intubation to male rats. Clinical signs of toxicity were observed in all dosed animals. Under the conditions of this test, the LD50 was 23 020 mg/kg of body weight. By the study report this substance is considered to have very low toxicity.

The result of this study would lead to no classification for acute oral toxicity according to EU Regulation No. 1272/2008 (CLP).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

23 020 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:

no study period reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Data obtained from peer-reviewed publication. 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 alcohols, ethyl acetoacetate and hydrated titanium dioxide. The half-life of hydrolysis is < 10 minutes @ 25 ˚C. This rapid hydrolysis 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 most hazardous degradation products released from the target substance. In addition, because of rapid hydrolysis the dermal effects of the target substance are similar to the irritating properties of the degradation products. The identification of degradation products from the hydrolysis study conducted for the target substance verifies that there are no impurities in the mixture of particular alcohol and ethyl acetoacetate which might change the hazardous properties of the target substance compared to the properties of the pure alcohol and ethyl acetoacetate. As there is a mechanistic reasoning to the read-across, the unnecessary animal testing is avoided by using the read-across from the most hazardous degradation products (alcohols) to evaluate irritation, sensitization and the short-term and long-term toxicological effects of the target substance.

Qualifier:

according to guideline

Guideline:

other: US EPA TSCA guidelines for neurotoxicity

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Spague-Dawley, Inc. (Indianapolis, IN)
- Age at study initiation: 9 to 11 weeks
- Weight at study initiation: 178 - 261 g males and 135 - 177 g females at the age of 10-11 weeks
- Housing: individually in stainless stell wire mesh cages
- Diet (e.g. ad libitum): Powdered food (Certified Rodent Chow 5002) ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: a 3-week period during which time a pretest health screen was conducted on randomly selected animals

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-25
- Humidity (%): 40 to 70
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other:

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: stainless steel and glass chambers
- Exposure chamber volume: 1330-liters
- Source and rate of air: filtered air at an airflow of ca. 300 l min-1
- Temperature, humidity in air chamber: recorded approximately 12 times during each exposure

TEST ATMOSPHERE
- Brief description of analytical method used: Perkin - Elmer 8500 flame ionization gas chromatographic (GC) technique
- Samples taken from breathing zone: yes

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

6 h

Concentrations:

500, 1500, 5000, 10000 ppm

No. of animals per sex per dose:

25 animals/sex/dose

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 24 hours
- Frequency of observations and weighing: mortality and signs of toxicity (twice daily), body weights were recorded during each behavioral session
- Necropsy of survivors performed: no
- Other examinations performed: mortality, clinical signs, body weight, other: behavioral testing, motor activity

Statistics:

The data for continuous, parametric variables were intercompared for the dose and control groups by use of Levene’s test for homogeneity of variances,by analysis of variance, and by pooled variance t-tests. The t-tests were used, if the analysis of variance was significant (P
Intra-session motor activity data was analyzed using a repeated measures analysis with dose as grouping factor and session time as the within subject factor. Group comparisons at each reporting epoch were made (as described above) if significant dose effects or time by dose interactions were observed. The epsilon-adjustment procedure (Greenhouse-Geisser correction) was used in repeated measures analysis of motor activity data.

Frequency data from FOB tests was evaluated using Fisher’s exact probability test. All statistical tests were performed using BMDP Statistical Software (Dixon, 1985 or Dixon, 1988). A P value of 0.05 was used as the critical level of significance for all tests.

Sex:

male/female

Dose descriptor:

other: sedation of central nervous system

Effect level:

5 000 ppm

Based on:

test mat.

Exp. duration:

6 h

Sex:

male/female

Dose descriptor:

other: decrease in motor activity

Effect level:

5 000 ppm

Based on:

test mat.

Exp. duration:

6 h

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 10 000 ppm

Based on:

test mat.

Exp. duration:

6 h

Mortality:

no mortalities observed

Clinical signs:

other: In the 10000 ppm group, prostration, severe ataxia, decreased arousal, slowed or labored respiration, decreased neuromuscular tone, hypothermia, and loss of reflex function was observed 1 and 6 hours after exposure. Concentration-related decreases in mean

Body weight:

Body weight was measured at the time of behavioral testing so that any possible confounding effect that body weight might have on behavior could be assessed. Mean body weights for the five exposure groups were not statistically significantly different at any time during the study. Mean body weight tended to be lower for animals in the 10000 ppm exposure group assigned to FOB testing at the 6-hour and 24-hour post-exposure evaluations. This decrease is considered to reflect decreased food consumption during the time period when prostration and narcosis were observed.

Gross pathology:

No gross pathology reported.

Read-across justifications and data matrices are presented in IUCLID section 13.

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

Acute inhalation toxicity of isopropanol was evaluated using a guideline neurotoxicity testing. The LC50 value for rats calculated after single 6-hour exposure was > 10 000 ppm (>24 600mg/m3).

Executive summary:

The purpose of the present study was to investigate the exposure concentration-response profile and time-course for behavioral effects in rats following a single 6 -h exposure to isopropanol vapor. This study was conducted according to EPA TSCA guidelines for neurotoxicity testing.

Male and female rats were exposed to isopropanol vapor at 0, 500, 1500, 5000 or 10 000 ppm. Behavioral observations were performed prior to and 1, 6 and 24 h after exposure. Motor activity was evaluated prior to and immediately following exposure. Exposure to isopropanol caused a spectrum of transient effects indicative of narcosis at 10 000 ppm and sedation at 5000 ppm. Prostration or severe anemia, decresed arousal, slowed or labored respiration, decreased neuromuscular function, hypothermia and loss of reflex function were observed 1 and 6 h after exposure to 10 000 ppm isopropanol vapor. Similar, but less severe alterations were observed in animals in the 5 000 ppm exposure group 1 h after exposure. Exposure concentration-related decreases in motor-activity were observed in males and females in the 5000 and 10 000 ppm groups and slight decrease in motor activity were observed in males in the 1500 ppm group. Animals in the 1500 and 5000 ppm exposure groups recovered from these motor activity effects within 5h. Based on this study, the no-observed-effect-level (NOEL) for isopropanol was 500 ppm.

According to CLP the substance has been classified under STOT single exposure category 3, H336 - may cause drowsiness or dizziness due to transient concentration-related narcosis and central nervous system sedation effects.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

24 600 mg/m³ air

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Data obtained from the secondary source. 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 alcohols, ethyl acetoacetate and hydrated titanium dioxide. The half-life of hydrolysis is < 10 minutes @ 25 ˚C. This rapid hydrolysis 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 most hazardous degradation products released from the target substance. In addition, because of rapid hydrolysis the dermal effects of the target substance are similar to the irritating properties of the degradation products. The identification of degradation products from the hydrolysis study conducted for the target substance verifies that there are no impurities in the mixture of particular alcohol and ethyl acetoacetate which might change the hazardous properties of the target substance compared to the properties of the pure alcohol and ethyl acetoacetate. As there is a mechanistic reasoning to the read-across, the unnecessary animal testing is avoided by using the read-across from the most hazardous degradation products (alcohols) to evaluate irritation, sensitization and the short-term and long-term toxicological effects of the target substance.

Qualifier:

no guideline available

Principles of method if other than guideline:

No principles of method provided in the publication

GLP compliance:

not specified

Species:

rabbit

Sex:

not specified

Dose descriptor:

LD50

Effect level:

12 870 mg/kg bw

Clinical signs:

other:

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

Based on the literature, acute dermal LD50 value of Propan-2-ol in rabbits was determined to be 12 870 mg/kg bw.

Executive summary:

As the target substance hydrolyses immediately (half-life < 3 minutes) the intrinsic properties are related to this main organic degradation product (IPA) of the target substance. This information is used as a weight of evidence in CSA.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

12 870 mg/kg bw

Additional information

Oral

There is one study available for bis(ethylacetoacetato-O1’,O3”) bis(propan-2-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 on acute toxicity comes from the degradation products of the target substance, isopropyl alcohol (IPA), ethyl acetoacetate (EAA) and titanium dioxide (TiO2).

In the study report by Kaplan, M. A. 1978, bis(ethylacetoacetato-O1’,O3”) bis(propan-2-olato)titanium was administered orally to male rats. Under the conditions of this test, the LD50 was 23 020 mg/kg of body weight. This substance is considered to be non-toxic. This study was regarded reliable with restrictions since only male rats were used in this study. Furthermore, the study report does not contain all details of test animals and the study does not include all details on test substance, test method and results. However, the study was performed in a consistent way and it is scientifically acceptable. Thus, it is used as a key study in CSA.

Supporting information for this endpoint comes from the acute oral studies conducted for isopropyl alcohol. The LD50 values for IPA varies between 4 475 mg/kg bw – 7 990 mg/kg bw (OECD, 2004). This proves that IPA has low order of acute toxicity after oral route of exposure. However, IPA has non-lethal effects causing drowsiness or dizziness, and has the harmonized classification entry as STOT SE 3 H336 according to CLP Regulation No. 1272/2008 and as R67 according to EU Directive 67/548/EEC.

Further supporting information comes from studies conducted for EAA. EAA has demonstrated low toxicity after oral application, with LD50 values for rats in the range of 3 980 – 12 300 mg/kg bw (European Chemicals Bureau, 2002).

Based on the acute toxicity data from 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, for 30-34 days. All animals remained healthy and behaved normally. Weight gain and food intake were comparable for the control group. No relevant gross pathology was observed at autopsy (WHO, 1982).

Lethality:

The key LD50-value for bis(ethylacetoacetato-O1’,O3”) bis(propan-2-olato)titanium and the supporting LD50-values for the decomposition products (IPA, 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 Kaplan, M.A. (1978) as this LD50-value (23 020 mg/kg) is presenting the only acute toxicity measured 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 IPA. A number of poisoning cases has been reported due to the intentional ingestion of isopropyl alcohol, particularly among alcoholics or suicide victims. Ingestion of IPA typically results in a comatose condition. Pulmonary difficulty, nausea, vomiting, and headache accompanied by various degrees of central nervous system depression is typical (OECD, 2004). As there is evidence of neurotoxicity caused by IPA 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(propan-2-olato)titanium, this leads also to the classification of this substance for hazard class STOT SE 3 H336.

Inhalation

There are no studies available on bis(ethylacetoacetato-O1’,O3”) bis(propan-2-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 isopropyl alcohol (IPA), 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 IPA also proves that the substance do not cause evident lethality. In the publication by Gill, M. W. et al. (1995) neurotoxicity effects of IPA were investigated in rats after 6-hour exposure. During the study no mortalities were observed at the highest concentration tested. Thus, the LC50 value was concluded to be > 10 000 ppm (>24 600 mg/m3). Behavioral observations were made prior to and 1, 6 and 24 h after exposure. Exposure to IPA caused spectrum of transient effects indicative of narcosis at 10 000 ppm and sedation at 5000 ppm. Prostration or severe anemia, decreased arousal, slowed or labored respiration, decreased neuromuscular function, hypothermia and loss of reflex function were observed 1 and 6 h after exposure to 10 000 ppm isopropanol vapor. Similar, but less severe alterations were observed in animals in the 5 000 ppm exposure group 1 h after exposure. Exposure concentration-related decreases in motor-activity were observed in males and females in the 5000 and 10 000 ppm groups and slight decrease in motor activity were observed in males in the 1500 ppm group. Animals in the 1500 and 5000 ppm exposure groups recovered from these motor activity effects within 5h. Based on this study, exposure of male and female rats to IPA vapor produced transient, concentration-related narcosis and/or sedation at concentration of 5000 and 10 000 ppm and minor decreases in motor activity in males at a concentration of 1500 ppm.

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(propan-2-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 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 IPA. As this alcohol causes defects indicative for CNS depression after single application, and has a harmonized classification to hazard class STOT SE 3H336, the weight of evidence approach suggests bis(ethylacetoacetato-O1’,O3”) bis(propan-2-olato)titanium to possess similar properties than IPA. 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(propan-2-olato)titanium decomposes very rapidly (half-life < 10 minutes) releasing IPA and non-hazardous EAA and TiO2.

IPA can be considered practically non-toxic via dermal route, since dermal LD50value for IPA has been determined to be 12 870 mg/kg (Smyth, H. F., Carpenter, C. P., (1948) cited in OECD 2004).

Also EAA is concluded to be non-toxic, since the dermal LD50 exceeds 10 300 mg/kg bw (Smyth, H. F., Carpenter, C. P., (1948) cited in European Cheicals 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
Reliable Klimisch score 2 study performed for the substance itself.

Justification for selection of acute toxicity – inhalation endpoint
Based on the read-across data from the main 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 main 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(propan-2-olato)titanium indicate a relatively low potential for acute toxicity.

Based on the lethal effects of bis(ethylacetoacetato-O1’,O3”) bis(propan-2-olato)titanium 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(propan-2-olato)titanium decomposes rapidly to IPA, EAA and TiO2. IPA has been shown to cause transient sedation of the central nervous system after exposure via oral and inhalation routes. As the intrinsic properties of the substance are related to the decomposition product, bis(ethylacetoacetato-O1’,O3”) bis(propan-2-olato)titanium has to be classified to hazard class STOT SE 3H336 according to CLP Regulation 1272/2008 and as R 67 according to Directive 67/548/EEC.