(ethyl acetoacetato-O1',O3)(pentane-2,4-dionato-O,O')[propane-1,3-diolato(2-)-O,O']titanium

Endpoint summary

Description of key information

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be in the range of 300 - 2000 mg/kg body weight (CLP - Category 4, H302: Harmful if swallowed.).

The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight. The test item does not meet the criteria for classification according to CLP Regulation.

The characterisation phase of the acute toxicity inhalation study according to OECD 436 resulted that a formal exposure is not required as it proved impossible to generate a suitable vapour atmosphere of the test item which would be in compliance with the test guideline.

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:

08-03-2017 to 29-03-2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Version / remarks:

17 Dec 2001

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

no

Species:

rat

Strain:

Wistar

Remarks:

RccHan:WIST

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Envigo RMS Limited, UK
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: 163 - 185g (main study)
- Fasting period before study: overnight fast immediately before and approx. 3 -4 hours after dosing
- Housing: in groups of up to four in suspended solid-floor polypropylene cages with woodflakes
- Diet: free access to food (2014C Teklad Global Rodent diet)
- Water: free access to main drinking water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25°C
- Humidity (%): 30 - 70%
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

oral: gavage

Vehicle:

DMSO

Doses:

300 mg/kg
2000 mg/kg

No. of animals per sex per dose:

2000 mg/kg: 1 animal (sighting study)
300 mg/kg: 1 animal (sighting study)
300 mg/kg: 5 animals

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Morbidity and mortality checks twice daily, once daily at weekend and public holidays; weighing on days 0, 7 and 14 d or at death
- Necropsy of survivors performed: yes
- Clinical observations: 30 min, 1, 2, 4 h afer dosing, then daily up to 14 d

Preliminary study:

Sighting study: In the absence of toxicity at a dose level of 300 mg/kg tested in one animal, an additional animal was treated with 2000 mg/kg. At this dose level, the signs of systemic toxicity noted were hunched posture, lethargy, noisy and labored respiration, pilo-erection and dehydration. The tested animal was killed for humane reasons, 1 day after dosing.
Due to mortality and signs of systemic toxicity in the "main test" a group of five animals was tested with 300 mg/kg.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 300 - < 2 000 mg/kg bw

Based on:

test mat.

Mortality:

Dose level - 2000 mg/kg (sighting study): the animal was killed 1 day after dosing, due to the occurrence of clinical signs of toxicity that were considered likely to exceed the severity limit.
Dose level - 300 mg/kg: no death

Clinical signs:

other: Dose level - 2000 mg/kg (sighting study): Signs of systemic toxicity noted were hunched posture, lethargy, noisy and labored restiration, pilo-erection and dehydration Dose level - 300 mg/kg: No signs of systemic toxicity noted during the observation peri

Gross pathology:

Necropsy:
Dose level - 2000 mg/kg (sighting study): Gaseous stomach and test item present in the stomach
Dose level - 300 mg/kg: No abnormalities

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be in the range of 300 - 2000 mg/kg body weight (CLP - Category 4).

Executive summary:

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be in the range of 300 - 2000 mg/kg body weight (CLP - Category 4).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

500 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2018-06-25 to 2018-07-20

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)

Version / remarks:

2009

Deviations:

yes

Remarks:

It proved impossible to generate a suitable vapour atmosphere of the test item which would be in compliance with the test guideline. This was considered not to have affected the validity of the study.

Qualifier:

according to guideline

Guideline:

EU Method B.52 (Acute Inhalation Toxicity - Acute Toxic Class Method)

Version / remarks:

2014

Deviations:

yes

Remarks:

It proved impossible to generate a suitable vapour atmosphere of the test item which would be in compliance with the test guideline. This was considered not to have affected the validity of the study.

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

The mean non-volatile component of the test item was found to be 70.88% (n=10).

The test item vapor was generated and the following results were achieved in terms of atmosphere concentrations: 

Duration of Exposure (minutes)	Flow (L/min)		Volume of Air Sampled (L)	Atmosphere Concentration (mg/L)
	Air	Exhaust
13	5	50	10	0.0059
30	10	50	2	0.1199
42	15	50	1	0.2219
53	20	50	1	0.2827

 

Although it was possible to generate a vapor atmosphere of the test item, the concentrations achieved were much lower than those required by the test guidelines (0.5 to 20 mg/L).  It was considered, that generation of the test item as an aerosol would not be appropriate due to the nature of the test item.

Interpretation of results:

study cannot be used for classification

Conclusions:

In view of the physical nature of the test item it is considered unlikely to represent a significant hazard by the inhalation route.

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

14-03-2017 to 05-04-2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

adopted 24 Februrary 1987

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

GLP compliance:

yes (incl. QA statement)

Limit test:

yes

Species:

rat

Strain:

Wistar

Remarks:

RccHan:WIST

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Envigo RMS (UK) Limited
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 8 to 12 weeks
- Weight at study initiation: at least 200 g
- Fasting period before study: no
- Housing: individually in the initial test, and individually in the "main test" during the exposure time and in groups of four, by sex, for the remainder of the study; suspended solid floor polypropylene cages furnished with woodflakes
- Water and Diet: free access to mains drinking water and food (2014C Teklad Global Rodent diet)
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25
- Humidity (%): 30 to 70
- Air changes (per hr): at least 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: back and flanks
- % coverage: approx. 10% of total body surface area
- Type of wrap if used: a piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with dimethyl sulphoxide to remove any residual test item.
- Time after start of exposure: 24h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

1 (initial test)
4 ("main test")

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 30 min, 1, 2 and 4 hours, subsequently once daily for 14 days.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, dermal reactions

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths

Clinical signs:

other: No signs of systemic toxicity were noted during the observation period.

Gross pathology:

No abnormalities were noted at necropsy

Other findings:

Dermal reactions:
Yellow colored staining, not preventing evaluation of dermal responses, was noted at the test sites of five animals 1 day after dosing.
Very slight erythema was noted at the test sites of the initial two treated animals 1 and 2 days after dosing and persisted in the initial treated male 3 and 4 days after dosing.
There were no signs of dermal irritation noted at the test sites of the additional group of eight animals.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight.
The test item does not meet the criteria for classification according to CLP Regulation.

Executive summary:

The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight.

The test item does not meet the criteria for classification according to CLP Regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Justification for classification or non-classification

The acute oral LD50 was estimated to be in the range of 300 - 2000 mg/kg bw, therefore the substance is classified as acute toxicity oral Category 4, H302 (harmful if swallowed).

In the available acute dermal test, no adverse effects were observed. Thus, the substance is not classified for dermal toxicity.