Ethoxybis(pentane-2,4-dionato-O,O')(propan-2-olato)titanium

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: oral

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

According to hydrolysis test results, the hydrolysis rate is estimated to be within 30 minutes. The hydrolysis products have been identified to be ethanol, 2-propanol, acetylacetone and titanium dioxide.
The properties of the target substance would lie in the hydrolysis products.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

chronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

exposure considerations

Justification for data waiving:

other:

Justification for type of information:

According to hydrolysis test results, the hydrolysis rate is estimated to be within 30 minutes. The hydrolysis products have been identified to be ethanol, 2-propanol, acetylacetone and titanium dioxide.
The properties of the target substance would lie in the hydrolysis products.

Reference 2

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Deviations:

no

GLP compliance:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: no vehecle

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

6 hours per day, 5 days per week

Dose / conc.:

100 ppm

Dose / conc.:

500 ppm

Dose / conc.:

1 500 ppm

Dose / conc.:

5 000 ppm

Dose descriptor:

NOAEC

Effect level:

ca. 5 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

Critical effects observed:

no

Conclusions:

Repeated exposure to propan-2-ol produced toxic effects only at 5000 ppm (12300mg/m3)

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

417 mg/m³

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

exposure considerations

Justification for data waiving:

other:

Justification for type of information:

According to hydrolysis test results, the hydrolysis rate is estimated to be within 30 minutes. The hydrolysis products have been identified to be ethanol, 2-propanol, acetylacetone and titanium dioxide.
The properties of the target substance would lie in the hydrolysis products.

Reference 2

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Deviations:

no

GLP compliance:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: no vehecle

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

6 hours per day, 5 days per week

Dose / conc.:

100 ppm

Dose / conc.:

500 ppm

Dose / conc.:

1 500 ppm

Dose / conc.:

5 000 ppm

Dose descriptor:

NOAEC

Effect level:

ca. 5 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

Critical effects observed:

no

Conclusions:

Repeated exposure to propan-2-ol produced toxic effects only at 5000 ppm (12300mg/m3)

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

According to hydrolysis test results, the hydrolysis rate is estimated to be within 30 minutes. The hydrolysis products have been identified to be ethanol, 2-propanol, acetylacetone and titanium dioxide.
The properties of the target substance would lie in the hydrolysis products.

Reference 2

Endpoint:

sub-chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Qualifier:

according to guideline

Guideline:

EU Method B.28 (Sub-Chronic Dermal Toxicity Test: 90-Day Repeated Dermal Dose Study Using Rodent Species)

GLP compliance:

yes

Limit test:

no

Species:

mouse

Strain:

C3H

Sex:

male/female

Details on test animals or test system and environmental conditions:

The animals were housed individually in suspended stainless-steel wire cages in a room with controlled lighting. Certified diet (Agway, Ithaca, USA) and water from an automatic watering system were provided ad lib.

Type of coverage:

open

Vehicle:

acetone

Details on exposure:

Test substances were applied using an Eppendorf automatic pipette, 50μl per application, to the back of each mouse from which the fur was clipped once weekly. The tip of the pipette was used to spread the test substance from the interscapular area to the lumbar area of each mouse.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

3 times a week for 13 weeks

Dose / conc.:

140 mg/kg bw/day (nominal)

Remarks:

male

Dose / conc.:

460 mg/kg bw/day (nominal)

Remarks:

male

Dose / conc.:

2 000 mg/kg bw/day (nominal)

Remarks:

male

Dose / conc.:

160 mg/kg bw/day (nominal)

Remarks:

female

Dose / conc.:

540 mg/kg bw/day (nominal)

Remarks:

female

Dose / conc.:

2 300 mg/kg bw/day (nominal)

Remarks:

female

No. of animals per sex per dose:

15

Control animals:

no

Clinical signs:

no effects observed

Description (incidence and severity):

No clinical signs of toxicity or skin irritation were observed during the study.

Dermal irritation:

no effects observed

Mortality:

mortality observed, non-treatment-related

Description (incidence):

A vehicle control male, a high-dose male and a low-dose femal died during the study.
These deaths were considered unrelated to TEA treatment.

Body weight and weight changes:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

> 2 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

clinical signs

Key result

Dose descriptor:

NOAEL

Effect level:

> 2 300 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

clinical signs

Key result

Critical effects observed:

no

Conclusions:

When TEA was applied to the skin of mice 3 times per week for 95 days, mild epidermal hyperplasia was observed without evidence of systemic toxicity.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

244 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

No studies were conducted on the target substance. As the target substance hydrolyses rapidly (half-life < 30 minutes) the intrinsic properties are related to hydrolysis products of the target substance. The hydrolysis products include ethanol, 2-propanol and pentane-2,4-dione, and non-hazardous titanium dioxide. This information is used as a supporting evidence on the toxicity of the target substance in CSA. Among the 3 organic hydrolysis products, the most hazardous compound – pentane-2,4-dione was considered.

 

 

Oral studies 

There is one study available for repeated oral toxicity, carried out on rats (strains not specified). The reported NOAEL was 100 mg/kg/bw/d. In this study test animals were given by gavage 0, 100, 500 and 1,000 mg/kg bw of test substance. Test substance was administered for 1 -15 days in 1-11 applications. In the highest dose group all animals died within 1 hour after dosing. In the 500 mg/kg bw group 3/5 animals died and 2/5 were sacrificed due to poor condition after four applications. Various substance related systemic effects were observable in this dose group such as distended bladder, congested lungs, clouding of cornea, thymic necrosis, hepatocyte swelling and congestion, nephrosis, lymphadenitis of mesenteric lymph nodes and inflammation of the heart. In the lowest dose group (100 mg/kg bw) no histopathological or gross pathological changes and no differences in weight gain, organ weights, hematology, clinical chemistry or clinical signs were evident.

(Eastman Kodak 1979, cited in UNEP SIDS, Pentane-2,4-dione)

  

 

Dermal studies 

NOAEL and LOAEL were 244 mg/kg bw/d and 975 mg/kg bw/d according to systemic effects observed.

(Ballantyne 2001, cited inUNEP SIDS, Pentane-2,4-dione)

 

 

Inhalation studies

NOAEL and LOAEL were 100 ppm (417 mg/m3) and 650 ppm (2711 mg/m3), respectively, determined in a 14 week inhalation study, conducted on 20 male and 20 female Fischer 344 rats. The test animals were exposed to 0, 100, 300 and 650 ppm (nominal conc., corresponding to 0, 417, 1217 and 2711 mg/m3) of pentane-2,4-dione vapor for 6 hour/day, 5 day/week. On histopathology, no substance related gross lesions were detectable in the organs examined in all dose groups with the exception of different regions in the brain where hemorrhage and neuronal degeneration was observable at a dose of 650 ppm.

In the 100 ppm group there were no substance related mortalities in either sex and on comparison with untreated controls no differences in clinical and urinary chemistry, hematology or after histopathological examination were detectable. 

(Dodd et al. 1986, cited in UNEP SIDS, Pentane-2,4-dione)

 

 

Justification for classification or non-classification

Based on the NOAEL (oral), NOAEC (inhalation) and NOAEL (dermal) of pentane-2,4-dione, there is no need for classification of the target substance in accordance with the criteria of CLP Regulation.