Bis(2-ethylhexan-1-olato)bis(pentane-2,4-dionato-O,O')titanium

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose 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 several minutes. The hydrolysis products have been identified to be 2-ethylhexnol, acetylacetone and titanium dioxide. The repeated dose toxicity of those organic parts have been well-investigated separately.
As the target substance hydrolyses rapidly (half-life < 30 minutes) the intrinsic properties are related to hydrolysis products of the target substance. This information is used as a supporting evidence on the toxicity of the target substance in CSA.

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:

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 several minutes. The hydrolysis products have been identified to be 2-ethylhexnol, acetylacetone and titanium dioxide. The repeated dose toxicity of those organic parts have been well-investigated separately.
As the target substance hydrolyses rapidly (half-life < 30 minutes) the intrinsic properties are related to hydrolysis products of the target substance. This information is used as a supporting evidence on the toxicity of the target substance in CSA.

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

Justification for type of information:

2-ethylhexanol and pentane-2,4-dione are two main hydrolysis prodcuts of the target substance. Properties of the the two substance are used for read-across.

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Duration of treatment / exposure:

90 days.

Frequency of treatment:

6 hours/day, 5 days/week.

Dose / conc.:

0 ppm (nominal)

Dose / conc.:

15 ppm (nominal)

Dose / conc.:

40 ppm (nominal)

Dose / conc.:

120 ppm (nominal)

No. of animals per sex per dose:

10

Control animals:

yes

Clinical signs:

no effects observed

Mortality:

no mortality observed

Other effects:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 120 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effect

Key result

Critical effects observed:

no

Conclusions:

No adverse effects were seen in this 90 day inhalation toxicity study (OECD TG 413) in male and female WIstar rats tested up to concentrations of 120 ppm (which was equivalent to saturation at 20°C according to the study authors). Thus the NOAELof this study was 120 ppm, i.e. 638.4 mg/m3.

Executive summary:

As the target substance hydrolyses rapidly (half-life < 30 minutes) the intrinsic properties are related to hydrolysis products of the target substance. This information is used as a supporting evidence on the toxicity of the target substance in CSA.

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

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

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, Reaction product of Titanium tetrakis(2-ethylhexan-1-olato) and pentane-2,4-dione. 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 2-ethylhexanol, 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.

 

Oral studies

2-Ethylhexanol

Long-term repeated oral studies carried out by Astill et al. (1996) were available on rats and mice. In the study with rats (Fischer 344), NOAEL of 250 mg/kg/bw/d was reported. Test animals received oral doses of 0, 50, 150 and 500 mg/kg per day EH in aqueous emulsion by gavage on 5 d/w for 90 dyas. Animals of the high dose group showed clinical signs of toxicity, increased mortality, retarded body weight gain and increased organ weights. The animals of these groups revealed congestion of the liver and lung, the males had increased incidences in prostate atrophy. In the mid dose animals, a reduced body weight gain, increased organ weights and clinical signs of toxicity were evident. (Astill, et. al. 1996)

 

Pentane-2,4-dione

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)

 

Based on these facts, the oral NOAEL 100 mg/kg/bw/d was chosen for the target substance.

 

 

Dermal studies

2-Ethylhexanol

No endpoints such as NOAEL or LOAEL value derived in existing studies.

Bushy Run Research Centre (1988) exposed rats dermally to 0, 417 and 834 mg/kg per day EH (9 occlusive applications for 6 h each within 12 days). Females of the higher dose revealed lymphopenia and decreased spleen weight. Increased triglyceride levels were observed in all exposed females. Histopathological lesions were restricted to the site of application.

Based on the acute dermal study, LD50 tested on rabbit was > 2600 mg/kg bw. 2-ethylhexanol was classified as Catagory 5 according to GHS and therefore was regarded as low dermal toxic. (Scala, R.A. 1973).

 

Pentane-2,4-dione

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)

 

Based on these facts, the dermal NOAEL 244 mg/kg/bw/d was chosen for the target substance.

 

 

Inhalation studies

2-Ethylhexanol

In a studied carried out according to OECD guideline 413, Wistar rats (10 per sex and group) were exposed by inhalation to 0, 15, 40 and 120 ppm (equivalent to 81, 217 and 650 mg/m3) on 5 days/week, 6 hours/day for 90 days. No signs of irritation were reported. There was no treatment-related toxicity (including peroxisome proliferation) even at the highest exposure concentration (NOAEL 120 ppm, equivalent to 650 mg/m3). (Klimisch et al., 1998).

 

Pentane-2,4-dione

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)

 

Based on these facts, the inhalation NOAEC 417 mg/m3 was chosen for the target substance.

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.