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

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vitro / ex vivo

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:

basic toxicokinetics in vivo

Type of 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:

guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

other:

Principles of method if other than guideline:

Intravenous study: The substance was given to four adult male Fischer 344 rats per dose by single intra-venous injection. Target radioactivity was 2 – 5 mCi. Blood was collected at appropriate intervals from a lateral tail vein until 30 hr post dosing. At 48 hr a cardiac puncture was performed for a final blood sam-ple with all groups. Urine and feces were. For airborne collections, room air was drawn through the me-tabolism cages at approximately 500 ml/min. Expired 14CO2 was trapped.

Inhalation study: A total of fifty animals were exposed 6 hours nose-only to a target concentration and serial groups of 3 animals were removed at the blood sampling intervals during the absorption phase. Included was a group of 4 rats which were monitored by plethysmography during exposure to ensure that there was no excessive peripheral sensory irritation with consequent changes in minute volume. Respira-tory rate was measured. After exposure the animals were transferred to metabolism cages.

GLP compliance:

yes

Radiolabelling:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male

Route of administration:

other: inhalation: dust; intravenous

Vehicle:

other: physiol. saline for intravenous, unchanged for inhalation

Duration and frequency of treatment / exposure:

IV: single exposure
Inhalation: single 6h exposure

Dose / conc.:

400 ppm

Remarks:

Inhalation

Dose / conc.:

4.3 mg/kg bw/day (nominal)

Remarks:

I.V

Dose / conc.:

43 mg/kg bw/day (nominal)

Remarks:

I.V.

Dose / conc.:

430 mg/kg bw/day (nominal)

Remarks:

I.V

Dose / conc.:

148.5 mg/kg bw/day (nominal)

Remarks:

I.V.

No. of animals per sex per dose / concentration:

I.V.: 4
Inhalation: 50

Conclusions:

Low bioaccumulation potential based on study results.

2,4-PD is readily absorbed during a 6 hr exposure to 400 ppm, and biexponentially eliminated from plasma postexposure. However, even at 48 hr postexposure, radioactivity derived from 14C-2,4-PD is still present. The majority of the dose is eliminated as CO2 and in urine, with at least 7 metabolites being detected in urine. Although there is no preferential tissue accumulation of 14C-2,4-PD-derived radioactivity, the plasma elimination profiles and the detection of some radioactivity in many tissues at 48 hr postexposure, indicates a potential for cumulative effects. The only definitive repeated exposure known toxicity, and with a latency to expression, is central neurotoxicity and 14C could still be detected in the brain 48 hr after a single exposure. The urinary elimination profiles suggest that biological monitoring might best be undertaken using a metabolite as marker. (from Frantz 1998).

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.

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Justification for type of information:

2-propanol and triethanolamine are two main hydrolysis prodcuts of the target substances.

Objective of study:

excretion

metabolism

toxicokinetics

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

no

GLP compliance:

not specified

Radiolabelling:

yes

Remarks:

14C

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

single exposure for 6 hr

Dose / conc.:

500 ppm

Remarks:

low dose group

Dose / conc.:

5 000 ppm

Remarks:

high dose group

No. of animals per sex per dose / concentration:

4

Control animals:

no

Positive control reference chemical:

none

Type:

absorption

Results:

rapid absorption

Type:

distribution

Results:

widely distributed without any accumulation

Type:

metabolism

Results:

major metabolites were acetone and carbon dioxide

Type:

excretion

Results:

predominant elimination pathway is exhaled breath

Details on absorption:

The concentration of radiolabel in the blood increased rapidly following the initiation of inhalation exposure at either concentration. The concentration of radiolabel appeared to still be rising at the end of the exposure to 500 ppm but appeared to have plateaued by the end of the exposure to 5000 ppm IPA.

Details on distribution in tissues:

Widely distributed among the tissues following nose only inhalation exposure to nominal concentrations of 500 and 5000 ppm. No evidence was observed to indicate that IPA or its radiolabeled metabolites accumulated in any tissue with the possible exception of kidney and liver, which had slightly elevated concentrations of radiolabel relative to the blood.

Details on excretion:

Following nose only inhalation of IPA the breath is, by far, the predominant route of excretion of radiolabel by both sexes. The excretion of the absorbed dose was rapid, with greater than 90% of the absorbed radiolabel being excreted from the breath, urine, and feces within 72 h of the beginning of the inhalation exposure. Exhalation in the breath accounted for a total of about 83% of the absorbed dose at the low exposure level while it accounted for just under 88% following the high exposure level. Even though total excretion of radiolabel in the breath was practically the same following either inhalation exposure, the distribution of radiolabel that appeared in the breath was dramatically different. Following exposure to 500 ppm males and females exhaled an average of 49% of the absorbed radiolabel as carbon dioxide in the breath. Following exposure to 5000 ppm, only 22% of the radiolabel present in the exhaled breath was found to be 14CO2. While the exhaled breath was the major route of excretion following both exposure levels, urine was a minor route of elimination of radiolabel and excretion in the feces was negligible.

Metabolites identified:

yes

Details on metabolites:

Acetone was found to be the primary radiolabeled metabolite of IPA. In the exhaled breath acetone accounted for 75-100% of the radiolabeled organic volatile compounds being exhaled. The balance of the exhaled radioactivity was accounted for by CO2 and IPA itself. A third radiolabeled metabolite (accounting for less than 5% of the total dose) was found when the urine was analyzed by HPLC; this urinary metabolite was identified as isopropyl glucuronic acid.

Bioaccessibility (or Bioavailability) testing results:

not reported.

Conclusions:

No bioaccumulation potential of 2-propanol based on the test results.
Pharmacokinetics of propan-2-ol (IPA) was studied in rats. Animals were exposed by inhalation for 6 hours to IPA vapor. Total exhalation of radiolabel (as CO2, acetone, propan-2-ol) was 83%-87% of the administered dose. Urine and feces accounted for excretion approximately 7% and 1%, respectively. No single tissue contained greater than 1.6% of recovered dose.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

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, acetylacetone and non-hazardous titanium dioxide. This information is used as a supporting evidence on the toxicity of the target substance in CSA.

Toxicokinetics of pentane-2,4-dione (2,4-PD)

No studies are available concerning the mode of action of the substance. It is known, however, that 1,3-diketones unfold metal chelating properties in vivo which may lead to inhibition of enzymatic activity of metal containing enzymes such as peroxidases or cytochrome P450 without concomitantly lowering protein contents. In an inhalation study conducted in male Fischer 344 rats it could be shown that 14C-labeled-2,4-PD was readily absorbed by the inhalation route. Nose-only exposure to 400 ppm 14Clabeled-2,4-PD resulted in a rapid increase in plasma radioactivity during the first 3 hours of exposure, with a tendency to plateau toward the end of the 6 hour exposure period. Plasma unmetabolized 14C-labeled-2,4-PD was present throughout the whole of the exposure phase, but was significantly less than total 14C. Immediately postexposure, radioacivity was present in all tissues examined, but on a concentration basis (µg equivalents/g) there was no preferential accumulation of 14C in any tissue or organ. On a total organ basis, highest contents were in liver and kidneys. Post-exposure, plasma unmetabolized 14C-labeled-2,4-PD declined rapidly to undetectable concentrations by 12 hours. Elimination of 14C from plasma followed a biphasic pattern with a terminal half-life (beta t½) of 30.72 hours. Excretion over 48 hours of 14C was approximately equivalent between urine (37.6 %, mainly not identified metabolites) and expired 14 CO2 (36.3 %), which the most part of the radioactivity was eliminated in the first 12 hours. Expired volatiles, feces, tissues and carcass accounted for 2.29, 2.78, 1.66 and 17.15 % of the total administered radioactivity dose 48 hours postdosing, respectively (Frantz et al. 1998). (Cited from OECD SIDS, pentane-2,4-dione)

 

Toxicokinetics of Titanium dioxide

 

Titanium dioxide is insoluble in water and most ingested titanium is eliminated unabsorbed. In rats, about 95% ingested dose of titanium dioxide is recovered from faeces indicating that the most ingested titanium is not absorbed from gastrointestinal tract by blood (Patty, F. 1965). However, in humans detectable amounts of titanium can be found in the blood, brain and parenchymatous organs (Friberg, L. et al.1986). Based on average titanium concentrations found in human urine of about 10 µg/liter, it can be calculated that the absorption is about 3% (WHO, 1982).