Bis[[2,2',2''-nitrilotris[ethanolato]](1-)-N,O]bis(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, this substance is hydrolytically unstable with hydrolysis rate estimated to be less than 30 minutes. The hydrolysis products have been identified to be 2-propanol, triethanolamine and titanium dioxide. The discussion of toxicokinetics is based on the hydrolysis/degradation products.

Reference 2

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:

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

Justification for type of information:

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

Objective of study:

absorption

distribution

excretion

metabolism

Qualifier:

according to guideline

Guideline:

other: See explanations

Principles of method if other than guideline:

Groups of four female mice received a single intravenous dose of 3 mg/kg [14C]-triethanolamine. Expired radioactivity was trapped and quantitated and urine and feces were collected from all B6C3F1 mice dosed intravenously up to 72 hours after dosing. Tissue samples at 72 hours after dosing were also examined.

GLP compliance:

no

Radiolabelling:

yes

Remarks:

14C

Species:

mouse

Strain:

B6C3F1

Sex:

female

Details on test animals or test system and environmental conditions:

Single intravenous doses contained approximately 6 μCi radiolabel for mice, an appropriate amount of nonradiolabeled triethanolamine, and isotonic saline as a vehicle that delivered a total dosing volume of 2 mL/kg to mice. Intravenous doses were drawn into a syringe equipped with a Teflon®-tipped plunger (Hamilton) and a 30 gauge hypodermic needle. Excess dose formulation was wiped off the needle before weighing the filled dosing syringe. Intravenous doses were injected into one lateral tail vein. After dosing, the needle was wiped clean with a Kimwipe®, and the empty syringe was reweighed. The Kimwipe® was placed into a vial containing 2 mL ethanol and analyzed by liquid scintillation spectrometry. Each dose was calculated as the difference between the weights of the filled and empty dosing apparatus less the amount found in the Kimwipe®. To determine the concentration of [14C]-triethanolamine in the dose formulation, two weighed aliquots were taken before, two after, and one during dosing.

Route of administration:

intravenous

Vehicle:

acetone

Duration and frequency of treatment / exposure:

72 hr

Dose / conc.:

3 mg/kg bw/day (nominal)

No. of animals per sex per dose / concentration:

4

Control animals:

no

Positive control reference chemical:

no

Details on study design:

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces, tissues, cage washes, CO2
- Time and frequency of sampling: 24, 48, 72 hrs

Details on distribution in tissues:

The distribution of radioactivity present in tissue samples from female mice showed that the heart, kidney, liver, lung, and spleen contained higher concentrations of triethanolamine equivalent relative to blood.

Details on excretion:

26% of the dose was recovered in the urine within 24 hours.
An average of 62% of the dose was recovered in the urine within 72 hours after dosing, and 27.6% was recovered in the feces during this time.

Metabolites identified:

no

Conclusions:

Intravenously administered triethanolamine was rapidly excreted by female rats and mice, primarily in the urine.
Less than 1% of the dose was present in tissues sampled 72 hours after dosing. In both species, the heart, kidney, liver, lung, and spleen contained higher concentrations of triethanolamine equivalents than did blood.

After intravenous and dermal dosing in female rats and mice, triethanolamine was excreted, for the most part, unchanged in urine. Two additional polar peaks, each less than or equal to 5% of the total, were present in the urine. At least one of these polar peaks may have originated from impurities in the [14C]-triethanolamine stock, which were better resolved from the test article peak during development of HPLC onditions for metabolite analysis.

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

 

Toxicokinetics of triethanolamine

Intravenously administered triethanolamine was rapidly excreted by female rats and mice, primarily in the urine. Less than 1% of the dose was present in tissues sampled 72 hours after dosing. In both species, the heart, kidney, liver, lung, and spleen contained higher concentrations of triethanolamine equivalents than did blood.

 

Dermal exposure: Only 20% to 30% of dermally applied 68 and 276 mg/kg triethanolamine was absorbed by female rats within 72 hours.

 

After intravenous and dermal dosing in female rats and mice, triethanolamine was excreted, for the most part, unchanged in urine. Two additional polar peaks, each less than or equal to 5% of the total, were present in the urine. At least one of these polar peaks may have originated from impurities in the [14C]-triethanolamine stock, which were better resolved from the test article peak during development of HPLC conditions for metabolite analysis.

Toxicokinetics of titanium dioxide 

Titanium dioxide is insoluble in water and most ingested titanium is eliminated unabsorbed.