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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 triethanolamine and zirconium dioxide. The discussion of toxicokinetics is based on the hydrolysis/degradation products.
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
Objective of study:
absorption
distribution
excretion
metabolism
Qualifier:
according to
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 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:
4
Control animals:
no
Positive control:
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.

Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - dermal (%):
30

Additional information

No studies were conducted on the target substance, Tetrakis [[2,2',2"-nitrilotris[ethanolato]](1-)-N,O]zirconium. 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 triethanolamine and non-hazardous zirconium 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 Zirconium dioxide 

Zirconium dioxide is insoluble in water and most ingested titanium is eliminated unabsorbed. Zirconium dioxide released from target substance exists as hydrated form and thus human exposure via inhalation is not relevant.