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Basic toxicokinetics

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Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Please find the attached justification.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
toxicokinetics
Principles of method if other than guideline:
Groups of four female rats 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 F344/N rats up to 72 hours after dosing. Tissue samples at 72 hours after dosing were also examined.
GLP compliance:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): Triethanolamine
Radiolabelling:
yes
Remarks:
14C
Species:
rat
Strain:
Fischer 344
Sex:
female
Route of administration:
intravenous
Details on exposure:
- Single intravenous doses contained approximately 47 μCi radiolabel for rats, an appropriate amount of nonradiolabeled triethanolamine, and isotonic saline as a vehicle that delivered a total dosing volume of 1 mL/kg to rats.
- Intravenous doses were drawn into a syringe equipped with a Teflon®-tipped plunger (Hamilton) and a 27 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.
Duration and frequency of treatment / exposure:
72 hrs
Dose / conc.:
3 other: mg/kg
No. of animals per sex per dose / concentration:
4
Control animals:
no
Details on study design:
- Groups of four female rats 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 F344/N rats dosed intravenously up to 72 hours after dosing.
- Tissue samples from all intravenous animals 72 hours after dosing were also examined. Intravenous doses were injected into one lateral tail vein.
- Urine and feces from rats were collected separately into round-bottom flasks cooled with dry ice at 6 (urine only), 24, 48, and 72 hours after dosing. The samples were stored in the dark at –20°C until analysis.
- Radiolabeled components in breath were collected by passing air from the metabolism cage (flow rate of 200 to 500 mL/minute) through two cold traps, each containing 100 mL of ethanol, and then through a series of two traps, each containing 400 mL of 1 N sodium hydroxide. The first cold trap was maintained at 0°C by an ice/water bath, and the second at –60°C by an isopropanol/dry ice bath. Traps were changed at 6, 24, 32, 48, and 56 hours, and the total weight of the solutions was measured.
- At the end of the intravenous studies, rats were anesthetized with ketamine:xylazine by intramuscular injection. Blood was drawn by cardiac puncture into heparinized syringes, and rats were sacrificed. Samples of adipose tissue, muscle, skin, and the entire brain, heart, kidney, liver, lung, and spleen were removed and assayed for [14C]content.
Details on dosing and sampling:
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:
0.9% of the dose remained in the tissues 72 hours after dosing
Details on excretion:
- The radioactivity was rapidly excreted in the urine, and 90% of the dosed radioactivity was recovered in the urine within 24 hours.
- An average of 98% of the dose was recovered in the urine within 72 hour after dosing, and approximately 0.6% of the radioactivity was recovered in the feces during this time.
- Less than 0.5% of the dose was recovered in carbon dioxide traps, and less than 0.1% was recovered in volatiles traps.
Metabolites identified:
no
Details on metabolites:
- Urine collected 6 to 24 hours after intravenous dosing and 48 to 72 hours after dermal application of test substance in female rats was analyzed by HPLC. The chromatogram obtained contained a peak that coeluted with triethanolamine and two other peaks that comprise about 5% of the radioactivity in the sample. These peaks, however, were also present in the chromatogram of the radiolabeled test article and may reflect the presence of impurities rather than metabolites.
- The metabolite fractions were collected and incubated with purified beta-glucuronidase, as was an aliquot of the whole urine. Analysis of these samples showed no change in the metabolite profile
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
toxicokinetics
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
Specific details on test material used for the study:
- Name of test material (as cited in study report): Triethanolamine
Radiolabelling:
yes
Remarks:
14C
Species:
mouse
Strain:
B6C3F1
Sex:
female
Route of administration:
intravenous
Vehicle:
acetone
Details on exposure:
- 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.
Duration and frequency of treatment / exposure:
72 hrs
Dose / conc.:
3 other: mg/kg bw
No. of animals per sex per dose / concentration:
4
Control animals:
no
Details on study design:
- 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 from all intravenous animals 72 hours after dosing were also examined. Intravenous doses were injected into one lateral tail vein.
- Urine and feces from rats and mice were collected separately into round-bottom flasks cooled with dry ice at 6 (urine only), 24, 48, and 72 hours after dosing. The samples were stored in the dark at -20°C until analysis.
- Radiolabeled components in breath were collected by passing air from the metabolism cage (flow rate of 200 to 500 mL/minute) through two cold traps, each containing 100 mL of ethanol, and then through a series of two traps, each containing 400 mL of 1 N sodium hydroxide. The first cold trap was maintained at 0°C by an ice/water bath, and the second at –60°C by an isopropanol/dry ice bath. Traps were changed at 6, 24, 32, 48, and 56 hours, and the total weight of the solutions was measured.
- At the end of the intravenous studies, mice were anesthetized with sodium pentobarbital by intraperitoneal injection. Blood was drawn by cardiac puncture into heparinized syringes, and mice were sacrificed. Samples of adipose tissue, muscle, skin, and the entire brain, heart, kidney, liver, lung, and spleen were removed and assayed for [14C]content.
Details on dosing and sampling:
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 test substance equivalent relative to blood.
Details on excretion:
- 26% of the dose was recovered in the urine within 24 hours.
- 40% of the dose was excreted 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.
- Less than 0.5% of the dose was recovered in carbon dioxide traps, and less than 0.1% was recovered in volatiles traps.
Metabolites identified:
no
Details on metabolites:
Urine collected 6 to 24 hours after intravenous dosing contained more than 95% radiolabeled components that coeluted with unchanged test substance.
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
toxicokinetics
Principles of method if other than guideline:
The distribution, metabolism and excretion of (14)C-TEA derived radioactivity were determined in male C3H/HeJ mice following intravenous (iv) injection of 1 mg/kg (14)C-TEA.
GLP compliance:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): Triethanolamine
Radiolabelling:
yes
Species:
mouse
Strain:
C3H
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 20-30 g
- Fasting period before study: none
- Housing: individually
- Individual metabolism cages: yes
- Diet: Certified Lab Diet, ad libitum
- Water: water ad libitum
Route of administration:
intravenous
Vehicle:
water
Dose / conc.:
1 other: mg/kg bw
No. of animals per sex per dose / concentration:
27 mice in total
Control animals:
not specified
Details on study design:
- Twenty-seven mice were administered radiolabeled test material as an aqueous solution via tail vein injection. They were administered 2 ml/kg bodyweight and the average amount of radioactivity injected per mouse was 1.7 uCi.
- Mice designated for excreta collection and sacrifice at 24 hours post-dosing were placed in Roth-style metabolism cages. Blood samples were collected by orbital sinus puncture from groups of three mice at 0.083, 0.167, 0.5, 1, 2, 4, 6, 12 and 24 hours post-dosing to determine kinetic parameters. Urine, feces and expired CO2 were collected at 12 and 24 hours from the 24-hour group of mice housed in metabolism cages. Following sacrifice of this group, tails were removed, and livers and kidneys excised. Roth cages were washed to recover urine. Radioactivity in aliquots of excreta, CO2 trapping solutions, cage-wash solutions, liver, kidneys, skin and remaining carcass was quantified using liquid scintillation spectroscopy. Selected urine samples were subjected to ion-exchange liquid chromatography for fractionation and gas chromatography and mass spectroscopy for analysis of metabolites of test material.
Details on excretion:
- Radioactivity in blood declined in a bi-exponential manner through 24-hour post-dosing with a rapid initial phase (half-life of 0.3 hr) followed by a slower terminal phase (half-life of 10 hr).
- Clearance of radioactivity from blood was calculated to be approximately 1.5 mL/hr/kg and the apparent volume of distribution was estimated to be approximately 11 mL.
Metabolites identified:
no
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
toxicokinetics
Principles of method if other than guideline:
The distribution and excretion of radiolabelled test chemical following intravenous application of 1 mg/kg bw was determined in male C3H/HeJ mice.
GLP compliance:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): Triethanolamine
- Physical state: viscous, colourless liquid
- Analytical purity: 99.6%
- Lot/batch No.: 7H-5317
- Radiochemical purity: 98.6 %
- Specific activity: 34.7 mCi/mmol
Radiolabelling:
yes
Remarks:
14C
Species:
mouse
Strain:
other: C3H/HeJ
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Jackson Laboratories, Bar Habour, ME, USA
- Weight at study initiation: 20.4 - 38.3 g
- Housing: 1-3/cage prior to study
- Individual metabolism cages: yes
- Diet: Purina Certified Rodent Chow 5002, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 40-60
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
intravenous
Vehicle:
water
Duration and frequency of treatment / exposure:
single treatment
Dose / conc.:
1 other: mg/kg bw
No. of animals per sex per dose / concentration:
27
Control animals:
no
Details on study design:
INTRAVENOUS ADMINISTRATION
- A aqueous solution of 14C-TEA with a concentration of approximately 0.5 mg/mL was administered intravenously via the tail vein to twenty-seven male mice. To facilitate making the injections, a device similar to that described by Keighley, 1966 was used for transillumination of the tail, and a device similar to that described by Grice, 1964 was used for restraining the mice.
- The dosing volume administered intravenously was 95.17 ± 6.79% (mean, ± S.D.) of the target dosing volume of 2 mL/kg body weight. The target dose level was 1 mg test substance/kg body weight and the average amount of radioactivity injected per mouse was 4.69 µCi/mouse. The specific activity of the dosing solution was 30.7 µCi/g.
- Immediately following dosing, the animals were returned to their cages, with the animals designated for excreta collection and sacrifice at 24 hours postdosing (final sacrifice) placed in Roth cages. Blood samples were collected from all animals via orbital sinus puncture just prior to their sacrifice by cervical dislocation in groups of three at 0.083, 0.167, 0.5, 1, 2, 4, 6, 12 and 24 hours post-dosing.
- Urine, faeces and expired C02 were collected at 12 and 24 hours from the mice in Roth cages. Urine and faeces were collected in containers cooled on dry ice. Expired C02 was trapped in a solution of monoethanolamine: ethylene glycol monornethyl ether (3:7). Subsequent experiments did not include trapping of expired C02 since none of administered dose was excreted via this route following intravenous administration. Following the sacrifice of this group, the Roth cage was washed with a solution of acetone and water. Radioactivity in the excreta, CO2 trapping solutions, cage wash solutions, liver, kidneys, skin and remaining carcass were determined.
Details on distribution in tissues:
The average amount of the administered dose remaining in the body at sacrifice was 3.6% of which 1% or less was found in the liver, kidneys and skin.
Details on excretion:
- Following a 1 mg/kg intravenous dose of 14C-TEA, the radioactivity in the blood was eliminated from the blood by an apparent firstorder process in a biphasic manner. The half-life of the alpha-phase of elimination of radioactivity from the blood was 0.58 hours with a terminal half-life for the elimination of radioactivity of 10.2 hours as estimated by the method of residuals (Gibaldi and Perrier, 1982).
- Urine was the primary route for elimination of radioactivity following intravenous administration of 14C-TEA. Approximately 65% of the administered dose was excreted via this route of elimination within 24 hours post-dosing.
- Faeces was the secondary route of elimination for the route under investigation. The mean percentage eliminated via the faeces ranged from 16.3 to 27.7.
- There were no marked differences observed across dose levels or routes of administration in the amounts of the dose eliminated via the urine and faeces.
Metabolites identified:
not measured

Data source

Materials and methods

Test material

Constituent 1
Chemical structure
Reference substance name:
2,2',2''-nitrilotriethanol citrate
EC Number:
249-576-7
EC Name:
2,2',2''-nitrilotriethanol citrate
Cas Number:
29340-81-6
Molecular formula:
C6H15NO3.xC6H8O7
IUPAC Name:
2,2',2''-nitrilotriethanol citrate
Test material form:
liquid

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
MICE
- The distribution of radioactivity present in tissue samples from female mice showed that the heart, kidney, liver, lung, and spleen contained higher concentrations of test substance equivalent relative to blood. (Result read-across source CAS No. 102-71-6)
- The average amount of the administered dose remaining in the body at sacrifice was 3.6% of which 1% or less was found in the liver, kidneys and skin. (Result read-across source CAS No. 102-71-6)

RAT
- 0.9% of the dose remained in the tissues 72 hours after dosing (Result read-across source CAS No. 102-71-6)
Details on excretion:
MICE
1) Result read-across source CAS No. 102-71-6
- 26% of the dose was recovered in the urine within 24 hours.
- 40% of the dose was excreted 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.
- Less than 0.5% of the dose was recovered in carbon dioxide traps, and less than 0.1% was recovered in volatiles traps.
2) Result read-across source CAS No. 102-71-6
- Radioactivity in blood declined in a bi-exponential manner through 24-hour post-dosing with a rapid initial phase (half-life of 0.3 hr) followed by a slower terminal phase (half-life of 10 hr).
- Clearance of radioactivity from blood was calculated to be approximately 1.5 mL/hr/kg and the apparent volume of distribution was estimated to be approximately 11 mL.
3) Result read-across source CAS No. 102-71-6
- Following a 1 mg/kg intravenous dose of 14C-TEA, the radioactivity in the blood was eliminated from the blood by an apparent firstorder process in a biphasic manner. The half-life of the alpha-phase of elimination of radioactivity from the blood was 0.58 hours with a terminal half-life for the elimination of radioactivity of 10.2 hours as estimated by the method of residuals (Gibaldi and Perrier, 1982).
- Urine was the primary route for elimination of radioactivity following intravenous administration of 14C-TEA. Approximately 65% of the administered dose was excreted via this route of elimination within 24 hours post-dosing.
- Faeces was the secondary route of elimination for the route under investigation. The mean percentage eliminated via the faeces ranged from 16.3 to 27.7.
- There were no marked differences observed across dose levels or routes of administration in the amounts of the dose eliminated via the urine and faeces.

RAT (Result read-across source CAS No. 102-71-6)
- The radioactivity was rapidly excreted in the urine, and 90% of the dosed radioactivity was recovered in the urine within 24 hours.
- An average of 98% of the dose was recovered in the urine within 72 hour after dosing, and approximately 0.6% of the radioactivity was recovered in the feces during this time.
- Less than 0.5% of the dose was recovered in carbon dioxide traps, and less than 0.1% was recovered in volatiles traps.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
Result read-across source CAS No. 102-71-6

Applicant's summary and conclusion