2-ethylaminoethanol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

no information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Published summary/review of data for the read-across substance 2-diethylaminoethanol

Data source

Reference

Reference Type:

secondary source

Title:

SIDS Initial Assessment Report for SIAM 15, 2-diethylaminoethanol

Author:

OECD SIDS

Year:

2002

Bibliographic source:

OECD SIDS

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Review /summary of studies: oral administration of single or repeated doses to rats, humans or dogs with assessment of absorption, tissue distribution, metabolism and excretion.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-diethylaminoethanol

EC Number:

202-845-2

EC Name:

2-diethylaminoethanol

Cas Number:

100-37-8

IUPAC Name:

2-(diethylamino)ethanol

Test material form:

not specified

Details on test material:

- Name of test material (as cited in study report): 2-diethylaminoethanol

Radiolabelling:

no

Test animals

Species:

other: rats, dogs and humans

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

Studies in rats, dogs and humans are summarised

Administration / exposure

Route of administration:

other: oral and intravenous

Vehicle:

not specified

Details on exposure:

Gastrointestinal absorption was investigated in rats and humans following single oral administration. In humans orally administered 2-diethylaminoethanol-HCl, plasma was assessed for peak concentrations and urinary excretion In a rat gavage study, radiolabelled 2-diethylaminoethanol-HCl was once or repeatedly administered up to levels of 679 mg/kg bw. Maximum blood concentration, elimination kinetics and tissue distribution were investigated. Rats were given an intravenous injection of 1.94 mg/kg bw (2.9 µmol/rat) and cumulative excretion via urine and faeces was measured over the following 24 and 48 hours. Biliary excretion was also measured over the first six hours following dosing. DIstribution was also assessed in dogs following intravenous infusion.

Duration and frequency of treatment / exposure:

Single or repeated administration. No information on exposure period

No. of animals per sex per dose / concentration:

No information

Control animals:

other: not required for this study type

Positive control reference chemical:

Not required for this study type

Details on study design:

Gastrointestinal absorption was investigated in rats and humans following single oral administration. In humans orally administered 2-diethylaminoethanol-HCl, plasma was assessed for peak concentrations and urinary excretion In a rat oral gavage study, radio-labelled 2-diethylaminoethanol-HCl was once or repeatedly administered up to levels of 679 mg/kg bw. Maximum blood concentration, elimination kinetics and tissue distribution were investigated. Rats were given an intravenous injection of circa 1.94 mg/kg bw (2.9 µmol/rat) and cumulative excretion via urine and faeces was measured over the following 24 and 48 hours. Biliary excretion was also measured over the first six hours following dosing. DIstribution was also assessed in dogs following intravenous infusion.

Details on dosing and sampling:

Oral absorption study in rats and humans investigated gastrointestinal absorption. Skin penetration was assessed in human skin. Following oral administration of 5.6g of 2-diethylaminoethanol to humans, plasma concentrations were assessed and similar assessments were made following intravenous injection. Absorption, elimination and tissue distribution were assessed in rats following oral administration

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

2-diethylaminoethanol is readily absorbed from the gastrointestinal tract in humans and rats

Main ADME results 2

Type:

distribution

Results:

A skin penetration rate of 3.44 mg/cm2 per hour was determined in human skin

Main ADME results 3

Type:

metabolism

Results:

Metabolites of 2-diethylaminoethanol identified included 2-ethylaminoethanol (~1%); phosphoric acid-mono-(2-diethylaminoethyester) (~2-8%); diethylaminoacetic (~10%); and the N-oxide of 2-diethylaminoethanol (~15-19%)

Main ADME results 4

Type:

excretion

Results:

Following oral administration of 5.6g 2-diethylaminoethanol about 25% was excreted unchanged in urine within the first 48 hours after dosing. Excretion in rats is primarily via the kidney, elimination by exhalation or faeces is a minor route.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

2-dethylaminoethanol was readily absorbed following oral administration to humans and rats.

Dermal absorption was estimated in humans - a skin penetration rate of 3.44 mg/m2/hr, was estimated.

In rats rapid absorption into blood was reported following oral exposure, the maximum blood concentration was reached in 30 minutes after dosing at 68 mg/kg bw and within an hour after dosing at 679 mg/kgbw.

Details on distribution in tissues:

Three hours after intravenous infusion in dogs, the tissue levels in muscle, heart, brain and lungs were higher than the plasma concentration.
In rats autoradiography highlighted wide tissue distribution, with maximum liver concentrations achieved approximately 7 hours after dosing.
The biological half-life following dosing at 679 mg/kg bw was 19 hours and 36 hours after dosing at 67.9 mg/kg bw.

Details on excretion:

In humans, plasma concentrations peaked 3 hours after oral dosing but the concentration fell to undetectable levels within 8 hours of dosing. 25% of the dose was eliminated unchanged in urine within the first 48 hours. Excretion was similar following intravenous administration.

In the radio-labelled study administration of 679 or 68 mg/kg bw to rats resulted in elimination primarily via the kidney (exhalation and faecal excretion was insignificant). 40% of the dose was eliminated in urine within 6 hours of dosing and 58.5% had been excreted within 24 hours at the high dose and 17.5 and 37.4% respectively at the lower dose level.
Cumulative excretion following intravenous administration, was 19.9 and 42.2% of administered radioactivity appearing in urine 24 or 48 hours after dosing. Faecal excretion was 8.5 and 29.5% at some intervals. Biliary excretion was measued over the first six hours after dosing and was reported as 5% of the administered dose.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The metabolites identified, based on the recovery of radioactive compounds, were 2-ethylaminoethanol (ca. 1 %), phosphoric acid-mono-(2-diethylaminoethylester) (2- 8 %), diethylaminoacetic acid (ca. 10%) and the N-oxide of 2-diethylaminoethanol (ca. 15 - 19%). Incorporation into phospholipids was also observed.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

No testing results presented

Any other information on results incl. tables

2 -Diethylaminoethanol has been reported to be readily absorbed from the gastrointestinal tract in humans and rats. In a limited study with humans, the plasma concentration peaked 3 hours after an oral administration of 5.6 g of 2-diethylaminoethanol-HCl, but was almost undetectable after 8 hours. About 25 % of the 2 -diethylaminoethanol was excreted unchanged in the urine within 48 hours. Similar excretion results were observed after intravenous administration. In the same publication it was reported that 2-diethylaminoethanol-HCl given to dogs by intravenous infusion (71 mg/kg bw), distributed rapidly. Three hours after infusion the level of 2-diethylaminoethanol was higher in the tissues examined (muscle, heart, brain, lung, liver and spleen) than in the plasma.

In a gavage study with rats, 14C-labeled-2-diethylaminoethanol-HCl was reported to be rapidly absorbed into the blood; with a dose of 68 mg/kg the maximum concentration in the blood was reached in 30 minutes and with 679 mg/kg it was reached within 1 hour. Elimination occurred primarily via the kidney. Elimination via exhalation and the feces played only minor role. The kinetics of urinary elimination was affected by the dose. In this regard, by 6 hours after the application of a 679 mg/kg bw dose 40 % was eliminated in the urine, and by 24 hours after application 58.5 % was eliminated. When a 68 mg/kg dose was given, then after 6 and 24 hours 17.5 % and 37.4 % were excreted via the urine, respectively. In the experiment with 679 mg/kg 2-diethylaminoethanol, 90 % of the test substance had been eliminated via the urine 10 days after treatment. Some radioactivity was still detectable in the urine 40 days after treatment. 2-diethylaminoethanol was predominantly (> 60 %) excreted unchanged over the first 96 hours. In the same period, the following metabolites were seen based on the recovery of radioactive compounds: 2-ethylaminoethanol (ca. 1 %), phosphoric acid-mono-(2-diethylaminoethylester) (2-8 %), diethylaminoacetic acid (ca. 10 %) and the N-oxide of 2-diethylaminoethanol (ca. 15 - 19 %).

 

Incorporation into phospholipids was observed. In this study, autoradiography indicated that 2-diethylaminoethanol was widely distributed throughout the body after gavage administration. 2-diethylaminoethanol was concentrated in the liver, reaching a maximum at 7 hours, but thereafter, it decreased. Initially, the central nervous system showed very low levels of activity, but by day 7 it had increased. For the oral dose of 679 mg/kg the biological half-life was 19 hours and for the 67.9 mg/kg dose it was 36 hours. In a separate study 14C-labeled-2-diethylaminoethanol-HCl was given to rats by intravenous injection at doses of 2.9 μmol/rat (ca. 1.94 mg/kg bw).

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: .there is some evidence for metaboic incorporation into phospholipids; however the rapid metabolism excretion suggests that true bioaccumulation is unlikely
There is some evidence for metaboic incorporation into phospholipids; however the rapid metabolism excretion suggests that true bioaccumulation is unlikely

Executive summary:

Studies investigating the toxicokinetics of the structurally-related read-across substance 2 -diethylaminoethanol are summarised in an OECD SIDS evaluation. Data indicate rapid oral absorption and extensive systemic distribution. The major rat metabolites were identified as diethylaminoacetic acid and diethyl-(2-hydroxyethyl)-amino-oxide; excretion was primarily via the urine. there is some evidence for metaboic incorporation into phospholipids; however the rapid metabolism excretion suggests that true bioaccumulation is unlikely.