1,1',1'',1'''-ethylenedinitrilotetrapropan-2-ol

Basic toxicokinetics

Administrative data

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:

other: Study well documented, meets generally accepted scientific principles, acceptable for assessment.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Dissertation: Quadrol, N, N, N', N'-Tetrakis(2-Hydroxypropyl)ethylenediamine: pharmacokinetics and assessment of acute toxicity.

Author:

Dunphy MJ

Year:

1991

Bibliographic source:

Graduate Faculty of the University of Akron

Reference 2

Reference Type:

publication

Title:

Dissertation: Quadrol, N, N, N', N'-Tetrakis(2-Hydroxypropyl)ethylenediamine: pharmacokinetics and assessment of acute toxicity.

Author:

Dunphy MJ

Year:

1991

Bibliographic source:

Dissertation Abstracts International B52/02, 762, Order No. 9119922

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Kinetics of absorption, distribution, metabolism and excretion of ethylenediamine, +4PO in orally and intravenously treated rats were determined.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

1,1',1'',1'''-ethylenedinitrilotetrapropan-2-ol

EC Number:

203-041-4

EC Name:

1,1',1'',1'''-ethylenedinitrilotetrapropan-2-ol

Cas Number:

102-60-3

Molecular formula:

C14H32N2O4

IUPAC Name:

1-({2-[bis(2-hydroxypropyl)amino]ethyl}(2-hydroxypropyl)amino)propan-2-ol

Details on test material:

- Name of test material (as cited in study report): Quadrol
- Physical state: viscous liquid
- Analytical purity: >90 %
- Impurities (identity and concentrations): no data

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Zivic Miller Laboratories
- Weight at study initiation: 250 - 300 g
- Housing: no data
- Individual metabolism cages: yes, but only for urine analysis
- Diet: standard rodent chow, ad libitum
- Water: ad libitum
- Acclimation period: one week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-25
- Humidity (%): 50-60
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

other: oral gavage and intravenously

Vehicle:

water

Duration and frequency of treatment / exposure:

One single administration either by oral gavage or i.v. via surgically implanted jugular vein cannula or caudal vein

Doses / concentrations

Remarks:

Doses / Concentrations:
50, 100, 200 mg/kg bw i.v. via implanted jugular cannula or orally by gavage
100 mg/kg i.v. via caudal vein

No. of animals per sex per dose / concentration:

30 males (10 x 3) gavage; 18 (3 x 6) males i.v. jugular cannula; 10 males i.v. caudal vein

Details on dosing and sampling:

ORAL DOSING GROUP
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: 5 ml blood from anaesthesized animals via orbital puncture
- Time and frequency of sampling: 5, 10, 20, 30, 45, 60, 90, 120, 240, 480 min after dosing
- From how many animals: 3 animals per time point
- Method type(s) for identification: GC-MS

I.V. (jugular cannula) DOSING GROUP
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: 0.5 ml blood from non-anaesthesized animals via implanted jugular cannula.
- Time and frequency of sampling: 5, 10, 20, 30, 45, 60, 90, 120, 240, 480 min after dosing
- From how many animals: all animals per time point for blood
- Method type(s) for identification: GC-MS

I.V. (caudal vein) DOSING GROUP
PHARMACOKINETIC STUDY (Absorption, distribution, excretion) AND METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: 0.5 ml blood from orbital puncture followed by urine sampling in metabolic cages
- Time and frequency of sampling: 2, 4, 6, 8, 10, 16 and 24 hr after dosing
- From how many animals: all animals per time point
- Method type(s) for identification: GC-MS

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

(oral) bioavailability factor F = 0.018

Main ADME results 2

Type:

distribution

Results:

minimal tissue distribution; volume of distribution 4 ml/ kg bw

Main ADME results 3

Type:

metabolism

Results:

no metabolites identified

Main ADME results 4

Type:

excretion

Results:

92 -96 % via renal clearance

Toxicokinetic / pharmacokinetic studies

Details on absorption:

At pH 7, ethylenediamine, +4PO will be a cation, and thus it is not expected to possess high Iipid solubility. The present data support the notion that ethylenediamine, +4PO does not diffuse through cellular membranes with ease. The calculated oral bioavailability factor (F = 0 .018) indicates that only about 2 % of orally administered ethylenediamine +4PO is absorbed through the cells lining the stomach or intestinal walls .

Details on distribution in tissues:

Ethylenediamine, +4PO conformed to a one-compartment model of distribution and is mainly located within the bloodstream. Ethylenediamine, +4PO is rapidly (though poorly) absorbed and virtually 100 % eliminated from the bioodstream within 24 hr following a single dose.

Details on excretion:

The route of elimination is 92-96 % via renal clearance. Ethylenediamine, +4PO excretion rate appears to be a function of simple glomeruiar filtration with negligible tubular reabsorption. However, it was not possible to recover 100 % of all dosed ethylenediamine, +4PO in the urine. Typicaliy 92-95 % recovery was obtained for IV dosing. This suggests that either ethylenediamine, + 4PO may be eliminated to a small extent via the bile (enterohepatic elimination) or that some ethylenediamine, +4PO may be biotransformed to very polar glucuronide conjugates (acetates or D-glucuronate).

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

No metabolites were identified, the only important peak corresponded to ethylenediamine, +4PO.

Any other information on results incl. tables

Pharmocokinetic parameters of ethylenediamine, +4PO:

Dose [mg/kg]	Cpmax [µg /ml]	tmax [min]	F	K [1/min]	Vd [ml]	Half-life [min]	Cl [ml/hr]	AUC iv (µg min /ml)	AUCpo  (µg min /ml)
50	12.5	40 - 45	0.018	0.0063	0.96	110	0.36	108600	2004
100	22.3	40 - 45	0.019	0.0056	0.91	105	0.36	185700	3537
200	45.9	40 - 45	0.018	0.0064	0.88	108	0.34	408000	7438

The data conform to a 'One Compartment Open Model of Distribution'. Ethylenediamine, +4PO is rapidly (though poorly) absorbed (time to Cpmax 40-45 min) and is virtually 100 % eliminated from the bloodstream within 24 hours following a single dose. The route of excretion is 92-96 % via renal clearance (average clearance 0.35 ml/hr). The elimination half-life averaged 108 min, and these data were consistent for doses up to 200 mg/kg bw. The mean first order elimination rate constant (K) was 0.0064 1/min for dosing with 200 mg/kg bw.

(Vd = volume of distribution; Cl = clearance rate; K = elimination rate constant; F = bioavailability factor; AUC = Area under the curve)