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Toxicological information

Basic toxicokinetics

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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

Referenceopen allclose all

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 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

Reference
Name:
Unnamed
Type:
Constituent
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 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:
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 resultsopen allclose all
Type:
absorption
Results:
(oral) bioavailability factor F = 0.018
Type:
distribution
Results:
minimal tissue distribution; volume of distribution 4 ml/ kg bw
Type:
metabolism
Results:
no metabolites identified
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)

Applicant's summary and conclusion