Reaction mass of ethoxylated N-oleyl-1,3-propanediamine, hydrofluorides of and ethoxylated N-palmityl-1,3-propanediamine, hydrofluorides of and ethoxylated N-stearyl-1,3-propanediamine, hydrofluorides of and olaflur

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2003

Report date:

2003

Materials and methods

Objective of study:

absorption

distribution

excretion

Test guideline

Qualifier:

according to guideline

Guideline:

other: Japanese Guidelines for Non-clinical Studies of Drugs Manual 1995; Guidelines for Toxicity Studies of Drugs. Japanese Ministry of Health and Welfare.

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Details on test material:

TEST SUBSTANCE - RADIOLABELLED
- Name of test material (as cited in study report):
a) N-Oleyldiethanolamine hydrofluoride, [hydroxyethyl-14C]
b) [1 -Oleyl-14C]-Diethanolamine hydrofluoride

TEST SUBSTANCE - UNLABELLED
- Name : Oleaflur

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland GmbH, Sandhofer Weg 7, D-97633 Sulzfeld
- Age at study initiation: 6-12 weeks
- Weight at study initiation: 150-259 g
- Housing: animals were kept singly in MAKROLON cages (type III) during adaptation period
- Individual metabolism cages: yes, during excretion study
- Diet (ad libitum): Altromm 1321 (ALTROMIN GmbH, D-32791 Lage/Lippe
- Water (ad libitum)
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C ± 3°C
- Humidity (%): 60% ± 20%
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

other: oral or intravenous

Vehicle:

other: aqua ad iniectabilia

Details on exposure:

Dose level and formulation:
Each rat received approx. 0.8 m g Hydroxyethyl-14C-Oleaflur or approx. 0.2 mg Oleyl-14C-Oleaflur, corresponding to a nominal radioactive dose of approx. 876 kBq (approx. 24uCi) per animal. Each animal received a dosage of approx. 3.5 MBq/kg bw .
Depending on the specific activity of the labelled substances, unlabelled test material was added until a specific total dosage of 20 mg/kg bw Oleaflur (labelled + unlabelled) was reached.

Oral formulation: the test articles were dissolved in aqua ad iniectabilia. A constant volume (10 mL) of dose formulation per kg body weight was administered (dose 20 mg/kg bw).

Intravenous formulation: the test articles were dissolved in aqua ad iniectabilia containing 33 mg/mL mannitol and 0.5 mg/mL sodium EDTA. A constant volume of dose formulation per kg body weight was administered. (dose: 20 mg/kg bw , application volume: 4.0 mL/kg bw)

Duration and frequency of treatment / exposure:

- 1 application day and up to 96 hours post administration sampling

Doses / concentrations

Dose / conc.:

20 mg/kg bw/day (nominal)

No. of animals per sex per dose / concentration:

- 6 per sex per dose per route of administration per compound

Control animals:

no

Results and discussion

Preliminary studies:

- no data

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Within 96 h of receiving a single oral administration of Hydroxyethyl-14C-Oleaflur, means of 90.74 % and 93.95 % of the administered radioactivity were recovered in urine (means 47.20 % and 51.63 %), faeces (means 27,65 % and 23.54 %), expired air (means 2.94 % and 2.01 %), carcass and organs (means 9.53 % and 10.86 %) and rinse water (means 3.41 % and 5.90 %) of male and female animals, respectively.

Within 96 h of receiving a single oral administration of Oleyl-14C-Oleaflur, (means of 95.78 % and 96.92 % of the administered radioactivity were recovered in urine (means 30.41 % and 33.11 %), faeces (means 30.83 % and 34.69 %), expired air (means 18.83 % and 18.49 %), carcass and organs (means - 13.16 % and 7.98 %) and rinse water (means 2.55 % and 2.66 %) of male and female animals, respectively.

Within 96 h of receiving a single intravenous administration of Hydroxyethyl-14C-Oleaflur means of 95.60 % and 91.54 % of the administered radioactivity were recovered in urine (means 49.43 % and 49.90 %), faeces (means 25.83 % and 23.86 %), expired air (means 3.94 % and 2.96 %), carcass and organs (means 13.34 % and 11.40 %) and rinse water (means 3.06 % and 3.42 %) of male and female animals, respectively.

Within 96 h of receiving a single intravenous administration of Oleyl-14C-Oleaflur means of 93.34 % and 90.67 % of the administered radioactivity were recovered in urine (means 39.14 % and 39.19 %), faeces (means 28.14 % and 21.62 %, expired air (means 14.83 % and 11.56 %), carcass and organs (means 8.17 % and 15.04 %, and rinse water (means 3.06 % and 3.27 %, of male and female animals, respectively.

Details on distribution in tissues:

A widespread and generally uniform distribution of radioactivity in the tissue was observed at 96 h after oral administration for both Oleaflur compounds. The highest concentrations of radioactivity were observed in the kidneys for Hydroxyethyl-14C-Oleaflur (males 16.35 ug-eq/g, females 30.42 ug-eq/g) and in the liver (males 12.58 ug-eq/g, females 18.64 ug-eq/g). Oleyl-14C-Oleaflur related radioactivity was counted mainly in the adipose tissue (males 31.68 ug-eq/g, females 16.99 ug-eq/g) and in the adrenals (males 8.86 ug-eq/g, females 5.94 ug-eq/g).


A widespread and generally uniform distribution of radioactivity in the tissue was observed at 96 h after intravenous administration for both Oleaflur compounds. The highest concentrations of radioactivity were observed in the kidneys for Hydroxyethyl-14C-Oleaflur (males 9.73 ug-eq/g, females 15.91 ug-eq/g) and in the liver (males 8.13 ug-eq/g, females 10.54 ug-eq/g). Oleyl-14C-Oleaflur related radioactivity was counted mainly in the adipose tissue (males 3.70 ug-eq/g, females 4.73 ug-eq/g) and in the pituitary (males 4.33 ug-eq/g, females 3.48 ug-eq/g).

Details on excretion:

The most important route of elimination was the urine with between 30 to 50 %: slightly more radioactivity was excreted with the urine for the Hydroxy14C-Oleaflur than for the Oleyl-14C-Oleaflur. The reverse was observed for expired air: approximately 12 to 19 % was excreted with the air for Oleyl-14C-Oleaflur and only 2 to 4 % for Hydroxyethyl-14C-Oleaflur.

Metabolite characterisation studies

Metabolites identified:

not measured

Applicant's summary and conclusion

Executive summary:

No study with Olaflur is available. However, the bioavailability of Olaflur can reliably be predicted, from data obtained with a chemically very similar compound (Oleaflur).

In an absorption, distribution and excretion study (LPT, 2003) two radiolabelled Oleaflur compounds, Hydroxyethyl-14C-Oleaflur and Oleyl-14C-Oleaflur, have been studied for 96 hours in Sprague-Dawley rats given a single oral or intravenous nominal dose level of 20 mg/kg bw.

The radiolabelled compounds were completely absorbed (> 90 %) following oral administration. Routes of excretion were fairly similar for both labelled compounds with a predominance of urinary excretion. There was no difference in the distribution of radioactivity in the tissues for both compounds or for the two routes of administration. Oral or intravenous administration resulted in no changes in the routes of excretion for both compounds.

No sex difference was observed in the plasma concentrations, excretion patterns and tissue distribution, and no indications were found that Oleaflur might accumulate in the body (t 1/2 i.v. = approx. 46 h for Hydroxyethyl-14C-Oleaflur and approx. 32 h for Oleyl-14C-Oleaflur; after absorption or intravenous administration, approximately 60 % of the dose was excreted within the first 24 hours).