1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)pyridin-2(1H)-one, compound with 2-aminoethanol (1:1)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1980

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was conducted prior to existing guidelines and prior to GLP but followed scientifically accepted standards at that time. The study itself is well conducted, well documented and scientifically acceptable.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1980

Report date:

1980

Materials and methods

Objective of study:

absorption

distribution

excretion

toxicokinetics

Test guideline

Qualifier:

no guideline available

Version / remarks:

Study followed generally accepted and still valid scientific principles at the time of implementation and

Principles of method if other than guideline:

Study carried out by intraindividual comparison. Animals recieved test compound orally by gavage for blood measurements and 14 days later they
received the compound intravenously for excretion studies. 7 days after intravenous injection, radioactive residues were measured in various
organs and tissues by autoradiography.

GLP compliance:

no

Remarks:

not requested at time of testing (internal QAU available)

Test material

Test material information

Constituent 1

Reference substance name:

Octopirox

IUPAC Name:

Octopirox

Constituent 2

Reference substance name:

Piroctone Olamine

IUPAC Name:

Piroctone Olamine

Constituent 3

Reference substance name:

1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)pyridin-2(1H)-one, compound with 2-aminoethanol (1:1)

EC Number:

272-574-2

EC Name:

1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)pyridin-2(1H)-one, compound with 2-aminoethanol (1:1)

Cas Number:

68890-66-4

Molecular formula:

C14H23NO2.C2H7NO

IUPAC Name:

1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)pyridin-2(1H)-one, compound with 2-aminoethanol (1:1)

Constituent 4

Reference substance name:

1- Hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2-pyridone, 2-aminoethanol salt

IUPAC Name:

1- Hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2-pyridone, 2-aminoethanol salt

Radiolabelling:

yes

Remarks:

C14 label

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Ivanovas, Kißlegg, Germany
- Weight at study initiation: approximately 185 g (oral application), approximately 220 g (intravenous
application)
- Fasting period before study: at least 8 hours
- Housing: metabolic cages
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): depending on application route
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 1 °C
- Humidity (%): 60 +/- 5 %
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hour interval

Administration / exposure

Route of administration:

other: oral by gavage followed by intravenous injection 14 days later

Vehicle:

polyethylene glycol

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Test material was dissolved in polyethylene glycol 400 at appropriate concentrations


VEHICLE
- Justification for use and choice of vehicle (if other than water): PEG 400, recommended and accepted vehicle for this type of testing

HOMOGENEITY AND STABILITY OF TEST MATERIAL: guaranteed

Duration and frequency of treatment / exposure:

Rats received one single oral dose via stomach tube followed 14 days later by one single intravenous application

Doses / concentrations

Remarks:

Doses / Concentrations:
0.24 mg Octopirox per kg body weight via oral via gavage followed 14 days later by 0.21 mg/kg body weight via intravenous injection

No. of animals per sex per dose / concentration:

12 male rats
Animals were used for both parts of the study for intraindividual comparison reason (oral part mainly for absorption measurements, intravenous
part mainly for excretion measurements)

Control animals:

other: intraindividual comparison, blanc values

Positive control reference chemical:

n.a.

Details on study design:

Study was carried out by intraindividual comparison. All rats were administered the same oral dose via stomach tube for blood measurements. 14
days later the same animals received an intravenous injection of test compound for excretion studies .The allocation to the group was randomly.
Dose selection was based on preliminary studies and expert judgement. At the end of the study radioactive residues were measured by whole body
autoradiography.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, metabolism, distribution, excretion):
The study was carried out by intraindividual comparison. 14 days after a single oral application (measurement of absorption and distribution) an intravenous injection was performed (measurement of distribution and excretion) using the same animals.
Absorption was measured following a single oral application of Octopirox to 12 rats
Time points of sampling: 0.25, 0.5, 1, 3, 6, 8, 24, 32, 48, 72, 96, 120, 144, 168 hours p.a.
Distribution was measured by whole body autoradiography at the end of the study (i.e. 7 days after the intravenous injection)
Excretion was measured following a single intravenous application starting 5 minutes after injection of test material.
Metabolism was covered by measuring radioactivity using liquid scintillation measurements, i.e. the concentrations given represent the total of
original substance and all radioactive labelled potential metabolites.

Statistics:

yes

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The absorption after oral application calculated from the ratio of radioactivity renally excreted after oral and intravenous treatment was 0.15 - 0.35 %of the administered dose.

Details on distribution in tissues:

After intravenous application the radioactivity was distributed in the entire organism but was concentrated mainly in the excretory organs liver and
kidneys 5 minutes after injection. One hour after intravenous injection the periphery was virtually free from radioactivity. High radioactivity
concentrations were measured in the small and large intestine while liver and kidneys showed markedly lower values than measured 5 minutes after
injection. One day after intravenous injection, only the intestinal contents showed low radioactivity levels while radioactivity was no longer detectablein kidneys and liver. Despite a principally similar pattern of distribution as after intravenous injection, the radioactivity after oral treatment in liver
and kidneys was markedly lower, most probable due to incomplete absorption. Specific cumulations in organs and tissues persisting for a longer
period were not observed. 7 days after intravenous injection the values of radioactivity in all organs were at or below the detection limit of 1 ng/g.
The relatively high radioactivity concentrations measured in the intestine after intravenous injection, together with the concentration in the liver and the proportionally higher fecal excretion, indicate a predominantly biliary excretion.

Transfer into organs

Transfer type:

other: cumulation in organs and tissues

Observation:

no transfer detectable

Details on excretion:

After oral as well as after intravenous administration of the test compound, the rats excreted more radioactivity with faeces than with urine. The renalexcretion was biphasic with half-lives between 8 and 23 hours. No differences between the various exposure routes were observed. Based on the
time-course a rapid and practically complete elimination occurred.

Toxicokinetic parameters

Toxicokinetic parameters 1

Toxicokinetic parameters:

half-life 1st: 8 hours

Toxicokinetic parameters 2

Toxicokinetic parameters:

half-life 2nd: 23 hours

Metabolite characterisation studies

Metabolites identified:

no

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Octopirox does not exhibite a conspicuous toxicokinetic behaviour. Indications of a bioaccumulative potential or biopersistenct behaviour were not observed. Oral absorption is incomplete and excretion is rapid and practically complete within 1 to 7 days after application. Differences between
various routes of exposure in the toxicokinetic behaviour do not exist.

Executive summary:

After oral administration of 0.24 mg/kg Octopirox to rats, maximum compound levels in blood of 0.006 - 0.014 microgram per mL were measured between 3 and 8 hours after treatment. Half-lives around 42 minutes and 14 hours were estimated for the biphasic elimination from blood after intravenous treatment. Independent of the route of administration, more radioactivity was excreted in faeces than in urine. After intravenous injection, the radioactivity was distributed in the entire organism and was concentrated mainly in the secretory organs liver and kidneys 5 minutes after injection. One hour after intravenous injection, the periphery was virtually free from radioactivity whereas high radioactivity concentrations were measured by whole body autoradiography in the small and large intestine. The radioactivity in liver and kidneys were markedly lower than those measured 5 minutes after injection. One day p.a. only the intestinal contents showed low radioactivity levels whereas almost no radioactivity was autoradiographically demonstrable in kidneys and liver. Despite a principally similar distribution pattern as after intravenous injection, after oral treatment the radioactivity in liver, kidneys and skeletal muscles was markedly lower which is attributable to inclompete absorption. The relatively high radioactivity concentrations measured in the intestine after intravenous injection indicate, in connection with the liver values, a predominantly biliary elimination. Specific cumulations in organs and tissues persisting for a longer period were not observed. Seven days after treatment the residues in the various compartments were in general less than 1 ppb which indicates complete elimination.