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

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1983

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: No OECD Guideline study but according to accepted scientific standards at time of performance

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1983

Report date:

1983

Materials and methods

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

Radiolabelled [C14]-Octopirox was administered in aqueous polyethylene glycol to rats by oral intubation, intraperitoneal and subcutaneous
injection and its absorption and route and rate of excretion was examined by radiotracer and thin layer chromatography techniques. For topical
administration to evaluate skin penetration, [14C]-Octopirox was dissolved in an anionic shampoo base.

GLP compliance:

yes

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:

Octopirox-(pyridone-6[C14])-ethanolamine salt

IUPAC Name:

Octopirox-(pyridone-6[C14])-ethanolamine salt

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Animals were housed in separate plastic metabolism cages and fed with Spital pelleted diet and water ad libitum.

Administration / exposure

Type of coverage:

other: occlusive / non-occlusive

Vehicle:

other: anionic shampoo solution

Duration of exposure:

Defined exposure periods for skin penetration evaluations. Contact times ranging between 2.5 and 20 minutes. Experiments with and without rinse-off treatment.

Doses:

Stock solutions were used and diluted for testing. Aliquots were used for determination of the dose of [C14]-Octoriprox. Oral application amounted to approximately 4.8 mg per kg body weight.

No. of animals per group:

12 rats (6 males and 6 females) divided into 3 groups of 2 males and 2 females each for oral, intraveneous and subcutaneous administration.
12 rats divided into 4 groups for analysing effect of occlusion and rinsing on skin penetration
12 rats divided into 4 groups for analysing effect of duration of contact on skin penetration
12 rats divided into 4 groups to analyse effect of test substance concentration on skin penetration
3 rats to analyse effect of hair on skin penetration
12 rats divided into 2 groups of 6 each to analyse blood and tissue levels of [C14]-Octopirox after dermal exposure without rinsing
12 rats divided into 2 groups of 6 each to analyse blood and tissue levels of [C14]-Octopirox after dermal exposure with rinsing

Control animals:

no

Details on study design:

DOSE PREPARATION
- Method for preparation of dose suspensions:
Turnover study:
9.9 mg [14C]-Octopirox was dissolved in 2 drops of absolute ethanol and 8.5 mL of a 50% (v/v) distilled water solution of polyethylenglycol 200.
Skin penetration study:
As vehicle a proprietory shampoo without Octopirox containing 16% of the detergent sodium lauryl ether sulphate was used.


VEHICLE
- Justification for use and choice of vehicle (if other than water):
PEG 200 is a recommended vehicle. The shampoo base a normal carrier for typical use conditions.

TEST SITE
- Preparation of test site: 24 hours before treatment the hairs on the backs of the animals was clipped off
- Area of exposure: 10 cm2
- % coverage: 100
- Type of cover / wrap if used: non-occlusive as well as occlusive for comparison reasons

SITE PROTECTION / USE OF RESTRAINERS FOR PREVENTING INGESTION: yes: protective patches


REMOVAL OF TEST SUBSTANCE
- Removal of protecting device:
- Washing procedures and type of cleansing agent:
- Time after start of exposure:


SAMPLE COLLECTION
- Collection of blood:
- Collection of urine and faeces:
- Collection of expired air:
- Terminal procedure:
- Analysis of organs:


SAMPLE PREPARATION
- Storage procedure:
- Preparation details:


ANALYSIS
- Method type(s) for identification (e.g. GC-FID, GC-MS, HPLC-DAD, HPLC-MS-MS, HPLC-UV, Liquid scintillation counting, NMR, TLC)
- Liquid scintillation counting results (cpm) converted to dpm as follows:
- Validation of analytical procedure:
- Limits of detection and quantification:


OTHER:

Results and discussion

Signs and symptoms of toxicity:

no effects

Dermal irritation:

no effects

Total recovery:

Recovery of applied doses acceptable in the various experiments (details see study report)

Percutaneous absorption

Dose:

2000 microgram

Parameter:

percentage

Absorption:

> 0.1 - < 1 %

Remarks on result:

other: 48 hours

Applicant's summary and conclusion

Conclusions:

Whether given by mouth, injection or application to the skin, Octopirox was excreted essentially unchanged. Based on the results of this study
systemic toxic effects of Octopirox due to absorption through the skin is negligible.

Executive summary:

Radiolabelled piroctone olamine was administered to rats in aqueous polyethylene glycol 200 solution, by oral intubation, intraperitoneal subcutaneous injection and its route and rate of excretion was examined by radiotracer methods. For topical treatment [¹⁴C]-piroctone olamine was dissolved in an anionic shampoo base and applied to rat skin.

When given by intubation or injection [C¹⁴]-Octopirox was excreted by the rat mostly in the faeces (65 – 85 % of the dose) with smaller amounts (6 – 19 %) in the urine. Most of excretion occurred within 24 hours of dosing.

Skin penetration of piroctone olamine at 1 % (w/v) in the shampoo without rinsing was 65.1 µg/cm² under occlusive and 38.2 µg/cm² under non-occlusive conditions. In a „rinse off“ treatment, penetration was reduced to 3.4 µg/cm² under occlusive and 2.0 µg/cm² under non-occlusive conditions. There was a dependence of skin penetration of piroctone olamine on duration of contact up to 10 minutes after application. . 48 hours after exposure, excretion was virtually complete.

Penetration increased significantly from 2.4 µg/cm² after 2.5 minutes exposure to 45 µg/cm² after 10 minutes duration of contact. There was no further increase in penetration of piroctone olamine at 20 minutes application of 1 % piroctone olamine in the shampoo. Skin penetration and deposition of piroctone olamine were both proportional to the piroctone olamine concentration between 0.1 and 1 % (w/v). Skin penetration increased from 0.31 to 3.6 µg/cm²while deposition increased from 0.8 to 7.6 µg/cm². There was no significant difference between the penetration through clipped skin and hairy skin from an application of 1 % piroctone olamine for 5 minutes followed by rinsing.

Blood levels after topical application (15.4 mg/kg body weight) without rinsing and with occlusion reached 0.32 µg/ml at 6 hours. However, when the skin was rinsed and protected with a non-occlusive patch, blood levels were reduced to a maximum of 0.02 ug/ml at 1 hour after application.

Whether given by mouth, injection or application to the skin, piroctone olamine was excreted essentially unchanged. Based on the results, systemic effects of piroctone olamine due to absorption through the skin is negligible.