Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Remarks:
Test substance represents a main component (stereoisomer) of the registered substance
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non GLP and non guideline study.

Data source

Reference
Reference Type:
publication
Title:
Resorption, Verteilung und Metabolismus von [14C] markierter Testsubstanz in der Haut
Author:
Hahn B., Hölzl J.
Year:
1987
Bibliographic source:
Arzneim.-Forsch./Drug res. 37(19), Nr. 6

Materials and methods

Principles of method if other than guideline:
no data
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Levomenol
EC Number:
245-423-3
EC Name:
Levomenol
Cas Number:
23089-26-1
Molecular formula:
C15H26O
IUPAC Name:
(2S)-6-methyl-2-[(1S)-4-methylcyclohex-3-en-1-yl]hept-5-en-2-ol
Details on test material:
- Name of test material (as cited in study report): Levomenol
Radiolabelling:
yes
Remarks:
14C

Test animals

Species:
mouse
Strain:
NMRI
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Central Institute for Laboratory Animals, Hannover
- Weight at study initiation: 13 g
- Fasting period before study: 15 hours
- Water: ad libitum


Administration / exposure

Type of coverage:
not specified
Vehicle:
other: Water with Arlatone 975 or Aceton
Duration of exposure:
1, 3 and 5 hours
Doses:
122 kBq of the radiolabelled test substance (1.44 kBq/µmol) were added with 90 mg Arlatone 975 (atlas Chemie, Essen) and then dissolved in 450 µL of water. Daily 150 µL of the test solution were applied to the neck area of the animals (40.6 kBq [14C]-test substance).
No. of animals per group:
no data
Details on study design:
SUBSTANCE PREPARATION
- For the production of 185 kBq [14C]-test substance, 150 chamomile flowers (Spanish origin; designation H29) were mixed with 370 kBq [2-14C-Acetate] and 20 µg saccharose in 10 µL tap water. After three days the essential oil was separated from the flowers by distillation. The isolation of the [14C]-test substance was carried out by chromatography. The radiochemical purity was determined by thin-layer chromatography on silica gel 60 and RP-18, followed by autoradiography. The purity was 96%.

DOSE PREPARATION
- Method for preparation of dose suspensions: 122 kBq of the radiolabelled test substance (1.44 kBq/µmol) were added with 90 mg Arlatone 975 (atlas Chemie, Essen) and then dissolved in 450 µL of water. Daily 150 µL of the test solution were applied to the neck area of the animals (40.6 kBq [14C]-test substance).


TEST SITE
- Area of exposure: neck area


SAMPLE COLLECTION
After 1, 3 and 5 hours, the animals were killed, bleed and skin areas of the application site and the lower extremities were removed. In addition, fat and muscle tissue was obtained below the neck skin.

Results and discussion

Signs and symptoms of toxicity:
not specified
Dermal irritation:
not specified
Absorption in different matrices:
Skin test site: 1 hour after application, 80% of the radioactivity were measured on and in the skin of the application site. Over the test period, the radioactivity decreased after 3 hours of incubation to 57% and after 5 hours to about 50%.

Any other information on results incl. tables

Table: Radioactivity on the application side [%]

 

Application of the [14C]-test substance in water with Arlatone

Application of the [14C]-test substance in Acetone

1 h

3 h

5 h

3 h

Skin in the neck area

(adsorption, mean+/- SD permeation)

82.34 (+/- 7.35)

57.22 (+/- 1.93)

48.73 (+/- 2.79)

60.52 (-)

Extractable radioactivity of the neck skin

96.9

96.4

96.3

96.9

Extractable intact [14C]-test substance

91.4

90.4

89.0

92.5

The aim of the study was to evaluate the absorption, distribution and metabolism of the test substance in the skin. The radiolabeled compound was prepared by biochemical incorporation of [14C] acetate into the molecule.The test substance was applied to the skin of nude mice of the NMRI strain. The mice were sacrified at 1, 3 and 5 hours after application and radioactivity was measured. Five hours after topical application of the [C14] labelled test substance onto nude mice, half of the radioactivity was detected in the skin. The other part was measured in tissue and organs. Ninety percent of this radioactivity was analysed as intact test substance.

In order to demonstrate the distribution of the test substance in the skin, a part of this tissue was cut into horizontal slices by a cryotome. Autoradiograms of these sliced were produced. Densitometric measurement showed that there was a fast penetration of the test substance into the skin. Five hours after the topical application, the test substance was displaced from outermost to innermost areas. According to the authors, these results suggest that a fast cutaneous absorption and a long therapeutic effect of the antiphlogistic spasmolytic test substance in the skin can be expected.

Applicant's summary and conclusion