Methyl 2,4-dihydroxy-3,6-dimethylbenzoate

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2002

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2002

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: FDA/AAPS guidelines

Version / remarks:

See "Principles of method if other than guideline"

Principles of method if other than guideline:

Testing was performed according to Skelly et al., "FDA and AAPS report of the workshop on principles and practices of in vitro percutaneous penetration studies: relevance to bioavailability and bioequivalence", Pharmaceutical Research 1987, 4, 265-267.
In short, full thickness human skin samples, resulting from the breast or the abdomen of cosmetic surgery patients, were heat separated and the epidermal membranes were used in the study. The epidermal membranes were mounted on filter paper supports. The supports, with the membranes, were then placed onto diffusion cells and trimmed to size. The integrities of the membranes were determined by using tritiated water. Twenty mL of a 1% test item solution in ethanol was applied to the surface of the membranes. At 2, 8, 24, 36, and 48 hours 200 mL samples of the receptor fluid (50% ethanol/ water solution) were taken from the receptor chamber and analysed by liquid scintillation chromatography. Evaporative loss of the test item was also determined. In parallel, PTFE sheet mounted in diffusion cells (at 32°C) was closed with 20 µL of 1% solution of the radiolabelled test item in ethanol. Six cells were prepared. Following dosing, one cell was dismantled at each of the following timepoints: 1, 2, 4, 8, 24 and 48 hours. The PFTE sheet was removed and washed twice with methanol (first with 10 mL, then 5 mL). The donor chamber was washed with 10 mL methanol. A sample of each wash solution was submitted to analysis by LSC that allowed the total remaining radiolabel at each time point to be determined.

GLP compliance:

not specified

Test material

Test material information

1

Reference substance name:

Methyl 2,4-dihydroxy-3,6-dimethylbenzoate

EC Number:

225-193-0

EC Name:

Methyl 2,4-dihydroxy-3,6-dimethylbenzoate

Cas Number:

4707-47-5

Molecular formula:

C10H12O4

IUPAC Name:

methyl 2,4-dihydroxy-3,6-dimethylbenzoate

Test material form:

other: solid

Specific details on test material used for the study:

Vapour pressure (mm Hg, 20°C) of the test item: 0.002 Pa

Radiolabelling:

yes

Remarks:

0.2mCi methyl artrarate, [1-14C], specific activity 46.02 mCi/mmol, radiochemical purity 98.01%

Administration / exposure

Doses:

1%

Results and discussion

Percutaneous absorption

Percutaneous absorption 1

Key result

Time point:

24 h

Dose:

1%

Parameter:

percentage

Absorption:

13.8 %

Percutaneous absorption 2

Key result

Time point:

48 h

Dose:

1%

Parameter:

percentage

Absorption:

20.3 %

Conversion factor human vs. animal skin:

Not relevant, human skin samples were used.

Any other information on results incl. tables

Recovery of the test item at 48 hours was 94.8%:

Surface wipe: 64.3%; tape strips: 4.6%; remaining epidermis: 3.8%; receptor phase: 20.3%; donor chamber: 1.8%.

There was no measured loss for the test item due to evaporation.

The liquid fragrances tested permeated the skin fairly rapidly, but the permeation subsequently plateaud as the donor phase became depleted through permeation. The permeation rate of methyl atrarate was slower and some plateauing occurred.

Applicant's summary and conclusion

Conclusions:

Percutaneous absorption of the test item was assessed by an in vitro skin penetration study. At 24 and 48 hours, 13.8% and 20.3% of the test item (radiolabelled, applied in 1% solution in ethanol) permeated through the membrane. Total recovery at 48 hours was 94.7%, there was no loss due to evaporation.

Executive summary:

Percutaneous absorption of the test item was assessed by an in vitro skin penetration study. At 24 and 48 hours, 13.8% and 20.3% of the test item (radiolabelled, applied in 1% solution in ethanol) permeated through the membrane. Total recovery at 48 hours was 94.7%, there was no loss due to evaporation.