Isocycloseram

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vitro / ex 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:

2019

Report date:

2019

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 428 (Skin Absorption: In Vitro Method)

Version / remarks:

2004

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl)-N-(2-ethyl-3-oxo-1,2-oxazolidin-4-yl)-2-methylbenzamide

Cas Number:

2061933-85-3

Molecular formula:

C23H19Cl2F4N3O4

IUPAC Name:

4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl)-N-(2-ethyl-3-oxo-1,2-oxazolidin-4-yl)-2-methylbenzamide

Test material form:

liquid

Radiolabelling:

yes

Test animals

Species:

other: Human

Administration / exposure

Type of coverage:

open

Vehicle:

other: The study was performed with a formulated product (suspension concentrate formulation type) containing the radiolabelled test substance at a concentration of 200 g/L

Duration of exposure:

10 hours

Doses:

Formulation concentrate (200 g/L), Spray dilution 1 (7.5 g/L), Spray dilution 2 (2 g/L), Spray dilution 3 (0.2 g/L): 10 µL/cm2, 6.4 µL/cell

Details on in vitro test system (if applicable):

A static diffusion cell with an exposed skin area of 0.64 cm2 was used for all tests. The membranes consisted of dermatomed skin with a thickness of 350 to 400 µm, obtained from male rats, 8 to 12 weeks old. Their integrity was tested by measuring the electrical resistance.

The receptor medium consisted of Phosphate buffered saline containing polyoxyethylene 20 oleyl ether (PEG, ca 6%, w/v), sodium azide (ca 0.01%, w/v), streptomycin (ca 0.1 mg/mL) and penicillin (ca 100 units/mL) at pH 7.4 + 0.1.

The exposure time was 10 hours, the following observation period was 14 hours. Samples were taken pre-dose, then after 2, 4, 6, 8, 12 and 24 hours. Washing was performed after the exposure period and at the end of the observation period. Tape stripping was performed as final procedure, and the strips were analysed separately.

The human skin was obtained from human female and male donors at the age of 28 to 63 years. The skin was taken from the abdomen, the arms or the breast. The number of valid and used cells per test concentration was 8.

Results and discussion

Total recovery:

200 g/L: 100 ± 10% for individual cells (n = 8), mean = 99.03%
7.5 g/L: 100 ± 10% for individual cells (n = 8), mean = 100.84%
2 g/L: 100 ± 10% for individual cells (n = 8), mean = 100.62%
0.2 g/L: 100 ± 10% for individual cells (n = 8), mean = 98.51%

Percutaneous absorption

Percutaneous absorption 1

Key result

Time point:

24 h

Dose:

200 g/L

Parameter:

percentage

Absorption:

0.01 %

Percutaneous absorption 2

Key result

Time point:

24 h

Dose:

7.5 g/L

Parameter:

percentage

Absorption:

0.02 %

Percutaneous absorption 3

Key result

Time point:

24 h

Dose:

2.0 g/L

Parameter:

percentage

Absorption:

0.09 %

Percutaneous absorption 4

Key result

Time point:

24 h

Dose:

0.2 g/L

Parameter:

percentage

Absorption:

0.18 %

Applicant's summary and conclusion

Conclusions:

The dermal absorption of substance through human split-thickness skin membranes over a period of 24 hours was 0.01% for the formulation concentrate (200 g/L) and ranged from 0.02%, 0.09% to 0.18% for spray dilutions (7.5, 2.0 and 0.2 g/L).

Executive summary:

The in vitro dermal absorption of the substance from a suspension concentrate was studied under GLP to OECD TG 428 using split-thickness human skin. Split-thickness membranes were prepared from full thickness membranes obtained from 28 to 63 years old female and male human donors. All tests were conducted in static diffusion cell systems, and the exposed skin surface within the cells was 0.64 cm2. All cells were placed on a magnetic stirrer plate that could be heated to maintain a skin surface temperature of 32 ± 1°C. The study was performed with a suspension concentrate formulation containing 200 g/L of radiolabelled test substance and with in-use dilutions containing 7.5, 2.0 or 0.2 g/L radiolabelled test substance. Aliquots of 10 μL of each test solution were applied per cm2 of skin membranes and left unoccluded for an experimental period of 24 h, with an interim wash at 10 h post-application. The absorption process was followed by collecting samples of the receptor fluid, phosphate buffered saline containing polyoxyethylene 20 oleyl ether (PEG, ca 6%, w/v), sodium azide (ca 0.01%, w/v), streptomycin (ca 0.1 mg/mL) and penicillin (ca 100 units/mL), pH 7.4 ± 0.1, at recorded intervals throughout the experimental period. The distribution of the substance within the test system and a 24 h absorption profile was determined using liquid scintillation counting. The study demonstrated that the amount of substance absorbed through human split-thickness skin membranes over 24 h (following a 10 h exposure) from the formulation concentrate (200 g/L) was 0.01% and the intended in-use dilutions (7.5 g/L, 2 g/L and 0.2 g/L) was 0.02%, 0.09% and 0.18% of the applied dose, respectively, as measured in the receptor fluid and receptor chamber wash.