Registration Dossier

Toxicological information

Dermal absorption

Currently viewing:

Administrative data

Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
05.03.2008 to 12.08.2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008
Report Date:
2008

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: Bronaugh Flow Through method
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Dimethylsilanediol
- Substance type: Silane
- Physical state: Colourless liquid
- Analytical purity: No data for unlabelled DMSD
- Purity test date: No data
- Lot/batch No.: 21229-79B
- Radiochemical purity (if radiolabelling):97.8 ± 0.06 %
- Specific activity (if radiolabelling): Neat 14C-DMSD: 387 mCi/g; Aqueous solution: 2.515 ± 0.07 mCi/g
- Locations of the label (if radiolabelling): C
- Expiration date of radiochemical substance (if radiolabelling): 28.02.2010
- Stability under test conditions: Stable. The concentration of 0.65% in water was considered to be the maximum achievable stable concentration
- Storage condition of test material: Refrigerated at 5±4oC
Radiolabelling:
yes
Remarks:
14C-dimethylsilanediol (14C-DMSD)

Test animals

Species:
human
Strain:
other: N/A
Sex:
male/female
Details on test animals and environmental conditions:
Not applicable to this test.

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
water
Duration of exposure:
24 hours
Doses:
The applied dose was determined gravimetrically by weighing the pipette pre- and post- dosing. Actual doses ranged from 9.7 to 10.4 mg of dosing solution/cell (15.2-16.2 mg/cm2 of exposed skin) and applied radioactivity ranged from from 38.7 to 41.4 µCi/cm2 of exposed skin. The applied doses delivered between 98.5 and 104.6 µg 14C-DMSD/cm2 of skin.
No. of animals per group:
3 males, 2 female
Control animals:
no
Details on study design:
DOSE PREPARATION
- Method for preparation of dose suspensions: A dose solution of 14C-DMSD in water was prepared by a synthesis chemist. The radioactivity concentration and homogeneity of the dosing solution was verified on the day of dosing by liquid scintillation counting. Concentration of 14C-DMSD in dosing solution (0.65%) was calculated from the specific activity of precursor material used in synthesis of 14C-DMSD.
- Method of storage: Refrigerated at 5 ±4oC.
Details on in vitro test system (if applicable):
SKIN PREPARATION
- Source of skin: Human cadaver
- Ethical approval if human skin: No data
- Type of skin: Abdominal skin
- Preparative technique: Skin samples were cleaned of underlying fat, as needed and thawed at the room temperature. Excessive hair was clipped off the skin. Each sample was sprayed with a 1% mild soap solution, and dermatomed with a mini-dermatome to separate epidermis from most of dermis. Dermatomed skin samples were placed on a gauze soaked with cell culture medium while the other skin sections were being processed. Three disc-shaped skin pieces, large enough to fit 0.64 cm2 flow-through diffusion cells, were punched out from the skin of each donor. Each skin disc was visually inspected and rinsed with ultrapure water.
- Thickness of skin (in mm): 0.3-0.45
- Membrane integrity check: yes (including test for effect of methanol on skin integrity)
- Storage conditions: Receptor fluid and extracts: refrigerated at 5±4 oC; Solubilised skin: ambient temperature
- Justification of species, anatomical site and preparative technique: None


PRINCIPLES OF ASSAY
- Diffusion cell: 0.64 cm2
- Receptor fluid: physiological buffer, Hank's Balanced Salt Solution with 0.6% HEPES, 0.005% Gentamicin and 4% Bovine Serum Albumin, pH 7.4 adjusted with 1N NaOH, and filtered through 0.22 micron filter.
- Solubility of test substance in receptor fluid: Soluble
- Flow-through system: Bronaugh flow-through apparatus was set-up with the skin area available for dosing after mounting into the diffusion cell of 0.64 cm2.
- Test temperature: No data
- Humidity: No data
- Occlusion: Semi-occlusive
- Reference substance(s): None

Results and discussion

Signs and symptoms of toxicity:
not examined
Dermal irritation:
not examined
Absorption in different matrices:
Skin samples from each donor were dosed in triplicates with 14C-DMSD in aqueous solution,
before the skin integrity data were available. The average dose applied to the all skin samples
was 15.7 mg of dosing solution/cm2 of skin delivering 102.2 μg of 14C-DMSD/cm2 and 40.1
μCi/cm2 of exposed skin. The percentage of applied 14C-DMSD recovered from all
acceptable samples was 91.66%. Considerable portion of the applied 14C-DMSD
(59.51%) volatilized from the skin surface and was captured in the charcoal baskets placed above
the exposure site. In order to recover the entire radioactivity absorbed in charcoal traps it was
necessary to oxidize charcoal samples after they were extracted in acetone. After 24 hr of
exposure, 18.27% of applied dose was found on the skin surface and recovered in skin washes
and tape strips.
The total percent dose absorbed was estimated to be 13.88% of applied dose. The majority of the
absorbed 14C-DMSD penetrated the skin into receptor fluid (82.1% of absorbed dose). Therefore,
11.40% of applied dose reached the receptor fluid and 2.48% of applied dose remained in the
skin after washing and tape stripping the exposure site after 24 hr of exposure. The penetration
curve showed that there was a 3-hr lag phase with steady state flux of 14C-DMSD
established between 3 and 8 hr of exposure (1.3 μg Equivalents/cm2/hr). The mean cumulative
penetration (± standard error of the mean) over the 24 hr diffusion period was estimated to be
11.7 ± 3.2 μg equivalents of 14C-DMSD /cm2 of exposed skin with more than 80% of
14C-DMSD penetrated into receptor fluid within first 12 hr of exposure. The permeability
coefficient, Kp was estimated to be 2.0x10-4 cm/hr.
Total recovery:
- Total recovery: 91.66%
Percutaneous absorption
Parameter:
percentage
Absorption:
11.4 %
Remarks on result:
other: 24 h
Conversion factor human vs. animal skin:
N/A

Any other information on results incl. tables

Percentage of the volatilized dose, dose remaining on the skin and penetrating into the skin and receptor fluid after 24 hours was determined relative to applied dose (applied radioactivity).

Applicant's summary and conclusion

Conclusions:
In a well conducted in vitro dermal absorption study conducted to GLP (reliability score 1), after 24 hr of exposure a considerable portion (59.51%) of 14C-DMSD applied in aqueous dosing solution volatilized from the skin surface and was captured in the charcoal baskets placed above the exposure site. The percent of applied 14C-DMSD recovered from all analysed samples was 91.66%. After 24 hr of exposure 18.27% of applied dose was found on the skin surface and 2.48% of applied dose remained in the skin after washing and tape stripping. The total percent dose absorbed was estimated to be 13.88% of applied dose.
The majority of the absorbed dose (82.1%) penetrated through the skin into receptor fluid with the estimated mean cumulative penetration of 11.7 ± 3.2 μg equivalents of 14C-DMSD /cm2 of exposed skin over the 24 hr diffusion period (11.40% of applied dose). The permeability coefficient (Kp) was estimated to be 2.0x10-4 cm/hr based on steady state flux established between 3 and 8 hours of exposure. It is considered appropriate to use this result as dichloro(dimethyl)silane hydrolyses rapidly to produce dimethylsilanediol and hydrogen chloride in contact with skin.
Executive summary:

In a well conducted in vitro dermal absorption study conducted to GLP (reliability score 1), after 24 hr of exposure a considerable portion (59.51%) of 14C-DMSD applied in aqueous dosing solution volatilized from the skin surface and was captured in the charcoal baskets placed above the exposure site. The percent of applied 14C-DMSD recovered from all analysed samples was 91.66%. After 24 hr of exposure 18.27% of applied dose was found on the skin surface and 2.48% of applied dose remained in the skin after washing and tape stripping. The total percent dose absorbed was estimated to be 13.88% of applied dose.

The majority of the absorbed dose (82.1%) penetrated through the skin into receptor fluid with the estimated mean cumulative penetration of 11.7 ± 3.2 μg equivalents of 14C-DMSD /cm2 of exposed skin over the 24 hr diffusion period (11.40% of applied dose). The permeability coefficient (Kp) was estimated to be 2.0x10-4 cm/hr based on steady state flux established between 3 and 8 hours of exposure. It is considered appropriate to use this result as dichloro(dimethyl)silane hydrolyses rapidly to produce dimethylsilanediol and hydrogen chloride in contact with skin.