Titanium(4+) ethanolate

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

2000

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Acceptable study with sufficient documentation which meets basic scientific principles. Read-across justification: The substance is hydrolytically unstable. When it comes in contact with water or moisture complete hydrolysis will take place with no significant reaction products other than alcohol and hydrated titanium dioxide. This rapid hydrolysis (hydrolysis half-life < 3 minutes to < 2 hours) is the driving force for the toxicokinetics of target substance. Because of the rapid hydrolysis, the influence of the mode of administration through inhalation, dermal and oral is related to the hazardous degradation product (alcohol) released from the target substance. The identification of degradation products from the hydrolysis study conducted for the target substance verifies that there are no impurities in the alcohol released from the target substance, which might change the hazardous properties of the target substance compared to the properties of the pure alcohol. As there is a mechanistic reasoning to the read-across, the unnecessary animal testing is avoided by using the read-across data from the degradation product (relevant alcohol) to evaluate irritation, sensitization and the short term and long-term toxicological effects and mutagenicity of the target substance.

Data source

Reference

Reference Type:

publication

Title:

Fate of ethanol applied topically to the skin

Author:

Pendlington RU, Whittle E, Robinson JA, Howes D

Year:

2001

Bibliographic source:

Food Chem Toxicol, 39, 169-74

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 428 (Skin Absorption: In Vitro Method)

Deviations:

yes

Remarks:

, no mention of integrity testing. Temperature and dose level slightly above recommended limits.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Constituent 2

Reference substance name:

Ethanol

EC Number:

200-578-6

EC Name:

Ethanol

Cas Number:

64-17-5

Molecular formula:

C2H6O

IUPAC Name:

ethanol

Details on test material:

- Name of test material (as cited in study report): ethanol
- Analytical purity: 'highest purity available'
- Radiochemical purity (if radiolabelling): no data
- Specific activity (if radiolabelling): 8mCi/mmol

Radiolabelling:

yes

Test animals

Species:

pig

Strain:

not specified

Sex:

female

Administration / exposure

Details on in vitro test system (if applicable):

SKIN PREPARATION
- Source of skin: Pig, 10 week old, female
- Type of skin: dorsal
- Preparative technique: Skin clipped, sc fat and muscle removed and then frozen at -70C until thawed immediately before use.
- Thickness of skin (in mm): no data
- Membrane integrity check: no data
- Storage conditions: -70C

PRINCIPLES OF ASSAY
- Diffusion cell: Bronaugh flow through cells
- Receptor fluid: Phosphate buffered saline with 5% bovine newborne calf serum and anti-biotics
- Solubility of test substance in receptor fluid: infinite
- Flow-through system:
- Test temperature: 37C
- Occlusion: half of cells occluded (double layer of parafilm) and microscope slide coverslip, half un-occluded
- Reference substance(s):
- Other: discs of 1.7cm skin used

Results and discussion

Total recovery:

- Total recovery:
- Recovery of applied dose acceptable: Occluded 40%, un-occluded 2.2%. Evaporation clearly explains the latter and may also account for the former being lower than ideal. The authors proposed that this was lost in the atmosphere of the cells, particularly since the total amount of radioactivity on the parafilm was higher than anywhere else except the receptor fluid. The fact that the outer skin digests were always higher than the inner skin digests also suggests loss through the cell flanges.
- Results adjusted for incomplete recovery of the applied dose: no

Percutaneous absorption

Percutaneous absorption 1

Dose:

10mg/cm2

Parameter:

percentage

Absorption:

ca. 21 %

Remarks on result:

other: 24 hours

Remarks:

under occlusive conditions

Percutaneous absorption 2

Dose:

10mg/cm2

Parameter:

percentage

Absorption:

ca. 1 %

Remarks on result:

other: 24 hours

Remarks:

under non-occlusive conditions

Any other information on results incl. tables

The amount penetrating was greater in the occluded than the unoccluded cells. The maximum flux rate was reached within 1 hour.

	Occluded cells	Un-occluded cells
Dose (mg)	3.93	3.93
Dose (mg/cm2)	10.34	10.34
Total penetrating to receptor fluid (%)	21.17	0.97
Total penetrating to receptor fluid in 24hrs (mg/cm2)	2.19	0.1

Note that if the total penetrating (in mg/cm2) is corrected for the recovered quantitities, the total penetrating would become 5.5 and 4.5mg/cm2 respectively, which suggests that occlusion state does not affect actual penetration rate significantly and that the total penetration is actually dependent on whether evaporation occurs or not.

The absolute total penetration figures in % are of direct use in suggesting usable figures for the penetration rate of ethanol under occlusive and non-occlusive skin working conditions. Under the worse case conditions (highest flux, occlusion) seen in this study , the amount of ethanol penetrating from a 0.1m2 area of skin (1000cm2) would give rise to a blood ethanol level of 4mg/l in a 70kg man.

Applicant's summary and conclusion

Conclusions:

Systemic doses of ethanol via skin absorption under practical conditions will be very low.

Executive summary:

In a study to assess the skin penetration potential of ethanol, an in vitro study was carried out using excised pig skin and radiolabelled ethanol. Ethanol penetration was greater under occlusion conditions than non-occlusive conditions, as might be expected. Absorption rates were around 21% and 1% of applied doses respectively.