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Toxicological information

Dermal absorption

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Administrative data

Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Publication

Data source

Reference
Reference Type:
publication
Title:
An in vitro study of the effects of formulation variables and product structure on percutaneous absorption of lactic acid
Author:
Sah, A, Mukherjee, S, Wickett, RR
Year:
1998
Bibliographic source:
J. Cosmet. Sci. 49, 257-273

Materials and methods

Principles of method if other than guideline:
In vitro dermal absorption study.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Several aqueous solutions of lactic acid in varying concentrations
Radiolabelling:
yes

Test animals

Species:
other: Pig skin

Administration / exposure

Type of coverage:
occlusive
Vehicle:
other: emulsion
Duration of exposure:
6 hours
Doses:
2 µL and 75 µL
Details on in vitro test system (if applicable):
SKIN SAMPLES
The in vitro percutaneous absorption measurements were carried out with 3-4 week old female porcine dorsal skin obtained from Buckshire Corp, (Perkasie, PA) and stored at -75 °C. The skin was thawed, and adipose tissue and hair were removed, The shaved skin was then dermatomed to 510 µm thickness using a Padgett Dermatome, and 13 mm discs were cut from the dermatomed skin and mounted on Bronaugh flow-through cells (14), After each skin disc was equilibrated for 30 minutes, transepidermal water loss (TEWL) measurements were carried out using an evaporimeter (Servo-Med AB, Stockholm, Sweden) to check its barrier integrity. Skins with TEWL values greater than 5 gmicm²/hour were rejected, TEWL measurements were also carried out to monitor the change in skin hydration after product application,

PERCUTANEOUS ABSORPTION MEASUREMENTS
The experiments were carried out at two dose levels, 2 µl topical film (finite dose) or 75 µL "infinite" dose applied on a 0.64 cm² skin disc, The product was spread evenly over the entire surface using an applicator, The cells were covered with parafilm in the case of infinite dose to avoid evaporation of the vehicle, Phosphate-buffered saline at pH 7.4 was used as the receptor fluid, The flow rate was controlled at 5 ml/hr, The receptor fluids were sampled every half hour for six hours after dosing the skins, At the end of six hours each flow cell was washed with deionized distilled water three times to remove the excess formulation from the surface, In the case of the infinite-dose application, the excess emulsion was removed with a cotton swab before washing the skin, The skin was dismounted from the cell and carefully swabbed with a Kimwipe™, The stratum corneum was obtained from the skin disc using nine tape strippings OM Scotch MagicTM Tape), TEWL measurements indicated that the corneum barrier was completely removed by nine tape strippings, The epidermis was then scraped from the dermis using a scalpel, and the dermis was digested in the tissue solubilizer solution, The applicators, cotton swabs, Kimwipes™, cell washes, cell ring washes, wash pipets, tape strips, epidermis, dermis, and the receptor fluids were assayed using a Beckman scintillation counter after addition of 15 mL of scintillation cocktail in each vial.

Results and discussion

Signs and symptoms of toxicity:
not examined
Dermal irritation:
not examined
Absorption in different matrices:
Absorption in stratum corneum, epidermis, dermis, and receptor fluid was determined
Percutaneous absorptionopen allclose all
Dose:
2 µL
Parameter:
percentage
Absorption:
ca. 16 %
Remarks on result:
other: 6 h
Remarks:
Worst case conditions: low dose, o/w emulsion; Stratum Corneum
Dose:
2 µL
Parameter:
percentage
Absorption:
ca. 2 %
Remarks on result:
other: 6 h
Remarks:
Worst case conditions: low dose, o/w emulsion; Epidermis
Dose:
2 µL
Parameter:
percentage
Absorption:
ca. 4 %
Remarks on result:
other: 6 h
Remarks:
Worst case conditions: low dose, o/w emulsion; Dermis
Dose:
2 µL
Parameter:
percentage
Absorption:
ca. 0.5 %
Remarks on result:
other: 6 h
Remarks:
Worst case conditions: low dose, w/o emulsion; Receptor fluid

Applicant's summary and conclusion

Conclusions:
Skin absorption of lactic acid can be substantial, with up to 25 % being present in skin after prolonged exposure to low doses of high concentration formulations. This is expected and often wanted as lactic acid is a well known humectant (skin moisturizer) in cosmetic applications. The dermal uptake of lactic acid leading to systemic exposure is much lower; even under worst case conditions, the transdermal uptake is less than 1 % of the applied dose.
Executive summary:

The efficacy of lactic acid-containing products is linked to their ability to deliver it to specific skin strata, The penetration of L(+)-lactic acid to different skin layers of porcine skin from various emulsions was measured in vitro using flow-through diffusion cells, The effects of pH, propylene glycol, product structure, and mode of application on percutaneous absorption of lactic acid were investigated, The absorption of lactic acid from oil-in-water (o/w) emulsions was measured at pH 3.8 and 7.0. The effect of propylene glycol (5 %) as a penetration enhancer for lactic acid was also investigated from an o/w emulsion, The emulsion was applied either as a finite dose 2 µl topical film or as a 75 µl "infinite" dose occluded patch on a 0.64 cm² skin disc, A key finding was that the effects of changes in product compositions such as vehicle pH and propylene glycol on percutaneous absorption of lactic acid depended on the application mode, Increasing the aqueous phase acidity in an oil-in-water emulsion enhanced lactic acid delivery in the finite dose but not in the infinite-dose application, Finite-dose films were significantly more efficient than infinite dose for lactic acid delivery to tissue compartments, The penetration enhancer propylene glycol was more efficacious at the infinite-dose application. However, it also significantly enhanced lactic acid delivery to viable epidermis in the finite-dose application, Finally, the effect of emulsion phase structure on lactic acid uptake was investigated by comparing delivery from oil-in-water (o/w), water-in-oil (w/o), and water-in-oil-inwater (w/o/w) multiple emulsions with identical compositions, The total tissue delivery of lactic acid from the three emulsions was in the order of o/w > w/o/w > w/o.