Cosmetic or Drug? What Skin Permeation Testing Can Support

Two creams can sit side by side on a drugstore shelf with nearly identical base formulas, one promising to soften dry skin and the other to relieve eczema itch. Under US law, that difference in wording places them in separate regulatory worlds. Label and marketing collateral claims, not the ingredients alone, decide whether a product is a cosmetic or a drug, and that decision shapes the evidence regulators expect to see. Skin permeation testing works on both types of products.

For a cosmetic, skin permeation testing helps estimate how much of an ingredient crosses the skin, a key input to any safety assessment. For a topical drug, the same Franz diffusion cells help show whether a generic product delivers its active ingredient the way the reference product does. The sections below trace how that testing serves each category, from cosmetics through OTC monograph drugs to prescription and generic topicals, including products that FDA regulates as both.

Key Takeaways

• Intended use sets the category. The FDA classifies a topical product as a cosmetic, a drug, or both based on its claims, consumer perception, and ingredients.
• Eczema relief is a drug claim. OTC Monograph M016 permits an eczema itch-relief indication only for colloidal oatmeal skin protectants.
• FDA’s IVPT and IVRT guidances remain drafts. Both date to October 2022, while four related topical and bioequivalence guidances reached final status in 2026.
• MoCRA covers safety, not efficacy. Cosmetic safety substantiation records are mandatory, and advertising claims fall under FTC substantiation standards.
• Model choice follows purpose. Excised human skin anchors drug IVPT, while porcine skin, Skin-PAMPA, and reconstructed epidermis serve screening and safety roles.

What Is In Vitro Skin Permeation Testing?

Skin permeation testing measures how an active ingredient in a topical product moves into and through skin, or a skin substitute, under controlled laboratory conditions. A Franz cell is a vertical diffusion cell: A membrane separates a donor compartment holding the product from a receptor compartment that analysts sample over time. IVRT measures how fast an active ingredient leaves the formulation. IVPT measures how fast and how much of it crosses the skin.

A 2024 review in the European Journal of Pharmaceutical Sciences traces the technique to work by Franz in the 1970s.

In Vitro Release Testing (IVRT)

The FDA’s IVRT draft guidance describes IVRT as a way to assess the rate of drug release from a topical product. Once validated, an IVRT method can also support quality control and post-approval manufacturing changes.

IVRT uses a synthetic membrane, often a filtration membrane, rather than skin. The draft points to equipment described in USP General Chapter <1724>, including vertical diffusion cells and immersion cells. It cites a membrane surface temperature of 32°C ± 1°C for skin products and 37°C ± 1°C for mucosal products.

In Vitro Permeation Testing (IVPT)

The FDA’s IVPT draft guidance describes IVPT as a way to assess the rate and the extent to which a drug becomes available at or near a site of action in the skin. The draft recommends excised human skin as the membrane. It calls for a barrier integrity test on each skin section.

The draft defines two endpoints. Flux (J) captures the rate of permeation, in units such as ng/cm²/hr. Total cumulative amount (AMT) captures the extent. Flux profiles resemble plasma pharmacokinetic curves. The FDA notes that IVPT characterizes absorption only, not distribution, metabolism, or excretion.

Several design figures in the draft draw frequent attention:

• a minimum of eight nonzero sampling time points across the study, for example over 48 hours.
• a pilot study using 4–6 skin donors, with at least four replicate skin sections per donor per treatment group.
• skin dermatomed to a relatively consistent thickness across donors.

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Where Does FDA Draw the Line Between Cosmetic and Drug Claims?

Under US law, a product’s intended use determines whether it is a cosmetic, a drug, or both. An eczema relief claim is a drug claim. A moisturizing claim is a cosmetic claim.

The FDA’s explainer “Is It a Cosmetic, a Drug, or Both?” quotes the statutory definitions. The FD&C Act defines cosmetics by purposes such as cleansing, beautifying, and altering the appearance. It defines drugs as articles intended to diagnose, cure, mitigate, treat, or prevent disease, or to affect the body’s structure or function.

The FDA lists three ways it establishes intended use:

• claims in labeling, advertising, websites, and other promotional materials.
• consumer perception, based on the product’s reputation.
• ingredients with a well-known therapeutic use, such as fluoride in toothpaste.

A product with both uses must meet both sets of requirements: The FDA cites an antidandruff shampoo as an example. The agency also notes that the term “cosmeceutical” has no meaning under the law.

The OTC Monograph Route for Eczema Claims

Nonprescription eczema claims have a defined path. OTC Monograph M016, the skin protectant final order, became effective under the CARES Act on March 27, 2020. It names eczema as a permitted use only for colloidal oatmeal products, alone or combined with mineral oil. The monograph sets a colloidal oatmeal minimum of 0.007%, or 0.003% in combination with mineral oil. M016 indication reads that the product temporarily protects and helps relieve minor skin irritation and itching due to eczema, among other listed conditions. Products that conform to M016 need no new drug application (NDA). As drugs, they still fall under drug labeling and GMP rules.

Claims outside the monograph’s scope, such as treating moderate atopic dermatitis, follow the NDA pathway. A generic version of an approved topical drug follows the abbreviated new drug application (ANDA) pathway. Permeation testing plays its largest regulatory role there.

How Do MoCRA and FTC Rules Apply to Cosmetic Claims?

Cosmetics follow a separate framework from drugs, and two agencies share oversight of their claims. The FDA enforces MoCRA’s safety requirements. The FTC polices advertising claims.

Under MoCRA, a responsible person must ensure and maintain records supporting adequate safety substantiation for each cosmetic product. The FDA states that neither the law nor its regulations require specific tests. It does expect the supporting data to come from scientifically robust methods. In the EU, the SCCS Notes of Guidance build dermal absorption into cosmetic ingredient safety evaluation.

MoCRA’s substantiation duty addresses safety and does not set an efficacy standard for marketing claims. The FTC’s December 2022 Health Products Compliance Guidance applies to health-related claims for products that include cosmetics and OTC drugs. It calls for competent and reliable scientific evidence and states that health-related benefit claims generally require randomized, controlled human clinical trials. The guidance describes itself as business guidance without the force of law.

Contract Laboratory covers the broader testing picture in A Laboratory Guide to Cosmetics Formulation Testing and its overview of claims substantiation testing.

Where FDA, EMA, and OECD Guidance Stands

Drug and cosmetic permeation work draws on different documents: The FDA and EMA guidance governs topical drug equivalence. OECD and SCCS documents govern dermal absorption for chemical and cosmetic ingredient safety.

Current Status of FDA’s Topical Framework

The FDA has finalized most of its topical generic framework, while its two core in vitro guidances, on IVPT and IVRT, remain in draft. Europe’s equivalent guideline has applied since April 2025.

Key Documents at a Glance

What Does OECD TG 428 Measure?

TG 428 accepts skin from human or animal sources, viable or non-viable. Both static and flow-through diffusion cells qualify. The guideline describes doses of 1–5 mg/cm² for solids and up to 10 µL/cm² for liquids. Viable skin is preferred, though nonviable skin is acceptable.

TG 428 serves regulatory dermal absorption work outside the drug space. A 2023 industry perspective in Regulatory Toxicology and Pharmacology notes that pesticide dermal absorption studies are mainly conducted under TG 428. Health Canada’s 2026 science policy note on in vitro dermal absorption cites TG 428 and the 2022 second edition of Guidance Notes 156.

How Drug IVPT and TG 428 Differ

The FDA’s IVPT draft compares a test product against a reference standard to support bioequivalence. TG 428 quantifies how much of a chemical crosses skin for exposure assessment. The two share hardware but differ in dosing, endpoints, and statistics: The FDA’s draft defines flux and cumulative amount as its endpoints, while TG 428 reports the distribution of the test substance across the test system over time.

Which Skin Model Fits Which Purpose?

Excised human skin remains the reference membrane for drug IVPT. Porcine skin, Skin-PAMPA, and reconstructed epidermis trade some fidelity for supply, cost, or throughput.

1. Human and Porcine Skin

The FDA’s IVPT draft recommends excised human skin for bioequivalence studies. Porcine skin often fills earlier development roles. A 2025 Molecular Pharmaceutics study found equivalent permeation results across marketed formulations in both porcine and human skin. Its authors concluded that porcine skin offers an alternative for ex vivo permeation profiling.

The two tissues do not always agree. A 2017 UCL doctoral thesis reported ibuprofen permeation far lower in human skin than in porcine skin. Caffeine permeation in Skin-PAMPA came closer to human skin values.

2. Skin-PAMPA

Skin-PAMPA adapts the parallel artificial membrane permeability assay to skin. A 2012 European Journal of Pharmaceutical Sciences paper introduced the model, built on synthetic certramides that mimic stratum corneum ceramides. The authors described it as a quick, cost-effective research tool for pharmaceutical and cosmetic work.

Nanocarrier work uses Skin-PAMPA as well. A Drug Delivery Letters study reported higher resveratrol permeability from liposomes and nanostructured lipid carriers. Ethosomes belong to the same family of lipid vesicle carriers.

3. Reconstructed Human Epidermis

RhE models anchor nonanimal irritation and corrosion testing under OECD TG 439 and TG 431. Researchers have also tested them as permeation membranes. A 2022 Pharmaceutics study used RhE in a modified IVPT for clotrimazole creams and observed higher permeability in RhE than in human skin. Its authors proposed comparing permeation profiles between products rather than drawing absolute conclusions.

RhE irritation testing is a staple of cosmetic toxicology testing. For hypoallergenic claims, clinical human repeat insult patch testing complements in vitro irritation data. Disease-state models add an eczema-specific option. A 2017 Frontiers in Medicine review describes RhE and skin equivalents treated with cytokines overexpressed in atopic dermatitis, or with silenced barrier genes.

Claim Tiers and the Evidence Each Draws On

The same in vitro methods serve different purposes at each regulatory tier. The table summarizes what the cited sources describe for US products.

Generic Topicals and EU Equivalence

For generic topicals, product-specific guidances set the study package. The FDA’s penciclovir cream guidance, revised in October 2022, lists Q3 characterization, an IVRT study, and an IVPT study. The doxepin hydrochloride cream guidance from the FDA specifies an unoccluded finite-dose IVPT design. Topical corticosteroids follow the vasoconstrictor approach in the July 2026 final guidance.

In the EU, the EMA cutaneous products guideline describes a stepwise approach that can establish equivalence without clinical endpoint studies.

What a Permeation Study Package Includes

The guidance documents define what a credible permeation study documents. The follwoing five elements recur.

1. Quality system: Regulatory dermal absorption studies often run under Good Laboratory Practice (GLP). The OECD Principles of GLP apply to nonclinical safety testing of items in pharmaceutical, pesticide, and cosmetic products, among others. Under OECD’s Mutual Acceptance of Data system, data generated under OECD Test Guidelines and GLP in one adhering country must be accepted for assessment in the others.
2. Skin sourcing: The FDA’s IVPT draft gives cadaver skin from the posterior torso as an example source. An FDA presentation from its 2022 topical generics workshop states that donor age, race, and sex be reported for all IVPT studies. OECD TG 428 accepts human or animal skin.
3. Barrier integrity: The IVPT draft describes three test types: transepidermal water loss, tritiated water permeation, and electrical resistance.
4. Analytical validation: The draft’s worked flux example uses a receptor concentration of 2.0 ng/mL. The IVPT draft calls for a validated analytical method and references FDA’s 2018 Bioanalytical Method Validation guidance. It also calls for qualifying the receptor solution for drug solubility and stability.
5. Mass balance: TG 428 and OECD Guidance Document 28 require mean recovery of 90–110% for nonvolatile test chemicals, according to a Regulatory Toxicology and Pharmacology analysis of the EFSA database. The 2024 review notes that many published studies report permeation alone. They omit the amount of active left on and in the skin at study end.

Matching the Study to the Claim

A product’s claims set its regulatory tier, and the tier shapes which skin data carries weight. A cosmetic moisturizer, an M016 skin protectant, and a generic corticosteroid cream can all use Franz cells, but for different questions and under different documents.

Contract Laboratory connects cosmetic, OTC, and topical drug developers with laboratories that offer IVRT, IVPT, OECD TG 428 dermal absorption, Skin-PAMPA, and reconstructed epidermis testing. Our roundup of top cosmetic testing labs and CROs profiles additional providers, and the network also covers related toxicology and biocompatibility testing and pharmacology and drug development services.

Connect on Contract Laboratory

• Submit a Request: Developers can post IVRT, IVPT, dermal absorption, or skin model testing needs and receive proposals from qualified laboratories.
• View Requests: Laboratories and CROs can browse open testing requests, including cosmetic and topical product projects.
• Register Your Lab: Laboratories offering Franz cell, skin permeation, or reconstructed epidermis services can list their capabilities on the network.

This article was created with the assistance of Generative AI and has undergone editorial review before publishing.

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