Advancing New Approach Methodologies (NAMs) for Skin Sensitization Potency
What Is Skin Sensitization Potency and Why Does It Matter?
Skin sensitization is a key toxicological endpoint describing the development of allergic contact dermatitis following repeated exposure to a sensitizing substance. But not all sensitizers are equal: some trigger strong reactions at very low doses, while others require much higher concentrations to elicit a response. This variability is known as skin sensitization potency.
Understanding a substance’s skin sensitization potency is crucial for:
- Chemical and ingredient risk assessment
- UN GHS/CLP classification (1A or 1B)
- Setting safe exposure limits
- Guiding product formulation and innovation
For professionals in toxicology, regulatory affairs, and product development, having access to accurate potency data allows for informed decision-making early in the development pipeline—ultimately reducing time to market and ensuring regulatory compliance.
Testing Methods for Skin Sensitization Potency: An Overview
Animal-Based Methods
Historically, skin sensitization assessments relied heavily on in vivo animal tests, such as:
- Guinea Pig Maximization Test (GPMT)
- Buehler assay
- Local Lymph Node Assay (LLNA)
Of these, the LLNA has been the most widely used for determining skin sensitization potency, as it provides a quantitative endpoint—the EC3 value (the effective concentration that induces a stimulation index of 3). This value enables sub-categorization into GHS/CLP categories and has been shown to correlate relatively well with human potency data.
However, ethical concerns, evolving legislation, and the demand for human-relevant, non-animal alternatives have driven a shift away from animal-based testing.
Human Data and HRIPTs
Human Repeat Insult Patch Tests (HRIPTs) are confirmatory studies and can provide human potency data often described in terms of:
- No Observed Effect Level (NOEL)
- Lowest Observed Effect Level (LOEL)
However, HRIPTs have major limitations:
- These tests are generally conducted only when preclinical data show minimal or no risk.
- The tests are performed typically at one concentration and does not provide any quantitative potency information of the test chemical.
- Ethical concerns are significant—deliberate exposure to potentially sensitizing substances poses risks.
Still, when available, data from LLNAs and HRIPTs can help estimate No Expected Sensitization Induction Levels (NESILs), which serve as Points of Departure (PoDs) in risk assessment frameworks.
New Approach Methodologies (NAMs) Included in OECD TG
NAMs offer modern, non-animal testing strategies for toxicological evaluation, with increasing acceptance in regulatory frameworks. For skin sensitization, NAMs align with key events in the Adverse Outcome Pathway (AOP) and include:
- OECD TG 442C: Direct Peptide Reactivity Assay (DPRA) – Key Event 1
- OECD TG 442D: EpiSensA, KeratinoSens™ – Key Event 2
- OECD TG 442E: GARD®skin, h-CLAT – Key Event 3
While these methods are widely accepted for hazard identification and classification (e.g. sensitizer vs. non-sensitizer), they provide limited information on potency. This creates a gap—particularly when potency data is needed for risk assessment, ingredient selection, or regulatory classification into UN GHS/CLP subcategories (1A/1B).
GARD®skin Dose-Response: A NAM for Skin Sensitization Potency Assessment
To bridge the gap in non-animal skin sensitization potency testing, the standard protocol of GARD®skin (OECD 442E) has been adapted to enable skin sensitization potency assessment. The adaptation, known as GARD®skin Dose-Response, is currently under evaluation within the OECD Test Guideline Programme (TGP 4.106) and provides:
- Support for GHS/CLP sub-categorization (1A/1B)
- Prediction of LLNA EC3 values and human NESIL estimates
- A Point of Departure (PoD) for risk assessment
- Quantitative potency ranking of test substances
By estimating the threshold concentration at which a test substance induces a skin sensitization response, where lower concentrations indicate higher potency, GARD®skin Dose-Response provides quantitative potency information that address a critical gap in non-animal skin sensitization potency assessment. The results support the prediction of LLNA EC3 values, human skin sensitizing potency NOEL/NESIL estimates, and UN GHS/CLP classifications (1A or 1B), all with high statistical significance.
Scientific Publications and Case Studies
Several studies have explored the application of GARD®skin Dose-Response and support the growing confidence in the assay as a next-generation NAM for both qualitative and quantitative skin sensitization potency assessment:
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2025: peer-reviewed article in collaboration with RIFM and IFF
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2024: peer-reviewed article in collaboration with L’Oréal
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2024: peer-reviewed article in collaboration with RIFM & IFF
Regulatory Toxicology and Pharmacology. GARDskin dose-response assay and its application in conducting Quantitative Risk Assessment (QRA) for fragrance materials using a Next Generation Risk Assessment (NGRA) framework.
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2021: peer-reviewed article proof-of-concept study
Nature Scientific Reports. Quantitative assessment of sensitizing potency using a dose-response adaptation of GARDskin.
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2022: Poster in collaboration with Takasago
Presented at ASCCT. The use of the GARD®skin Dose-Response assay to assess skin sensitizing potency in developing novel fragrance ingredients
Conclusion
As regulatory expectations shift and industry demand for non-animal testing grows, the need for robust, human-relevant tools to assess skin sensitization potency becomes increasingly clear. While traditional animal methods have provided a foundation, NAMs like GARD®skin Dose-Response are advancing the field—offering quantitative insights and aligning better with human biology.
With continued validation and real-world application, GARD®skin Dose-Response stands out as a promising solution for industries seeking to enhance safety assessment while reducing reliance on animal testing.
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