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Applicability of New Approach Methodologies (NAMs) to Skin Sensitization: Insights...
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Applicability of New Approach Methodologies (NAMs) to Skin Sensitization: Insights from Industry and Regulatory Perspectives

A special issue of Toxics (ISSN 2305-6304). This special issue belongs to the section "Novel Methods in Toxicology Research".

Deadline for manuscript submissions: 30 June 2026 | Viewed by 7522

Special Issue Editors

Dr. Gertrude-Emilia Costin

E-Mail Website
Guest Editor
Institute for In Vitro Sciences, Inc., 30 W Watkins Mill Road #100, Gaithersburg, MD 20878, USA
Interests: in vitro testing; new approach methodologies; dermal safety; skin sensitization; mucosal irritation
Dr. Argel Islas-Robles

E-Mail Website
Guest Editor
Institute for In Vitro Sciences, Inc., 30 W Watkins Mill Road #100, Gaithersburg, MD 20878, USA
Interests: skin sensitization; dermal safety; medical devices; in vitro testing; new approach methodologies

Special Issue Information

Dear Colleagues,

Skin sensitization is a key endpoint within the safety assessment framework that needs to be addressed prior to launching finished products for consumer use. In recent years, through converging efforts of the scientific community from academic, industry and regulatory institutions, it became possible to address skin sensitization without the use of animal testing. The complex skin sensitization adverse outcome pathway can be investigated using equally sophisticated testing strategies based on new approach methodologies (NAMs) of various levels of complexity. Depending on the industry branch employing defined approaches based on NAMs to address skin sensitization, the data can be submitted for regulatory purposes or can be used to inform internal decisions.

This Special Issue is focused on how NAMs are practically used in regulatory and non-regulatory applications, addressing skin sensitization as a safety concern. We welcome original papers, review articles, short communications and regulatory position articles detailing the use of modern non-animal approaches for skin sensitization. We also encourage contributions on established and emerging methodologies derived from academic research, as well as perspectives on the current global regulatory landscape concerning the use of NAMs for skin sensitization. This Special Issue is open to receiving reports on chemicals, agrochemicals, medical and consumer devices, botanical extracts, cosmetic and personal care industry, etc., that facilitate a comparative analysis of the use and regulatory acceptance status of NAMs for skin sensitization within multiple industry sectors.

Dr. Gertrude-Emilia Costin
Dr. Argel Islas-Robles
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • skin sensitization
  • allergic contact dermatitis
  • new approach methodologies
  • regulatory testing
  • defined approaches
  • adverse outcome pathway
  • cosmetic industry
  • medical devices
  • mixtures
  • botanicals

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Published Papers (4 papers)

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Research

16 pages, 1271 KB  
Article
Validation of the Epi2SensA Method Using the EpiDerm™ Model for Skin Sensitization Testing Under OECD TG442D
by Christian Pellevoisin, Hajime Kojima, Sebastian Hoffmann, Takao Ashikaga, Timothy Landry, Celina Romero, Kalyani Guntur, Mitchell Klausner, Jennifer Stadnicki, Helge Gehrke, Robert Mills-Goodlet, Niki Panousi, Victor J. Johnson, Gary R. Burleson, Kazuto Narita, Shigehiro Tachibana, Kohichi Kojima, Jan Markus and Alexander Armento
Toxics 2026, 14(4), 295; https://doi.org/10.3390/toxics14040295 - 28 Mar 2026
Viewed by 1414
Abstract
The Epi2SensA method is a method similar to the validated EpiSensA assay for assessing the skin sensitization potential of chemicals. The Epi2SensA protocol includes adaptation (changes to exposure conditions and the controls) for using an alternative reconstructed human epidermis (RhE) model, the EpiDerm™ [...] Read more.
The Epi2SensA method is a method similar to the validated EpiSensA assay for assessing the skin sensitization potential of chemicals. The Epi2SensA protocol includes adaptation (changes to exposure conditions and the controls) for using an alternative reconstructed human epidermis (RhE) model, the EpiDerm™ model. The interlaboratory validation study evaluated the reliability and predictive capacity of Epi2SensA according to OECD Performance Standards. Four laboratories (Mattek, Now Part of Sartorius, Eurofins Munich, Burleson Research Technologies, Inc., and Food and Drug Safety Center) conducted blinded testing of 20 coded reference substances representing various chemical categories and sensitization potencies. Statistical analysis using modified acceptance criteria (a 60% cell viability threshold) and a modified prediction model (requiring at least two positive gene markers) demonstrated substantially improved performance compared to the original EpiSensA criteria. The between-laboratory reproducibility (BLR) was 85%, the average within-laboratory reproducibility (WLR) was 83.3%, and the average predictivity parameters were 88.1% for sensitivity, 88.9% for specificity, and 88.3% for accuracy. Epi2SensA achieved performance metrics comparable to the validated reference method (EpiSensA), supporting regulatory acceptance of the Epi2SensA assay using the EpiDerm™ model (Mattek Corporation, Now Part of Sartorius, Ashland, MA, USA) as an alternative RhE source for OECD TG 442D skin sensitization testing. Full article
(This article belongs to the Special Issue Applicability of New Approach Methodologies (NAMs) to Skin Sensitization: Insights from Industry and Regulatory Perspectives)
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18 pages, 1542 KB  
Article
RNA-Seq Can Be Used to Quantify Gene Expression Levels for Use in the GARDskin Assay
by Robin Gradin, Johan Andersson, Andy Forreryd and Henrik Johansson
Toxics 2026, 14(1), 9; https://doi.org/10.3390/toxics14010009 - 20 Dec 2025
Viewed by 846
Abstract
Non-animal methods for identification and characterization of skin sensitizers are continuously evolving, advancing towards more effective, accurate, and informational assays. The GARDskin assay is a scientifically and regulatory recognized assay for the assessment of skin sensitizers. It currently relies on targeted gene expression [...] Read more.
Non-animal methods for identification and characterization of skin sensitizers are continuously evolving, advancing towards more effective, accurate, and informational assays. The GARDskin assay is a scientifically and regulatory recognized assay for the assessment of skin sensitizers. It currently relies on targeted gene expression measurement to derive hazard classifications. With the progression of next generation sequencing technologies, whole transcriptome analysis provides an interesting alternative to the currently implemented targeted gene expression approach. RNA-seq was evaluated for its use in the GARDskin assay as a gene expression quantification method. Based on 24 paired samples acquired on both RNA-seq and the NanoString nCounter platform (the currently standard GARDskin acquisition method), gene expression profiles were found to be highly similar. Comparisons of treatment effects yielded a Spearman’s correlation coefficient of 0.95 and a Lin’s concordance correlation coefficient of 0.87. RNA-seq data was also used to classify the sensitizing hazard of 24 treatments using the standard GARDskin analysis pipeline. The classifications corresponded completely with references, rendering correct classifications for all treatments. In conclusion, it was found that the RNA-seq data strongly resembled NanoString nCounter data, and that it could be used to derive reliable hazard classifications in the GARDskin assay. Full article
(This article belongs to the Special Issue Applicability of New Approach Methodologies (NAMs) to Skin Sensitization: Insights from Industry and Regulatory Perspectives)
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25 pages, 863 KB  
Article
Comprehensive In Vitro Safety Assessment of Acorus calamus Rhizome Oil Using OECD-Compliant New Approach Methods: Classification as a GHS Category 1B Sensitiser and Category 2 Irritant
by Karishma R. Desai, Jay R. Ranade, Rajendra M. Nagane, Manish V. Patel, Abhay D. Deshpande, Clive S. Roper and Gireesh Babu Kantli
Toxics 2025, 13(12), 1006; https://doi.org/10.3390/toxics13121006 - 21 Nov 2025
Viewed by 2170
Abstract
Background: Acorus calamus (sweet flag) is widely used in traditional medicine, yet its dermal safety profile remains insufficiently defined under modern regulatory standards. Objective: To comprehensively evaluate the skin irritation, corrosion, and sensitisation potential of A. calamus rhizome oil using new [...] Read more.
Background: Acorus calamus (sweet flag) is widely used in traditional medicine, yet its dermal safety profile remains insufficiently defined under modern regulatory standards. Objective: To comprehensively evaluate the skin irritation, corrosion, and sensitisation potential of A. calamus rhizome oil using new approach methodologies’ (NAMs) test batteries under GLP conditions. Results: The A. calamus rhizome oil was predicted as a Category 2 skin irritant, non-corrosive and GHS Category 1B skin sensitiser. Chemical analysis revealed β-asarone as the major constituent (~40.75%). The reconstructed human epidermis models established reversible irritation without corrosion. Mechanistic concordance across the Direct Peptide Reactivity Assay, KeratinoSens™, and Human Cell Line Activation Test showed activation of the three key events of the skin sensitisation adverse outcome pathway. Using the “2-out-of-3” Defined Approach with the KE 3/1 sequential strategy allowed for hazard classification into GHS Category 1B. Quantitative risk modelling using SARA-ICE models and SCCS parameters yielded conservative safe-use concentrations ranging from 0.13 to 0.78% (w/w) for leave-on products and up to 7.46% (w/w) for rinse-off formulations. Conclusions: The combined evidence from the NAM-based assays showed that A. calamus rhizome oil is a moderate sensitiser and irritant but not corrosive, providing critical data for risk assessment and regulatory decision-making, which was previously unknown. The SARA-ICE PoD-derived safe-use concentrations provide guidance for cosmetic formulators to ensure consumer safety, particularly in leave-on applications such as face and hand creams, where sensitisation risk is highest. This study demonstrates the utility of NAMs for botanical safety assessment and regulatory decision-making. Full article
(This article belongs to the Special Issue Applicability of New Approach Methodologies (NAMs) to Skin Sensitization: Insights from Industry and Regulatory Perspectives)
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20 pages, 489 KB  
Article
Development of Preliminary Candidate Surface Guidelines for Air Force-Relevant Dermal Sensitizers Using New Approach Methodologies
by Andrew J. Keebaugh, Megan L. Steele, Argel Islas-Robles, Jakeb Phillips, Allison Hilberer, Kayla Cantrell, Yaroslav G. Chushak, David R. Mattie, Rebecca A. Clewell and Elaine A. Merrill
Toxics 2025, 13(8), 660; https://doi.org/10.3390/toxics13080660 - 2 Aug 2025
Viewed by 1236
Abstract
Allergic contact dermatitis (ACD) is an immunologic reaction to a dermal chemical exposure that, once triggered in an individual, will result in an allergic response following subsequent encounters with the allergen. Air Force epidemiological consultations have indicated that aircraft structural maintenance workers may [...] Read more.
Allergic contact dermatitis (ACD) is an immunologic reaction to a dermal chemical exposure that, once triggered in an individual, will result in an allergic response following subsequent encounters with the allergen. Air Force epidemiological consultations have indicated that aircraft structural maintenance workers may experience ACD at elevated rates compared to other occupations. We aimed to better understand the utility of non-animal testing methods in characterizing the sensitization potential of chemicals used during Air Force operations by evaluating the skin sensitization hazard of Air Force-relevant chemicals using new approach methodologies (NAMs) in a case study. We also evaluated the use of NAM data to develop preliminary candidate surface guidelines (PCSGs, maximum concentrations of chemicals on workplace surfaces to prevent induction of dermal sensitization) for chemicals identified as sensitizers. NAMs for assessing skin sensitization, including in silico models and experimental assays, were leveraged into an integrated approach to predict sensitization hazard for 19 chemicals. Local lymph node assay effective concentration values were predicted from NAM assay data via previously published quantitative models. The derived values were used to calculate PCSGs, which can be used to compare the presence of these chemicals on work surfaces to better understand the risk of Airmen developing ACD from occupational exposures. Full article
(This article belongs to the Special Issue Applicability of New Approach Methodologies (NAMs) to Skin Sensitization: Insights from Industry and Regulatory Perspectives)
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