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Roadmap Implementation: Skin Sensitization

Prior to marketing, manufacturers test pesticides, cosmetics, household cleaners, and other chemical products to identify skin sensitizers, or substances with the ability to cause allergic contact dermatitis. There is a widespread international need for non-animal test methods that can identify these substances.

The ICCVAM Skin Sensitization Workgroup (SSWG) coordinated the implementation of the roadmap goals for skin sensitization testing. The workgroup had members from seven ICCVAM agencies and representation from ICATM.

Definition of Testing Needs

The SSWG and representatives from other U.S. federal agencies published a scoping document to identify U.S. agency information requirements, needs, and decision contexts for skin sensitization testing (Strickland et al. 2018). A white paper characterizing international regulatory requirements for skin sensitization testing (Daniel et al. 2018) was developed through interactions between ICCVAM and NICEATM and their international counterparts.

Identification of Available Alternative Tests and Computer Models

ICCVAM and NICEATM facilitate public-private partnerships to share data and information on the development and evaluation of alternative methods for skin sensitization assessment. For example, EPA established a stakeholder group to discuss the development, evaluation, and implementation of alternatives for the “six-pack” of acute toxicity tests required for pesticide registration. Activities within this group have informed EPA efforts toward adoption of alternative methods.

To provide high-quality data to support the development of new testing approaches, NICEATM is working with stakeholders to expand its database of in vivo and in vitro skin sensitization testing data. Contact NICEATM if your organization has skin sensitization data that it would like to share.

  • NICEATM compiled high-quality reference data for local lymph node assay (LLNA) and human skin sensitization outcomes from the published literature and data submissions. NICEATM has also compiled data for in chemico and in vitro methods from the public literature. These data sets are available through the NICEATM Integrated Chemical Environment (ICE).
  • EPA provided NICEATM with data submitted to support Federal Insecticide, Fungicide, and Rodenticide Act registrations of pesticide formulations and active ingredients. These data, which include LLNA data, are also available via ICE.
  • NTP tested approximately 200 chemicals of interest to ICCVAM agencies in three in chemico/in vitro assays: the direct peptide reactivity assay, the KeratinoSens assay, and the human cell line activation test. Testing was completed in 2020 and data will be made available via ICE.
  • NICEATM is working with the German Federal Institute for Risk Assessment (BfR) to compile and curate a database of human predictive patch test data. These will serve as reference data for assessing performance of defined approaches and facilitate analysis of reliability and variability of human data. A presentation at the 2020 ASCCT annual meeting (Strickland et al.) described the data set. 
  • NICEATM and ICCVAM are currently identifying potential companies and organizations for further skin sensitization data requests.

ICCVAM activities to support the regulatory acceptance and facilitate the use of non-animal approaches include:

  • Collaboration with Cosmetics Europe to evaluate the performance of defined approaches (described in "Developing IATA and Defined Approaches" below).
  • Validation of the electrophilic allergen screening assay.
  • Ongoing review of published literature by NICEATM to identify promising defined approaches: nominations are welcomed from stakeholders.
  • Serving on a peer review panel for an OECD-coordinated study evaluating the use of the kinetic direct peptide reactivity assay for classifying substances for skin sensitization potency.
  • Submission of comments on OECD test guidelines for the direct peptide reactivity assay, the KeratinoSens assay, and the human cell line activation test.
  • Serving on the OECD expert group for skin sensitization since 2015.
  • Leading the OECD project to establish a test guideline for defined approaches to skin sensitization (described in “Developing IATA and Defined Approaches” below).
Developing IATA and Defined Approaches

NICEATM and ICCVAM agencies are considering a number of different approaches to reduce animal use for required testing. These include the use of integrated approaches to testing and assessment (IATA) and defined approaches to enable prediction of skin sensitization hazard through high-throughput screening assays and in silico models.

NICEATM and Cosmetics Europe collaborated to evaluate multiple defined approaches for skin sensitization safety assessment that had been submitted to OECD. The effort produced a set of human, animal, and non-animal test data for 128 chemicals (Hoffman et al. 2018) and an analysis of multiple defined approaches for skin sensitization assessment of cosmetics ingredients (Kleinstreuer et al. 2018)

In April 2018, EPA released a draft Science Policy to reduce animal use through defined approaches to identify potential skin sensitizers. Under this policy, EPA's Office of Pesticide Products and Office of Pollution Prevention and Toxics will accept submissions for single chemicals that can be tested using non-animal methods used in two specific defined approaches. The draft policy is the result of the Cosmetics Europe collaboration described above as well as other collaborations among ICCVAM, NICEATM, the European Union Reference Laboratory for Alternatives to Animal Testing, and Health Canada’s Pest Management Regulatory Agency.

ICCVAM coordinates evaluation of skin sensitization test methods in part through its participation in ICATM. SSWG members participated in an October 2016 ICATM workshop on skin sensitization. The work products from the workshop included:

  • A white paper (Daniel et al. 2018) characterizing international regulatory requirements for skin sensitization testing.
  • A position paper (Casati et al. 2017) summarizing workshop outcomes and ICATM recommendations.
  • A proposal to OECD for development of a test guideline for defined approaches to testing and assessment for skin sensitization (added to the OECD workplan in April 2017).

Material developed for the test guideline will be discussed at a workshop organized by NICEATM and ICCVAM in partnership with stakeholder groups. This workshop, to be planned following the release of the test guideline, will cover best practices for implementation of defined approaches to skin sensitization testing and assessment.

NICEATM and ICCVAM actively participate in the OECD Test Guidelines Programme, which supports the development of IATA and defined approaches. Recent activities include:

  • Serving on the drafting group for Guidance Document 255, Guidance Document on the Reporting of Defined Approaches to be Used within Integrated Approaches to Testing and Assessment, and Guidance Document 256, Guidance Document on the Reporting of Defined Approaches and Individual Information Sources to be Used within Integrated Approaches to Testing and Assessment (IATA) for Skin Sensitisation.
  • Drafting the test guideline for defined approaches to testing and assessment for skin sensitization.

ICCVAM evaluations (Kleinstreuer et al. 2018; Strickland et al. 2016; Strickland et al. 2017; Zang et al. 2017) indicate that most defined approaches evaluated so far perform better than standard animal methods in predicting human skin sensitization hazard and potency.

Addressing Regulatory and Other Challenges

NTP has completed testing substances of regulatory interest to ICCVAM agencies (including mixtures) using the in vitro direct peptide reactivity assay, KeratinoSens assay, and human cell line activation test. Reports on this testing are being prepared for publication in 2021. Defined approaches that use these test methods will be evaluated for predictive performance across this chemical set and for applicability to the different regulatory programs.

NICEATM and ICCVAM played key roles in the development of draft human health and ecological risk assessments issued by EPA in 2020. These risk assessments evaluate dermal sensitization potential for a group of antimicrobial chemicals known as isothiazolinones. In a May 2020 announcement, EPA requested comment on the use of an in vitro and artificial neural network-based defined approach to determine points of departure used in the isothiazolinone draft risk assessments instead of using laboratory animal data.  NICEATM analyzed the in vitro data and ran the artificial neural network-based defined approach to provide quantitative potency predictions used to determine points of departure. The ICCVAM Skin Sensitization Expert Group reviewed the NTP testing report and the NICEATM analyses before data were provided to EPA for development of the risk assessments. The use of in vitro and in chemico assays and neural network-based defined approaches is the first use of such information in regulatory risk assessment.

A common theme that has emerged from past NICEATM workshops is the need for training opportunities to inform industry and regulatory staff about the use and interpretation of in vitro and in silico data and defined approaches. Thus, efforts to facilitate regulatory acceptance and use of defined approaches and other alternative methods will include the development of training materials and technical support to assist agencies in issuing guidance.