Roadmap Implementation: Skin and Eye Irritation

The ODIWG published a manuscript identifying U.S. agency information requirements, needs, and decision contexts for skin and eye irritation testing (Choksi et al. 2018).

ICCVAM and NICEATM facilitate public-private partnerships to share data and information on the development and evaluation of alternative methods to assess skin and eye irritation hazards. These partnerships include companies that develop products that are tested for skin and eye irritation, as these companies have experience and data that can be applied to alternative method development, evaluation, and use.

• 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.
• NICEATM, EPA, and CropLife America companies established a forum to share paired data sets for agrochemical formulations tested both in vivo and in vitro. These data sets were used to assess the utility of in vitro methods compared to in vivo rabbit eye tests for agrochemical formulations.
• EPA is supporting the Institute for In Vitro Sciences in a collaboration with antimicrobial cleaning products manufacturers, CropLife America, and the PETA Science Consortium International e.V. to optimize a protocol using a reconstructed human epidermal model to evaluate the skin irritation potential of agrochemical formulations.

Recent and ongoing NICEATM and ICCVAM efforts to identify and evaluate non-animal alternative approaches to skin and eye irritation testing include:

• Participation in a validation study of the Vitrigel test method, an in vitro method to identify eye irritants, coordinated by the Japanese Center for Evaluation of Alternative Methods (adopted in 2019 as OECD Test Guideline 494).
• A NICEATM-coordinated validation study of the OptiSafe test method, an in vitro method to identify eye irritants (Choksi et al. 2020). The OptiSafe test method is under consideration by OECD for addition to Test Guideline 496, which describes in vitro methods to identify potential eye irritants.
• NICEATM-led development of computational models to predict eye irritation potential from chemical structure (Sedykh et al. 2022). These models may be used in screening chemicals and/or inclusion in a tiered-testing strategy for eye irritation potential. 
• NICEATM contributions to a review article (Clippinger et al. 2021) describing available non-animal test methods and their relevance to eye anatomy and mechanisms of eye irritation in humans. Combinations of the reviewed methods may be used in development of human-relevant integrated testing approaches.

NICEATM acquired and curated high-quality reference data for skin and eye irritation data, including data on pesticide formulations from EPA registration submissions. These data will be used both to evaluate the inherent variability of in vivo data and for ongoing and future evaluations of non-animal approaches. A NICEATM analysis of variability in in vivo rabbit skin irritation data was described in Rooney et al. (2021), which noted that such variability should be considered when evaluating nonanimal alternative methods as potential replacements. Data from this analysis are publicly available via the NICEATM Integrated Chemical Environment (ICE). NICEATM continues to accept data from stakeholder groups and literature sources. 

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

NICEATM reviews the published literature to identify promising defined approaches to testing and assessment for skin and eye irritation testing, and welcomes nominations for evaluation from stakeholders. Promising defined approaches will be evaluated for their regulatory applicability by characterizing their performance against external test sets of chemicals (i.e., chemicals that were not used to develop the defined approaches) of interest to the regulatory programs of ICCVAM agencies.

NICEATM, EPA, and the PETA Science Consortium International e.V. collaborated with CropLife America to develop in vitro defined approaches for classification of eye irritation potential of agrochemical formulations. A three-phase, multi-laboratory evaluation assessed the applicability of different in vitro eye irritation test methods to this product class. A report published in 2021 describes generation and evaluation of data to support Phases 1 and 2 of the study. A presentation at the 12th World Congress on Alternatives and Animal Use in the Life Sciences (Daniel et al., Session S402, "Unlocking a New NAM-Based Paradigm: Transforming the Evaluation of Agrochemicals") describes outcomes of the study and an evaluation of the potential usefulness of defined approaches for classification of agrochemical formulations under GHS. A subsequent publication (van der Zalm et al. 2023) describes potential usefulness of defined approaches for classification of agrochemical formulations based under the EPA system.

A common theme that has emerged from past NICEATM workshops is the need for training opportunities to inform industry and regulatory scientists 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.