Defined approaches to classify agrochemical formulations into EPA hazard categories developed using EpiOcular^TM reconstructed human corneal epithelium and bovine corneal opacity and permeability assays

Abstract

Many sectors have seen complete replacement of the in vivo rabbit eye test with reproducible and relevant in vitro and ex vivo methods to assess the eye corrosion/irritation potential of chemicals. However, the in vivo rabbit eye test remains the standard test used for agrochemical formulations in some countries. Therefore, two defined approaches (DAs) for assessing conventional agrochemical formulations were developed, using the EpiOcular^TM Eye Irritation Test (EIT) [Organisation for Economic Co-operation and Development (OECD) test guideline (TG) 492] and the Bovine Corneal Opacity and Permeability (OECD TG 437; BCOP) test with histopathology. Presented here are the results from testing 29 agrochemical formulations, which were evaluated against the United States Environmental Protection Agency’s (EPA) pesticide classification system, and assessed using orthogonal validation, rather than direct concordance analysis with the historical in vivo rabbit eye data. Scientific confidence was established by evaluating the methods and testing results using an established framework that considers fitness for purpose, human biological relevance, technical characterisation, data integrity and transparency, and independent review. The in vitro and ex vivo methods used in the DAs were demonstrated to be as or more fit for purpose, reliable and relevant than the in vivo rabbit eye test. Overall, there is high scientific confidence in the use of these DAs for assessing the eye corrosion/irritation potential of agrochemical formulations.

Keywords:

• Eye irritation
• regulatory
• human relevance
• in vitro
• Draize
• EPA
• agrochemicals
• EpiOcular
• BCOP
• scientific confidence

Acknowledgements

The authors thank staff from Canada’s Pest Management Regulatory Agency (PMRA), European Commission Joint Research Center, U.S. Consumer Product Safety Commission, and the U.S. Food and Drug Administration for their feedback on the study design. The authors also thank staff from PMRA, as well as Niladri Bhowmik, Neelima Verma, and Shelley DuTeaux, from the California Department of Pesticide Regulation, for their review of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The project was funded in part (including the funding of materials and a portion of the testing conducted by MatTek) with federal funds from the National Institute of Environmental Health Sciences, National Institute of Health, under contract no. HHSN273201500010C to Integrated Laboratory Systems LLC, an Inotiv company, and by National Institutes of Health Intramural Research Project ES103386-01, Research Operations Supporting the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods. PETA Science Consortium International e.V. and CropLife America provided funds that supported testing conducted by Institute for In Vitro Sciences.