The impossible made possible through the use of New Approach Methodologies: Dermal safety assessment of potential insect repellent or insecticidal active ingredients using a high-throughput approach to the <i>in vitro</i> Skin Irritation Test (OECD T

Toxicological profiling is a critical component of the regulatory process required to inform the hazard characterisation and labelling of chemicals, thus guiding their safe handling and use. Skin irritation is a key endpoint for regulatory registrations, traditionally assessed by using the Draize rabbit test, which was introduced in 1944. Advances in New Approach Methodologies (NAMs), and particularly those based on reconstructed skin models, have led to more human-relevant alternatives, as compared to the <i>in vivo</i> test method. Here, we report on some groundbreaking high-throughput adaptations to the validated <i>in vitro</i> Skin Irritation Test (SIT; OECD TG 439) with the commercially available EpiDerm™ reconstructed human epidermis (RhE) model from MatTek Corporation. These minor adaptations enabled the safety evaluation of over 3000 chemicals in just ten months. This was necessary due to the large number of chemicals that needed to be pre-screened for dermal safety, after the insect repellent or insecticidal activity was predicted and assessed. The data obtained in the SIT were then used to train a new Artificial Intelligence (AI) tool, designed to predict the skin irritation potential of large libraries of molecules within (but not limited to) the chemical space which the AI tool is based upon. Our work exemplifies the integration of AI with existing non-animal-based approaches, in order to further develop chemical safety assessment by taking advantage of this new technology.