Evaluation of new approach methodologies (NAMs) to assess acute and subchronic inhalation toxicity

Evaluation of inhalation toxicity is a frequent requirement in the regulation of agrochemicals. Traditionally, animal models have been used for assessing inhalation acute and subchronic toxicity of substances including agrochemicals. This testing provides information about potential risk and enables informed decisions regarding safety assessment. However, differences between species along with ethical issues raised with animal testing, have greatly promoted the use of human-relevant in vitro methods. Therefore, health effects due to inhalation of substances such as air pollutants, consumer products and agrochemicals are of considerable interest to many and form the basis for the use and development of new approach methodologies (NAMs). New approach methodologies include in vitro and in silico methods, and waivers, using a weight of evidence approach to fulfill data requirements for regulatory acceptance. Syngenta is committed to reducing the use of animals in our testing paradigms and increasing the applicability of NAMs to human health risk assessment. Currently, for acute toxicity there is no non-animal method for assessing toxicity via inhalation that is accepted by regulatory authorities. A tiered testing approach has been used in Syngenta to assess the need of generating such data. The tiered testing approach includes waiving and bridging principles. In case no criteria are met, and there is a regulatory need to generate the data, an attempt should be made to predict the outcome by using read-across and acute toxicity estimate (ATE) calculations in order to minimize the number of animals used. For subchronic toxicity, the implementation of NAMs such as the in vitro MucilAir™ assay, computational fluid dynamics (CFD) and benchmark dose modeling, are currently utilized for hazard screening purposes during the early stages of agrochemical development and as part of the registration data package for the fungicide, Chlorothalonil. This approach for the determination of point of departure for use in safety assessment is under review by the US Environmental Protection Agency.