European safety requirements allow for more in vitro studies and improved toxicity tests
The worldwide agrochemical market, which analysts suggest could exceed a healthy US$250 billion by 2020, is becoming a much more regulated industry in Europe. In recent years, there have been new guidance documents on endocrine disruptors and a genotoxicity assessment, and revised document on dermal absorption. In addition, many new guidance documents were published on birds, mammals, bees, amphibians, drift and soil degradation. In general, the backbone for all data requirements is given in Regulation 283/2013 and 284/2013, and based on these regulations together with the technical EU or EFSA guidance documents, the dossier of the active substance or plant protection product is in a continuous process of development. Lastly, many new guidance documents have been published in the last year around ecotoxicology and environmental fate and behavior.
Just as no new prescription of over-the-market drug can make it to market without convincing regulators that the recommended dosage is safe for consumers to use, agrochemicals would need to pass an indepth assessment in order to be sold commercially. Iris van de Gevel, Regulatory Affairs Manager at Charles River’s Den Bosch facility in the Netherlands and an expert on agrochemicals, says agrochemical developers need to consider the regulatory requirements for approval early in the process, and to design the right studies for further development of the active substance.
“For agrochemical active development, the data required for mammalian toxicology is used to draw conclusions on the safe use of agrochemicals for man, animal, and environment,” van de Gevel said. “Authorities and consumers are asking for safe agrochemicals. So we need to know how hazardous the active substance is for the environment and for human health.”
She says we also need to know what metabolites are formed in plants and animals, which metabolites and how much will reach the food chain and what the exposure to the active and relevant metabolites will be during and after application of the plant protection product. This includes the exposure of consumers, both adults and children, but also operators, workers, bystanders and residents.
“For example, a toxicological dossier must be created for each chemical under consideration without having to perform too many cost-prohibitive tests or using too many animal test subjects,” she says. “The EU’s goal is to obtain an accurate model of a chemical’s progress through the food chain, from crop to table and every stage in between, while leaving room for newer, better testing methods.”
Laboratories doing the toxicological tests on agrochemicals (Charles River being one of them) are finding both challenges and benefits with the new regulatory landscape. “In development of agrochemicals, the toxicology data processed in research and candidate selection move towards the data processed for pharmaceuticals,” van de Gevel said. “In the past there was a standard list of studies required, which was performed and submitted. Nowadays, there are more in vitro and tailor-made options in research and candidate selection to consider, which might speed up the process, reduce the number of animals used and increase the knowledge obtained from it.”
Moving towards more pharmaceutical-based testing regulations makes sense, since agrochemicals are by definition going to be used on biological organisms. Though the use of drugs and the use of pesticides may differ, the science behind their effect on biological pathways is similar.
These changes could also mean new work for Charles River. The company’s experience with both pharmaceutical testing and industry collaboration offers a unique perspective on changes in the regulatory toxicology such as these.
“Charles River can help industries with an integrated approach from early development to dossier preparation of agrochemicals,” van de Gevel said. “With all fields of expertise within Charles River, and with our in-depth knowledge of the regulatory process and understanding of how authorities interpret data, Charles River can help industries shorten time to market.”
Iris van de Gevel will join Mira Wenker, section head at DMPK Charles River in the Netherlands; and Sabitha Papineni, senior toxicologist at Dow AgroSciences for a March 11 discussion on new agrochemical regulations at the 2018 Society of Toxicology meeting in San Antonio. Check out our blogs in the ongoing series, Chemical Attractions, about scientific developments in the industrial and angrochemical industries,