EFSA Pilot Project on New Approach Methodologies (NAMs) for Tebufenpyrad Risk Assessment. Part 2. Hazard characterisation and identification of the Reference Point

This Project was performed to provide an in vitro Point of Departure (PoD) for Adverse Outcome Pathway (AOP)-informed Integrated Approach Testing and Assessment (IATA), concerning a potential risk parkinsonian motor deficits after long-term exposure Tebufenpyrad. The AOP considered AOP:3. Assays were Key Event (KE) 1, KE2 (mitochondrial dysfunction) KE4 the AOP, based on use human dopaminergic neurons (LUHMES cells). KE1 (inhibition complex I mitochondrial respiratory chain) equivalent molecular initiating event (MIE). (dopaminergic cell degeneration) as alternative AO (target degeneration). All necessary linear steps (i.e. KE2,3,4) investigated by experimental test methods. three major objectives were: (i) generation PoD data from each assay; (ii) evaluation optimization consistency these data; (iii) selection be used further assessment. During phase, assay conditions that reflect brain metabolism (MitoMet conditions) implemented, degeneration neurites most relevant neuropathological endpoint. With this setting, ranged 6 nM 45 nM. put emphasis more chronic effects closest AO. Thus assay, measuring neurite under MitoMet chosen, 8 value has confidence interval about one log10-fold change lowest highest estimate (range: 3 – 30 nM), variations we observed. Some biokinetics measurements undertaken help estimating concentrations. These had high uncertainty model assumptions. Based assumptions consider realistic robust, suggest cell/tissue (brain) concentration 8-40 associated with onset toxicity