EU-ToxRisk - Repeated dose toxicity (RDT)/ Developmental and reproductive toxicity (DART) – Mitochondrial toxicity. The case of the strobilurin fungicides

Keywords

REACH, read-across, RDT, DART, NAM, AOP

Objective

A large group of pesticides used in the agrochemical sector targets mitochondria functionality. The synthetic strobilurin fungicides, derived from the naturally occurring strobilurin A and B, belong to this group. Strobilurin fungicidal mode of action is known. The chemical binds to the quinol oxidation site of cytochrome b of complex III (CIII) of the mitochondria. The degree of in vivo inhibition of the mitochondrial respiratory system depends on the respiratory activity and thereby tissues like the brain can be more susceptible if exposed. Evidence of potential neurotoxicity was also shown in in vitro studies. The objective of this case is to characterise potential CIII-mediated neurotoxicity of target compound azoxystrobin by NAM-enhanced read-across. The objective is to answer the question: ‘Can the absence of a neurotoxic potential of azoxystrobin-mediated inhibition of complex III of mitochondria be predicted by toxicodynamic and toxicokinetic NAM data?’

Testing Strategy

Source compounds selected in this case study are other strobilurin fungicides. Existing regulatory in vivo data was collected for the source and target compounds with a focus on ADME, neurotoxicity, as well as target organ toxicity data. Source compounds showed no signs of neurotoxicity, neither in neurotoxicity studies nor in other RDT studies. Overall, based on the generated data on kinetics and effect data, there is no evidence for a stronger neurotoxic potential of azoxystrobin mediated by a CIII inhibitory mode of action as compared to the source compounds. Since source compounds did not elicit neurotoxicity in vivo, we concluded that also the target compound azoxystrobin is not a neurotoxicant.

Publications

Wink et al. 2018 [link]; Hiemstra et al. 2019 [link]; Delp et al. 2018 [link]; Terron et al. 2019 [link]; van der Stel W et al. 2020 [link]; Fisher et al. 2017 [link]; Delp et al. 2019 [link]; Hemmerich et al. 2020 [link]; Troger et al. 2020 [link]; Delp et al. 2019 [link]; Delp et al. 2018 [link]; Delp et al. 2021 [link]; Hemmerich et al. 2020 [link]; van der Stel et al. 2021 [link]; van der Stel et al. 2020 [link]; Troger et al. et al. 2020 [link]; Vrijenhoek et al. 2022 [link]; Escher et al. 2019 [link]; Rovida et al. 2021 [link]