Permethrin in companion animals: Mechanistic neurotoxicity, dermal pharmacokinetics, and secondary exposure pathways

Permethrin remains one of the most widely used pyrethroids in companion animal ectoparasite control, yet its toxicological profile reflects a complex interplay between mechanism of action, dermal delivery, formulation behaviour and secondary exposure. Its primary activity is mediated through state–dependent modification of voltage–gated sodium channels, resulting in delayed channel deactivation/inactivation, repetitive firing and excitatory neurotoxicity. While this mechanism underpins insecticidal and repellent efficacy, it also explains adverse effects in non–target species. Following topical application, permethrin preferentially partitions into the lipid–rich stratum corneum and hair coat, forming a persistent cutaneous reservoir. This reservoir supports sustained ectoparasiticidal activity while limiting systemic absorption under labelled conditions, but it also maintains surface residues that may be transferred through contact, grooming, bathing or water exposure. Comparative toxicology reveals a marked divergence between relative canine tolerance and pronounced feline susceptibility. This difference should not be reduced to impaired glucuronidation alone, but rather interpreted as a dose–formulation–species interaction involving high–concentration canine products, low feline body weight, grooming–mediated oral uptake and metabolic constraints. Secondary exposure is discussed using a cautious, evidence–weighted framework. Companion animal topical products are biologically plausible contributors to domestic and environmental residues, but permethrin–specific source apportionment remains limited. This review integrates mechanistic toxicology, dermal pharmacokinetics and comparative susceptibility to provide a formulation–centred framework for interpreting non–target risk associated with veterinary permethrin use.