Elimination and Accumulation of the Rodenticide Flocoumafen in Rats Following Repeated Oral Administration

Abstract

1. Following multiple oral administration of 14C-flocoumafen to rats at 0.02 and 0.1 mg/kg per week, appreciable cellular accumulation was seen in the liver. 2. Residues in the liver increased with dose throughout the duration of the experiment (14 weeks) at the low dose, but reached a plateau after 4 weeks at the high dose. The major component was unchanged flocoumafen together with a minor polar metabolite seen also in faeces. 3. The data suggest the presence in rat liver of a saturable high-affinity binding site for flocoumafen and a second binding site of lower affinity. 4. Lethal anticoagulant action occurs only when the binding sites have become saturated. 5. A range of haematological and clinical chemistry measurements failed to predict the onset of anticoagulant toxicity seen in the high dose treatment group. 6. Flocoumafen was not extensively metabolised; at the low dose, approximately 30% of the cumulative administered dose was eliminated in the faeces within 3 days of each dosing, mainly as unchanged rodenticide. At the high dose, this value ranged from 18% after the first dose to 59% after the tenth dose. 7. Two more polar metabolites and a lipophilic compound were minor products in faeces. Amounts of the polar products increased with cumulative dosage received. The urinary route of elimination was a very minor one (less than 1.6%) at both doses.

Pharmacokinetics of eight anticoagulant rodenticides in mice after single oral administration

“…, 1989a). Also, a high degree of body retention was found 7 days after repeated oral dosing, approximately half the dose was found in the liver of rats (Huckle et al. , 1988).…”

“…Anticoagulant rodenticides are categorized as either first‐generation anticoagulants like chlorophacinone, coumatetralyl and warfarin or as second‐generation anticoagulants such as brodifacoum, bromadiolone, difenacoum, difethialone and flocoumafen, which are more efficacious due to the greater affinity to binding sites in the liver and consequently greater accumulation and persistence (Parmar et al. , 1987; Huckle et al. , 1988).…”

Second generation anticoagulant rodenticides in tawny owls (Strix aluco) from Great Britain

“…SGARs have been in use in Britain since the mid-1970s. Like warfarin, they are derived from coumarin but are approximately 100-1000 times more acutely toxic and have relatively long biological half-lives in tissues such as the liver (Parmar et al, 1987;Huckle et al, 1988;Huckle et al, 1989;Eason et al, 1995). Both characteristic s enhance the potential for these compounds to cause secondary poisoning in predators.…”

A review of existing and potential New World and Australasian vertebrate pesticides with a rationale for linking use patterns to registration requirements

“…Their superior potency, and their associated greater potential to affect wildlife compared to first generation anticoagulants, is related to their greater affinity for vitamin K-epoxide reductase, and subsequent accumulation and persistence in the liver and kidneys after absorption (Huckle et al 1988;Parmar et al 1987). Only brodifacoum will be discussed.…”