Oxadiazine Toxicosis in Animals

The oxadiazine class of insecticides includes indoxacarb. Chemically, indoxacarb is [(S)-methyl 7-chloro-2,5-dihydro-2-[[(methoxycarbonyl) [4-trifluoromethoxy) phenyl]amino]-carbonyl]indeno[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylate]. Indoxacarb exists as two enantiomers (S and R) but only the S enantiomer exerts insecticidal activity.

Structure of indoxacarb

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Courtesy of Dr. Ramesh Gupta and Dr. Robin Doss.

Indoxacarb has been approved for use against fleas on dogs and cats. The fleas on animals ingest the indoxacarb, and through bioactivation the metabolite is formed, which is highly toxic to insects. Indoxacarb exerts its insecticidal action at voltage-dependent sodium channels by blocking the flow of sodium ions into the nerve cells. The parasites become paralyzed and unable to feed.

The acute oral LD₅₀ for indoxacarb is 1,730 mg/kg in male rats and 268 mg/kg in female rats. The NOAEL for a 90-day dog study was 3 mg/kg/d, whereas that for a 1-year study was 1.1 mg/kg/d. The acute dermal LD₅₀ for indoxacarb in rats is >5,000 mg/kg. Following oral ingestion, indoxacarb is rapidly absorbed, metabolized, and excreted in the urine and feces. Females metabolize indoxacarb more slowly than males, and as a result, females produce almost 10 times the amount of the toxic metabolite. In mammalian neurons, indoxacarb has potent modulating actions on the nicotinic acetylcholine receptors (nAChRs). In rats and dogs, clinical signs of toxicosis may include ataxia, immobility, lethargy, and tremors.

Dogs treated topically with a single application of a product containing indoxacarb (13.01%) and permethrin (42.5%) exhibited no adverse effects, nor did they exhibit any skin reactions at the site of application. The residue of indoxacarb can persist on the dog coat for up to three weeks.

Diagnosis of indoxacarb poisoning is based on the detection of indoxacarb residue in body tissues or fluid and clinical observations.

There is no specific treatment, so treatment rests with supportive measures. Indoxacarb-induced methemoglobinemia can be treated with methylene blue.