Neonicotinoid Toxicosis in Animals

Neonicotinoids are a newer class of synthetic insecticides, including imidacloprid, thiacloprid, acetamiprid, dinotefuran, nitenpyram, thiamethoxam, and clothianidin. Imidacloprid was the first commercially successful insecticide of this class, registered in 1991 for use in agriculture and in animal and public health products. Since then, the use of neonicotinoids has increased tremendously due to these products' broad-spectrum insecticidal effects against sucking and chewing pests. Imidacloprid, dinotefuran, and nitenpyram are commonly used as ectoparasiticides on pets and non–food-producing animals. The neonicotinoids have a high specificity for target species and a low risk for nontarget organisms; however, the neonicotinoids have been implicated in bee colony collapse disorder.

Following oral administration, neonicotinoids are rapidly absorbed and widely distributed throughout the body. Neonicotinoids in general, and imidacloprid in particular, are not distributed to the CNS, as only a small amount crosses the blood-brain barrier. Neonicotinoids are rapidly metabolized and excreted. Approximately 80% of the dose of imidacloprid is excreted in the urine, with the remainder eliminated in the feces.

In acute dosing studies in rats, imidacloprid at a dose of 300 mg/kg produced clinical signs and 500 mg/kg produced 100% lethality. The acute oral LD₅₀ of imidacloprid is in the range of 379–648 mg/kg in rats and 130–170 mg/kg in mice. In a 13-week study in dogs, oral doses of imidacloprid ≥15 mg/kg produced tremors. Other clinical signs with sublethal dose exposure to imidacloprid may include dilated or pinpoint pupils, staggering gait, salivation, trembling, spasms, and hypothermia. At lethal doses, death may occur within 4 hours. Following sublethal dose exposure, recovery can occur within 8–24 hours. Based on chronic studies, a no observed adverse effect level (NOAEL) of imidacloprid was established at 5.7 mg/kg/d in male rats, 25 mg/kg/d in female rats, and 15 mg/kg/d in dogs. Dogs receiving a single dermal application of imidacloprid showed no signs of adverse effects, even though imidacloprid was present in the blood.

Nitenpyram is of low mammalian toxicity, compared with imidacloprid. The acute oral LD₅₀ of nitenpyram in rats is 1,575–1,680 mg/kg and the acute dermal LD₅₀ is >2,000 mg/kg.The NOAEL in rats is 129 mg/kg/d for males and 54 mg/kg/d for females; in dogs, the NOAEL is 60 mg/kg/d. Dinotefuran has very low acute oral or dermal toxicity in rats and mice (LD₅₀ >2,000 mg/kg). The acute and subchronic NOAELs of dinotefuran are 750 and 327 mg/kg/d, respectively. Nitenpyram tablets are used to treat flea infestations in dogs and cats. Cats treated with nitenpyram usually show signs of scratching, biting, licking, and twitching. In some studies, adverse effects also included panting, vomiting, fever, salivation, incoordination, seizures, pupil dilation, decreased heart rate, trembling, and nervousness.

Dinotefuran is an insecticide used in veterinary medicine as a flea and tick preventive for dogs and as a flea preventive for cats. It is used in combination with pyriproxyfen and permethrin as a broad-spectrum insecticide for the control of fleas and ticks. The product formulated at 3.6 mL for a dog contains 4.95% dinotefuran, 0.44% pyriproxyfen, and 35.06% permethrin. It is safe for its use in dogs as it produces no toxic effects and no skin reaction at the site of application.

In insects, neonicotinoids exert neurotoxic effects by irreversibly binding to the nicotinic ACh receptors (nAChRs) of the postsynaptic membrane of nerve cells in the CNS and by acting as an nAChR agonist. This leads to a stop of the flow of ions in the postsynaptic membrane of neurons, leading to paralysis and death. Neonicotinoids are much less toxic to vertebrates because of the combined effects of low affinity for vertebrate nAChRs and relatively poor penetration of the blood-brain barrier. Imidacloprid and thiamethoxam can induce neurotoxicity without being associated with any persistent neurobehavioral changes. These compounds can also cause hepatotoxicity.

There is no specific antidote for poisoning by imidacloprid or any other neonicotinoid, so treatment is supportive. In the case of oral exposure, emetics, adsorbents, or cathartics could be used. If the exposure is dermal, washing the animal with mild soap and water is indicated.