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Phenylpyrazole (Fipronil) Toxicosis in Animals

By

Ramesh C. Gupta

, DVM, PhD, DABT, FACT, FACN, Toxicology Department, Breathitt Veterinary Center, Murray State University;


Robin B. Doss

, BS, Murray State University, Breathitt Veterinary Center

Last full review/revision Aug 2022 | Content last modified Aug 2022
Topic Resources

The class of second-generation insecticides called phenylpyrazoles includes fipronil and pyriprole.

Fipronil is an active ingredient in several ectoparasiticidal products, including two forms of a commercially available preparation (a spray and a spot-on topical application) for dogs and cats. Fipronil is meant to kill fleas and all stages of brown dog ticks Rhipicephalus spp Approximately 60 of the 84 described rhipicephalid species are found in sub-Saharan Africa. The other rhipicephalid species have their origins in Eurasia and northern Africa, with R sanguineus... read more , mites, American dog ticks Dermacentor spp Of the 35 currently recognized Dermacentor spp, 19 inhabit temperate zones and 13 are found exclusively in the palearctic region. Among the tropical species, D nitens is of major... read more <i >Dermacentor</i> spp , and lone star ticks Amblyomma spp More than half of the approximately 135 known Amblyomma species are endemic to the New World. Amblyomma ticks are large, three-host parasites. They have eyes and long, robust mouthparts... read more <i >Amblyomma</i> spp , which may carry Borrelia burgdorferi, the causative agent of Lyme disease. Fipronil is used in combination with methoprene (9.8% fipronil plus 11.8% methoprene for cats; 9.8% fipronil plus 8.8% methoprene for dogs) for additional control of immature flea stages. Fipronil is also formulated as insect bait for roaches, ants, and termites; as sprays for pets; and as a granular turf product to control mole crickets. Fipronil kills fleas and mites within 24 hours.

The acute oral LD50 of fipronil is 97 mg/kg in rats and 95 mg/kg in mice. In a chronic study in dogs, fipronil at 2 mg/kg/d caused clinical signs of neurotoxicity. The NOAEL of fipronil is established at 5 mg/kg/d in rats and 0.2 mg/kg/d in dogs. It is nontoxic to slightly toxic via the dermal route with a dermal LD50 >2,000 mg/kg in rats. The dermal LD50 in rabbits is 354 mg/kg. Dermal toxicity of fipronil is low because the absorption of fipronil is <1% after a dermal application. In clinical studies, fipronil-containing products did not cause skin irritation at the site of application in dogs. Most fipronil poisoning cases occur in dogs and cats due to from licking the product or other accidental ingestion. Despite its typical wide margin of safety, fipronil can be rather toxic to rabbits.

In humans, poisoning from fipronil is mainly due to accident or suicidal attempt. Poisoned animals show signs of neurotoxicity (convulsions, twitching, tremors, ataxia, rigidity of limbs, hyper- or hypoactivity, vocalization, aggression, and abnormal neurologic response). In a subacute study, buffalo calves orally exposed to fipronil (0.5 mg/kg/d) produced toxic signs including salivation, lacrimation, depression, decreased body weight gain, muscle weakness, alopecia, and sunken eyes. The EPA has determined fipronil to be safe for use on dogs and cats, and it is not harmful to humans who handle these animals if proper precautions are taken.

After dermal application, fipronil spreads and sequesters in the lipids of the skin and hair follicles and continues to be released onto the skin and coat, resulting in residual activity against fleas and ticks for a month. Following oral ingestion, the absorption of fipronil is rapid with a long half-life in rats (183 hours in males, and 245 hours in females). One of the photometabolites of fipronil is fipronil desulfinyl, which is more toxic than the parent compound. Fipronil and its major metabolites are deposited in the fat and fatty tissues. Excretion of fipronil and its metabolites occurs through feces and urine.

Fipronil, and its major metabolite fipronil sulfone can produce neurotoxicity by blocking the GABAA-regulated chloride channels, resulting in hyperexcitation. Fipronil has a greater specificity for the GABAA receptor (beta-3 subunit) found in insects than the mammalian GABAA receptors. As a result, fipronil exhibits >500-fold selective toxicity toward insects over mammals. Fipronil and its metabolites can produce toxic effects in the liver, kidney, and other vital organs by dysregulating mitochondrial bioenergetics (inhibiting mitochondrial respiratory chain) and calcium homeostasis, oxidative, and nitrosative stress, as well as by damage to DNA and proteins. Cell death occurs due to apoptosis or autophagy.

Diagnosis of fipronil poisoning in animals can be based on circumstantial evidence, clinical manifestations, and the detection of fipronil or its metabolite (fipronil sulfone) in body tissues or fluid.

There is no specific treatment for fipronil toxicosis, and therefore treatment relies on supportive measures.

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