Fipronil belongs to the family of phenylpyrazoles, a class of broad-spectrum, second-generation pesticides used in agriculture, veterinary care and in the household. The insecticidal activity of fipronil, which was discovered in 1987 and registered as an insecticide in the USA in 1996, works by contact or ingestion. In the field of veterinary care fipronil is used particularly as a spot-on or spray insecticide for dogs and cats, in order to control fleas (Ctenocephalides spp), ticks (Ixodes spp, Dermacentor spp, Rhipicephalus spp) and dog-biting lice (Trichodectes canis). Fipronil is also included in other pesticides destined for use as insecticide bait, for the treatment of soil and seeds 
(given its marked toxicity to bees, the use of fipronil for seed treatment is currently suspended in Italy – Decree of 16 September, 2010: Extension of the precautionary suspension of authorization of the use, for seed treatment, of pesticides containing the active substances clothianidin, thiamethoxam, imidacloprid and fipronil, from the directive decree of 14 September, 2009).
Fipronil-based products are considered safe for both the treated dogs and cats and the people handling the product. Nevertheless, cases have been reported of human and animal toxicity (see adverse effects). Most of the cases of intoxication in dogs and cats occur after accidental ingestion or incorrect application, such that the animal is able to reach and lick the treated part. Intoxication can also occur when specific products are used in a species for which they are not intended (e.g., in the case of the spot-on product destined for dogs, which normally contains 67 to 402 mg of fipronil, used on a cat, whose specific product contains 50 mg of fipronil). In humans, poisoning is ususually accidental or the result of a suicide attempt.
| IUPAC name | 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoro-methylphenyl)-4-trifluoromethylsulfinylpyrazole |
| CAS number | 120068-37-3 |
| Molecular weight | 437.15 |
| Solubility in water | 22 mg/L |
| Summary of potential toxic features | |
| WHO Acute Hazard | II, Moderately hazardous |
| Acute oral toxicity | Moderate |
| Acute contact toxicity | Low-moderate |
| Carcinogenicity | Possible |
| Ground water contaminant | Potential |
| Endocrine disruptor | Suspected |
Tab. 1. Physico-chemical characteristics and toxicity of fipronil.
MECHANISM OF ACTION
Fipronil acts on the central nervous system of insects by non-competitive inhibition of the passage of Cl- ions through gamma aminobutyric acid (GABA) and glutamate receptor-channels. Fipronil also affects the GABA receptors of mammals, while its inhibition of the glutamate receptors occurs only in insects suggesting that the drug has multiple target sites in insects. Furthermore, fipronil’s binding to the GABA receptor is less selective in mammals than in insects (about 500 times less), thus contributing to its wide margin of safety. Binding between fipronil and the GABA receptor blocks the inhibitory action of GABA, leading to hyperexcitation and, at appropriate doses, death. The toxic effect in mammals occurs through the same mechanism of action as that in the insect, but thanks to the selectivity of the compounds, the toxicity is much less severe in mammals than in insects.
Fipronil is metabolised, in both mammals and insects, into fipronil sulphone which not only maintains the capacity of the parent compound to bind to the GABA receptor, but indeed is more potent than the initial compound on mammalian receptors. Simultaneous exposure to other drugs that can potentiate the formation of the metabolite could potentially increase the toxicity of fipronil in mammals.
Absorption, distribution, metabolism, excretion (ADME)
Following topical application, fipronil is distributed on the superficial layers of the skin, but is not found in the deeper layers of soft tissue (dermis and adipose tissue). In a study of dogs and cats given radiolabelled fipronil, the product was found to be concentrated in the epithelial layers surrounding hairs (follicles) and in sebaceous glands, suggesting that it diffuses passively towards the sebum that covers the skin and fur. The loss of fipronil from animals treated with a topical product is maximal in the 24 hours following the treatment and decreases linearly over time; the product can no longer be found 36 days after its application.
Following ingestion, fipronil distributes mainly into adipose tissues. In the rat, the highest concentrations were found in the gastrointestinal tract, adipose tissue and adrenal glands; more modest concentrations were found in the liver, pancreas, thyroid and ovaries; concentrations were low in muscle, brain, heart and the circulation. Fipronil is metabolised mainly into fipronil sulphone, while fipronil desulfinyl is the main product deriving from photodegradation. Following oral administration, both unchanged fipronil and its sulphone metabolite are excreted in the faeces (45-75% for fipronil) and urine (5-25%).
TOXICITY
The World Health Organization (WHO) classifies fipronil as a class II, moderately hazardous pesticide (Tab. 1). Given that the LD50 for the cutaneously administered product is about 2000 mg/kg in the rat and the rabbit (Tab. 2), because the dermal absorption of fipronil is limited (less than 1% after 24 h), topical application of fipronil is considered not toxic or weakly toxic. No adverse effects were seen in dogs and cats treated with doses 5-fold higher than the maximum. However, mild irritation of the skin and eyes can occur following exposure to the product. Fipronil is highly toxic to fish. The sulphone metabolite is much more toxic than its parent compound in some species of birds.
| Oral LD50 | Dermal LD50 | Inhalation LC50 | |
| Rat | 97 mg/kg | >2000 mg/kg | 0.682 mg/l |
| Mouse | 95 mg/kg | 2000 mg/kg | |
| Rabbit | |||
| Water fowl | >2000 mg/kg | ||
| Duck | >5000 mg/kg (5 days) | ||
| Quail (Colinus virginianus) |
11.3 mg/kg 49 mg/kg (5 days) |
||
| Rainbow trout (Oncorhynchus mykiss) | 0.246 mg/l | ||
| Bluegill (Lepomis macrochirus) | 0.083 mg/l |
Tab. 2. LD50 for fipronil.
CLINICAL SIGNS
The clinical signs of poisoning by fipronil are manifestations of central nervous system hyperexcitability, including tremors, agitation, convulsions and death.
There are no specific antidotes. The treatment is symptomatic and consists of decontaminating the animal by thorough washing if exposed to the product by the topical route. If the intoxication is the result of oral ingestion, repeated doses of activated charcoal are recommended. Diazepam or barbiturates [6]can be prescribed to control convulsions.
ADVERSE EFFECTS
At recommended doses, fipronil-based products are very effective and have a wide margin of safety. Monthly topical treatment of the dog and cat with a dose five times higher than recommended doses for 6 consecutive months did not cause adverse effects.
The wide margin of safety of fipronil has led to its use in other species for which there are few registered products and no alternatives. The rabbit has been found to be a species particularly sensitive to fipronil toxicity. In fact, numerous cases of adverse events have been notified and, although many rabbits have been successfully treated, young or small animals can easily be exposed to excessive doses. The clinical signs include anorexia, lethargy, convulsions and death. In the absence of data on the safety and efficacy of fipronil-containing products in species other than those for which the drug is approved, these products should not be used off-label.
There is one case report in the literature of a severe adverse reaction to the application of a spot-on fipronil product in a cat. Within a few hours of the application the animal developed hyperaesthesia, manifested by repetitive licking and pruritus of all parts of the body, sudden contractions and running as if trying to flee from something. The signs, which worsened gradually, had already occurred a few months previously following application of the same product. The animal recovered completely within 2-3 days following treatment with prednisolone and mepyramine maleate.
Information concerning intoxication of humans is limited. The cases reported in the literature indicate that conjunctivitis, headache, vertigo, nausea, vomiting, abdominal or oropharyngeal pain, cough, sweating, asthenia, agitation and convulsions are the most common signs and symptoms.
In a recent study carried out in the USA in which the dimensions and characteristics of human exposure to fipronil were examined, 103 cases of fipronil-related illness were reported between 2001 and 2007. In most cases (89%) the adverse effects, which were mainly neurological and ocular, were mild and temporary. Besides exposure in the work-place, a sizeable percentage of cases occurred due to exposure in the household. Pet-care products containing fipronil were the cause of intoxication in 37% of the affected adults and 64% of the children. It is, therefore, important that pet-owners handle and administer this type of product to their animals following the indications and precautions reported in the product information leaflet.
Suggested readings
- Baynes RE. Ectoparasiticides. In: Veterinary Pharmacology and Therapeutics. Ed. Riviere JE, Papich MG. 9th edition Wiley-Blackwell, 2008.
- Cochet P, Birckel P, Bromet-Petit M, et al. Skin distribution of fipronil by microautoradiography following topical administration to the beagle dog. Eur J Drug Metab Pharmacokinet 1997;22:211-6.
- Gupta CG. Fipronil. In: Veterinary Toxicology. Basic and Clinical Principles. 1st edition. Academic Press, Elsevier, USA, 2007:502-4.
- Jackson D, Cornell CB, Luukinen B, Buhl K, Stone D. Fipronil Technical Fact Sheet; National Pesticide Information Center, Oregon State University Extension Services. http://npic.orst.edu/factsheets/fiptech.pdf[7], updated 2009
- Mengozzi G. Pesticidi. In: Tossicologia Veterinaria. Ed. Mengozzi G, Soldani. Casa Editrice Idelson-Gnocchi, 2010.
- Silley P. Adverse effects of veterinary pharmaceutical products in animals. In: Veterinary Pharmacovigilance: Adverse Reactions to Veterinary Medicinal Products. Ed. Woodard K. Wiley-Blackwell, 2009.
- Lee SJ, Mulay P, Diebolt-Brown B, et al. Acute illnesses associated with exposure to fipronil—surveillance data from 11 states in the United States, 2001–2007. Clin Toxicol 2010;48:737-44.
- Webster M. Product warning: Frontline. Aust Vet J 1999;77:22.
- Zhao X, Yeh JZ, Salgado VL, Narahashi T. Sulfone metabolite of fipronil blocks gamma-aminobutyric acid- and glutamate-activated chloride channels in mammalian and insect neurons. J Pharmacol Exp Ther 2005;314:363-73.
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