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Toxicology of newer pesticides for use in dogs and cats
Vet Clin Small Anim 32 (2002) 455–467
Toxicology of newer pesticides for use in dogs and cats Lynn R. Hovda, DVM, MSa,*, Stephen B. Hooser, DVM, PhDb,c a
Prosar International Animal Poison Center, 1295 Bandana Boulevard, Suite 335, St. Paul, MN 55108, USA b Toxicology Section, Animal Disease Diagnostic Laboratory, Purdue University, 1175 ADDL, West Lafayette, IN 47907 c Department of Veterinary Pathobiology, Purdue University, 1175 ADDL, West Lafayette, IN 47907, USA
A century ago, many insecticides contained salts of heavy metals such as copper, lead, and arsenic. Acetylcholinesterase-inhibiting organophosphorous and carbamate insecticides such as parathion and carbaryl were introduced in the middle to late 1940s and 1950s [37]. In 1948, Mueller received a Nobel Prize for the discovery of the organochlorine insecticide DDT, which he had developed in 1939. At that time, it was believed that organic insecticides would help to rid the world of arthropod-borne diseases such as malaria and sleeping sickness. The development of organophosphorous, carbamate, and organochlorine insecticides was followed by synthetic pyrethroids (although naturally occurring pyrethrin has been used for centuries) [37]. Although their use is of considerable benefit to society, we have since discovered that significant acute and chronic toxicity can be associated with these older pesticides. As a result, there has been considerable impetus to develop newer insecticides with minimal mammalian and avian toxicity. The last decade of the second millennium witnessed the discovery, development, and use of several new insecticidal and acaricidal pesticides such as fipronil, imidacloprid, lufenuron, nitenpyram, and selamectin. These have been specifically designed by their manufacturers for rapid killing of pests as well as for their safety to pets and people. The mechanisms of action of these pesticides exploit unique physiologic differences between mammals and insects or ticks, resulting in low toxicity in mammals. Specifically, they
* Corresponding author. E-mail address: [email protected] (L.R. Hovda). 0195-5616/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved. PII: S 0 1 9 5 - 5 6 1 6 ( 0 1 ) 0 0 0 1 3 - 4
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prevent the development of flea eggs, larvae, and pupae in the environment. The incidences of pesticide-induced toxicity in dogs and cats associated with the use of these newer pesticides seem to be limited. This article briefly reviews several of these new compounds. Fipronil Fipronil, an N-phenylpyrazole with a trifluoromethylsulfinyl moiety, was introduced in the United States in 1996 for use in animal health, indoor pest control, and commercial turf and crop protection [52]. Currently, it is marketed for veterinary use as Frontline TopSpot for dogs and cats (Merial Labs, Duluth, GA) and Frontline Spray (Merial Labs). Frontline TopSpot contains 9.7% fipronil wt/wt [43], and Frontline Spray contains 0.29% fipronil wt/wt [44]. Veterinary products are labeled for use against fleas and ticks [52]. Products marketed for nonveterinary use contain varying concentrations of fipronil depending on the end use of the product. Technical-grade fipronil contains 95.6% fipronil. Veterinary products carry the signal word ‘‘caution,’’ which means low toxicity [43,44]. All technical grade and most fipronil products formulated for agricultural use in the United States carry the signal word ‘‘warning,’’ which means moderate toxicity [29]. Mechanism of action Fipronil works by disrupting normal function in the central nervous system of target insects. It is believed to act on the c-aminobutyric acid (GABA) receptor as a noncompetitive blocker of the GABA-gated chloride channel [7,14]. There is currently some controversy over whether GABA-gated chloride channels or glutamate-gated channels are actually targeted [7,52]. The GABA receptor system is inhibitory and acts to prevent excess stimulation of nerves. Blockade of the GABA receptors by fipronil results in neural excitation and death in target insects. Fipronil is more toxic to insects than to mammals because of a difference in GABA receptor sensitivity. Toxicity Fipronil products for veterinary use as well as other end-use fipronil products have a low order of toxicity by dermal, oral, or inhalation exposure, except possibly with extralabel use in rabbits [43,44,53]. Fipronil is not a skin sensitizer. It may cause slight skin irritation and mild irritation to the eyes. In rabbits, minimal eye irritation occurred after eye exposure [43]. Signs resolved spontaneously in 3 days. The technical product has a high order of toxicity after oral and inhalation exposure in the rat. Dermal toxicity seems to be low even for the technical-grade product [52]. Chronic feeding studies in rats using the commercial product resulted in seizures, decreased appetite and body weight, liver dysfunction, and change in blood cell counts and biochemistry parameters. Liver dysfunction included
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increased liver weight as well as changes in total protein and bilirubin. In most animal studies, the central nervous system seems to be the target organ of toxicity [52]. Significant oral exposure is expected to cause neurologic problems, including seizures. Other affected organs may include the thyroid and kidney [43,52]. Frontline has been used off label in other species for which there are few registered products. Use in young or small rabbits has been reported to cause anorexia, lethargy, convulsions, and death [53]. No minimal toxic dose LD50 has been established in domestic animals [43,44]. Reported LD50 doses for technical-grade product are 95 mg/kg (rat, oral), greater than 2000 mg/kg (rat, dermal), and 354 mg/kg (rabbit, dermal) [52]. Reported LD50 doses for veterinary product formulations are greater than 5000 mg/kg (rat, oral) and greater than 2000 mg/kg (rabbit, dermal). In multigenerational rat studies, high dosages of fipronil (26.03 mg/kg/d for male rats and 28.4 mg/kg/d for female rats) were associated with reproductive effects, including decreased litter sizes, decreased body weights in litters, decreases in mating percentiles, reduced postimplantation survival, reduced postnatal offspring survival, and a delay in physical development [52]. The results of mutagenic and teratogenic studies were negative. Although a delay in development was noted, there was no evidence that fipronil caused birth defects [43,44,52]. Fipronil has been classified as a group C (possible human) carcinogen based on rat studies showing an increase in thyroid follicular cell tumors in both sexes [43]. In mice fed large daily amounts, there was no evidence of fipronil causing cancer [22,52]. Pharmacokinetics In rat studies, oral fipronil at a rate of 150 mg/kg (single dose) or 4 mg/kg/d for 14 days resulted in significant residual amounts in the carcass, gastrointestinal tract, liver, adrenals and abdominal fat [52]. The half-life ranged from 149 to 200 hours in whole blood at 4 mg/kg, with a shorter half-life at higher doses. Frontline TopSpot applied topically to pets spreads over the skin for 24 hours in a process known as translocation [3,12]. The product is not absorbed through intact skin but is stored in the oil glands of the skin and slowly shed with hair and sebum [3]. Fipronil has a major sulfone metabolite and a desulfinyl photoproduct (trifluormethylsulfinyl moiety) produced by photodegradation [16,35]. In mouse studies, sulfone was the major metabolite found, with the sulfone and desulfinyl photoproduct more persistent than the parent compound. In rat studies, 5% to 25% of the parent compound and metabolites was excreted in the urine, and 45% to 75% was excreted in the feces [52]. Clinical effects and treatment Clinical effects from commercially available veterinary products are expected to be mild and self-limiting. Oral exposure may result in transient
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drooling and intermittent vomiting, but the carrier rather than the active ingredient is often implicated. Treatment is symptomatic and supportive. Animals exhibiting a hypersensitivity reaction to the topically applied product should be bathed in a noninsecticidal shampoo and treated accordingly. Reactions after eye exposures are expected to be mild. Nevertheless, a thorough eye lavage should be performed, followed by a fluorescein dye or slit-lamp examination if signs persist. Animals with oral exposures to the technical-grade product need to be treated aggressively with gastric lavage, followed by activated charcoal with a cathartic. Induction of emesis is not recommended because of the potential for seizures. Additional treatment is symptomatic and supportive, as there is no specific antidote for fipronil. Neurologic and hepatic function should be monitored closely, with seizures expected with ingestion of high doses of the technical-grade product.
Imidacloprid Imidacloprid, a chloronicotinyl nitroguanidine compound, was introduced in the United States in 1994 as a veterinary flea control treatment, structural pest insecticide, crop insecticide, and seed treatment. Chemically, it is 1-[(6-chloro-3-pyridinyl) methyl]-N-nitro-2-imidazolidinimine and is synthesized from the nitromethylene class of compounds [2,34]. Currently, it is marketed as Advantage Topical Solution (Bayer Animal Health, Shawnee Mission, KS) as a 9.1% wt/wt imidacloprid solution for use in dogs and cats [2]. Numerous other commercial products are available with varying concentrations. The technical product contains 94% wt/wt imidacloprid. All veterinary, agricultural, and end-use imidacloprid-containing products carry the label ‘‘caution,’’ which means they are of low-order toxicity [29]. Technicalgrade imidacloprid carries the signal word ‘‘warning,’’ which is associated with moderate toxicity [29]. Mechanism of action Imidacloprid works on the nervous system of the target insect as a competitive inhibitor at nicotinic acetylcholine receptors [1,55]. It binds to nicotinergic receptors in postsynaptic nerves to prevent acetylcholine from binding and transmitting information [9,17]. Receptor blockade results in impairment of normal nerve function and death of the insect. It is not degraded by acetylcholinesterase [1,9]. Imidacloprid is most effective against insects with a large proportion of nicotinergic acetylcholine receptors and has a higher binding strength to specific insect nerve receptors than to mammalian receptors [26]. It has selective activity against fleas and other species of insects but not against ticks [2,9].
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Toxicity Imidacloprid products formulated for veterinary use as well as most other products containing imidacloprid have a low order of toxicity in domestic animals. The technical-grade product has a higher degree of toxicity by ingestion in rats. Inhalation and dermal exposures are associated with lower degrees of toxicity [18]. A reported dermal rat LD50 dose for end-use products is 2000 mg/kg, and oral rat and mice LD50 doses for technical-grade products are 450 mg/kg and 131 mg/kg, respectively [2]. These doses are not toxic to the skin or eyes based on rat studies and are not skin sensitizers based on guinea pig studies [34]. Eye irritation may occur but is generally related to the vehicle or another inert ingredient and not to the active ingredient. In short-term feeding studies, high doses of imidacloprid were associated with thyroid lesions [51]. Chronic feeding studies in rats over a 2-year period showed a decrease in weight gain and increase in thyroid lesions. Dogs fed up to 41 mg/kg for a year showed only increased cholesterol levels and increased ‘‘stress’’ to the liver as measured by increased concentrations of cytochrome P-450 [19]. Signs of significant oral exposure would be expected to mimic toxicity from nicotine, including fatigue, twitching, cramps, and muscle weakness [19]. There is a single case report of a cat developing dermatosis and associated systemic signs shortly after being treated with a topical imidacloprid preparation [20]. Nicotinic signs were not noted. A thymoma was subsequently discovered, which might have been the stimulus for the onset of erythema multiforme. Three-generation, high-dose, reproductive studies in rats resulted in decreased body weight gain in pups and decreased body weight in litters. Higher doses resulted in an increase in skeletal abnormalities and reduced body weights in fetal rats and rabbits [18,34]. Imidacloprid may be weakly mutagenic. In 23 laboratory mutagenic assays, imidacloprid tested negative for all but two effects. Positive test results included genotoxicity in Chinese hamster ovary cells and changes in human lymphocyte chromosomes [51]. Imidacloprid has been classified as a group E compound (evidence of noncarcinogenicity for human beings) [34]. There were no carcinogenic effects noted in a 2-year rat carcinogenicity study. Pharmacokinetics Advantage applied topically to dogs and cats spreads rapidly over the skin by translocation. The product is not absorbed systemically but goes to the hair follicles and glands, where it is shed with hair and sebum [2]. Oral ingestion of imidacloprid is rapid and nearly complete. The product is degraded to 6-chloronicotinic acid (among others), a compound that also acts on the central nervous system [2]. This compound may be conjugated with glycine and eliminated or reduced to guanidine. Elimination primarily occurs in the urine (70%–80%), with 20% to 30% excreted in the feces. Excretion is almost complete in 48 hours [2,34].
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Clinical effects and treatment Clinical effects from Advantage are expected to be mild and caused primarily by the carrier or other ingredients in the formulation. Oral exposure to the veterinary product, especially in self-grooming cats, may result in transient and self-limiting drooling or retching. Animals exhibiting hypersensitivity reactions to the topically applied product should be bathed with a noninsecticidal shampoo and treated symptomatically and supportively. Eye exposures are expected to be mild and caused by the carrier or other inert ingredient. Eyes should be lavaged well, followed by an ophthalmic examination with fluorescein dye or a slit-lamp examination if needed. Animals ingesting technical-grade product or massive doses of end-use products should be treated with gastric lavage followed by activated charcoal with a cathartic. Induction of emesis is controversial because of the expected neurologic and respiratory effects. Signs of toxicity in rats included lethargy, respiratory disturbances, decreased movement, staggering gait, spasms, and occasional trembling. There is no specific antidote for imidacloprid; further treatment is symptomatic and supportive.
Selamectin Approved by the US Food and Drug Administration and introduced to the veterinary market in 2000, selamectin (Revolution; Pfizer Animal Health, Exton, PA) is a semisynthetic avermectin developed specifically for use in dogs and cats. Revolution is a single-entity topical endectocide with broad-spectrum action against endoparasites and ectoparasites [4]. It is marketed for use against fleas (Ctenocephalides felis), heartworms (Dirofiilaria immitis), and ear mites (Otodectes cynotis) in dogs and cats; sarcoptic mange mites (Sarcoptes scabiei) in dogs; ticks (Dermacentor variabilis) in dogs; and hookworms (Ancyclostoma tubaeforme) and roundworms (Toxocara cati) in cats. Selamectin is derived from a precursor avermectin produced from a bioengineered new strain of Streptomyces avermitilis [45]. Chemically, selamectin is (5Z,25S)-25-cyclohexyl-4¢-O-de(2,6-dideoxy-3-Omethyl-a-L-arabino-hexopyranosyl)-5-demethoxy-25-de(1-methylpropyl)22,23-dihydro-5-hydroxyiminoavermectin A1a and contains macrocyclic lactone structures [45,46]. Mechanism of action Similar to other avermectins, selamectin has a mechanism of action that may involve more than one site [11,38]. Selamectin causes neuromuscular paralysis in target species by increasing permeability in neuronal chloride channels primarily through glutamate-gaited channels [4]. There is some controversy regarding the channels, as GABA-gaited channels may also be used. Once selamectin is bound to the receptor, the chloride channel
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remains open, and chloride ions flow into the nerve cell. This increase in permeability and rapid influx of chloride ions inhibits the electric activity of target insects and results in rapid flaccid paralysis with death and elimination from the host. Mammals are less likely to be affected because of less sensitive and less accessible chloride channels [45]. Toxicity Selamectin applied topically in a unit dose of 6 to 12 mg/kg is absorbed systemically into the bloodstream, where it protects against heartworms [40]. Fecal excretion is responsible for its effectiveness against roundworms and hookworms in cats [38]. and perhaps in dogs [6]. Selamectin is selectively distributed from the bloodstream to sebaceous glands of the skin, where it forms reservoirs against fleas, ear mites, and sarcoptes mites [38,39]. Acute and chronic studies have shown selamectin to be safe for topical use in heartworm-positive dogs; Collies with dose-related ivermectin sensitivity; breeding, pregnant, and lactating female dogs and cats; and breeding male dogs and cats [23,36]. It has a wide margin of safety in puppies and kittens greater than 6 weeks of age [38]. Selamectin showed no adverse effects on reproduction in adult male or female cats at three times the recommended dose. Sporadic birth defects occurred, but the distribution was similar to that of a saline control group [23]. In another study, 6-week-old kittens received 10 times the smallest unit dose volume (doses of 237–367 mg/kg of body weight). All measured parameters, including clinical signs, neurologic signs, clinical pathologic values (blood urea nitrogen, creatinine, and liver enzymes), and histopathologic findings, were normal [23]. In adult male and female dogs, selamectin showed no adverse effects on reproduction when administered at three times the recommended dose. In another study, 6-week-old dogs received 10 times the recommended dose (actual doses of 72–114 mg/kg of body weight). All measured parameters, including clinical signs, neurologic signs, clinical pathologic values (blood urea nitrogen, creatinine, and liver enzymes), and histopathologic findings, were normal. No abnormalities were noted when a topical dose of 40 mg/kg was applied to ivermectin-sensitive Collies [36]. Studies of accidental oral dosing of the commercial product in dogs and cats showed no effects in dogs and salivation and intermittent emesis in cats. As with other products, these signs are most likely related to the carrier or another ingredient in the formulation [38]. Pharmacokinetics In cats and dogs, the oral bioavailability of selamectin is reported to be 100% and 62%, respectively [45,46]. Bioavailability after dermal application in cats and dogs is 74% and 4.4%, respectively. Grooming may
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account for the high bioavailability in cats [23,33]. Respective topical and oral Tmax values are reported to be 15 and 7 hours in cats and 3 and 8 hours in dogs [33]. The topical half-life (t1/2) is 8 days in cats and 11 days in dogs [33]. Clinical effects and treatment Clinical effects from selamectin at up to 10 times the normal dose are expected to be mild and self-limiting [23,36]. Minor skin irritation or transient alopecia may occur. Stiff or clumping hair as well as discolored hair or a powdery residue has been reported at the treatment site [33]. Other signs reported in clinical and residential trials include vomiting, loose stool or diarrhea, anorexia, lethargy, tachypnea, and muscle tremors [33]. There is no antidote. Treatment is symptomatic and supportive. Eye exposure should be treated with a thorough lavage, followed by fluorescein dye or a slit-lamp examination if needed. Animals exhibiting a hypersensitivity reaction should be bathed in a noninsecticidal shampoo and treated symptomatically and supportively. Accidental or self-grooming oral exposure in cats is generally self-limiting, and no treatment is needed.
Lufenuron Lufenuron (Program; Novartis Animal Health, Greensboro, NC) is a benzoylphenyl urea insect development inhibitor introduced in the United States in 1990 to control fleas on pets, as a public health insecticide, and on field crops [47]. Currently, it is marketed for veterinary use as once-amonth Program Tablets for dogs and cats and as Program Suspension for cats. Tablets are formulated for dogs from 45 mg to 410 mg per tablet. For cats, they are formulated at 90 mg or 205 mg per tablet or in packs of suspension at 135 mg or 270 mg per pack. The recommended dosage for dogs is 10 mg/kg, and for cats, it is 30 mg/kg [31,32]. Lufenuron is also formulated with milbemycin oxime and marketed as Sentinel (Novartis Animal Health) for heartworm prevention and flea control in dogs and puppies 4 weeks of age and older at 2 lb of body weight or greater. Mechanism of action Lufenuron is an insect development inhibitor that breaks the flea life cycle. The adult female flea is exposed to the drug when it feeds on a treated dog or cat. The drug, which has no deleterious effects on the adult fleas, disrupts the synthesis and deposition of chitin by blocking the enzyme chitin synthetase [13,17]. Because chitin is necessary for the survival of ova and larvae, lufenuron has ovicidal and larvicidal activity. Female fleas that feed on animals given oral lufenuron produce nonviable eggs for 2 weeks. Although a few eggs may hatch, they do not progress to the pupal stage, because the
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flea feces, an important part of the larval diet, contain enough lufenuron to inhibit further growth [21,25]. Toxicity Lufenuron seems to be safe for use in mammals, because they do not have chitin. A search of the literature did not reveal any published reports of lufenuron toxicosis in animals. In several clinical efficacy studies, no adverse effects were noted when lufenuron was used at recommended doses (10 mg/kg in dogs and 30 mg/kg in cats) [5,21,41]. Safety studies have also been performed in over 40 breeds of dogs and 9 breeds of cats, including pregnant female animals, breeding male animals, and puppies and kittens over 6 weeks of age [42]. In these studies, dogs have been given up to 20 times and cats up to 10 times the recommended single oral dose of lufenuron with no or minimal adverse side effects noted [31,32]. In the dogs given 20 times the recommended single oral dose of lufenuron (200 mg/kg), soft stools or diarrhea and lacrimation were noted for several days after administration [32]. Cats given up to 10 times the recommended dose of lufenuron (300 mg/kg) exhibited no adverse effects [31]. In breeding studies, male and female dogs and cats were administered lufenuron daily before, during, and after pregnancy (including lactation). No adverse effects were noted in parents or offspring [31,32]. Lufenuron has also been tested in dogs in combination with carbaryl, permethrin, chlorpyrifos, and cythioate (at their recommended rates) and in cats in combination with carbaryl, pyrethrin, and propoxur (at their recommended rates), with no adverse effects noted for any combination [31,32]. Pharmacokinetics In one pharmacokinetic study, a dog and a cat were administered a single intravenous dose of lufenuron at 10 mg/kg. A half-life of 60 days was reported in both species [24]. Lufenuron concentrates in the milk of lactating bitches. When measured 49 to 56 days after whelping, milk lufenuron concentrations were 14 to 49 times higher than blood concentrations [32]. Blood concentrations in pups measured at the same time that blood concentrations were measured in their dams were four to six times higher in the puppies than in the dams. Elevated levels were detected in the pups 4 to 5 weeks after whelping. This did not seem to have any adverse effects on the pups, however [32]. Clinical effects and treatment Based on numerous safety and efficacy studies in dogs and cats, few adverse reactions are expected even at high doses. If adverse reactions are suspected, symptomatic and supportive therapy should be initiated. Eye exposure should be treated with a thorough lavage, followed by fluorescein dye or a
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slit-lamp examination if needed. Animals exhibiting a hypersensitivity reaction should be bathed in a noninsecticidal shampoo and treated accordingly.
Nitenpyram Nitenpyram (Capstar, Novartis Animal Health, Greensboro, NC) was specifically developed as an oral agent against adult fleas (C. felis) in dogs and cats [40,48]. It was approved by the US Food and Drug Administration as a veterinary drug late in 2000 and introduced to the veterinary market early in 2001 [30]. There are currently no other end-use products marketed or approved for use in the United States. Chemically, nitenpyram is a neonicotinoid with the chemical name (E)-N-(6-chloro-3-pyridylmethyl)-Nethyl-N¢-methyl-2-nitro-vinylidenediamine [40]. It is a systemically active drug, with a minimum recommended dose of 1 mg/kg. Capstar is available in 11.4-mg tablets for cats and dogs weighing up to 11 kg and in 57-mg tablets for dogs weighing between 11 kg and 57 kg. The product can be administered as often as once a day when fleas are seen on the animal. Flea kill is expected to begin in 30 minutes [40]. Mechanism of action Similar to other neonicotinoids, nitenpyram is an agonist to nicotinic acetylcholine receptors in postsynaptic nerve membranes [8,50]. It is insect specific and does not inhibit acetylcholinesterase [49]. Toxicity Nitenpyram has a low acute toxicity. Oral LD50 doses for male and female rats are 1680 mg/kg and 1575 mg/kg, respectively [40]. A dermal LD50 dose for rats is greater than 2000 mg/kg. It is not an irritant to skin or eyes or a dermal sensitizer. It was demonstrated to be neither mutagenic nor teratogenic in clinical and residential studies [10,15]. Target animal safety studies have shown it to be safe in puppies and kittens older than 4 weeks and greater than 2 lb of body weight, in mature dogs and cats, and in reproducing dogs and cats [30]. No adverse reactions were found in acute oral toxicity studies in dogs and cats given 10 times the recommended dose. In addition, no adverse reactions were noted in chronic feeding studies using lower doses (3 and 5 times the recommended dose) or in reproductive toxicity studies [30]. Nitenpyram in cats at 125 mg/kg (125 times the recommended dose) caused some salivation, inactivity, vomiting, and tachypnea. These signs started 1 to 2 hours after treatment, began to resolve by 4 hours after treatment, and were completely gone by 24 hours after treatment [30]. In another study, kittens fed increasing doses from 62.5 mg/kg to 148 mg/kg (62.5–148 times the recommended dose) developed emesis, soft stools, and salivation.
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At the high end of the study, neurologic signs occurred (tremors, tenseness, and decreased activity) [30]. Pharmacokinetics Orally administered nitenpyram has a high bioavailability [27,28,54]. Half-lives in dogs and cats are 2.8 hours and 7.7 hours, respectively. Respective maximum blood concentrations are reached at 1.2 hour and at 0.6 hour in dogs and cats. Excretion is primarily (>90%) via urine [27,28,54]. Clinical effects and treatment Based on safety studies in dogs and cats, few adverse reactions are to be expected even at markedly elevated doses. Because there is no specific antidote, treatment would be symptomatic and supportive. Eye exposure should be treated with a thorough lavage, followed by fluorescein dye or a slit-lamp examination if needed. Animals exhibiting a hypersensitivity reaction should be bathed in a noninsecticidal shampoo and treated accordingly.
Summary The past 10 years have witnessed the development of several new insecticides that have been specifically designed to exploit physiologic differences between insects and mammals. This has resulted in products that seem to have a wide margin of safety when used in dogs and cats. Compared with the more acutely toxic organophosphorous, carbamate, and heavy metal insecticides as well as with the environmental problems of bioaccumulation associated with some of the organochlorine insecticides, these newer insecticides such as fipronil, imidacloprid, selamectin, lufenuron, and nitenpyram seem to alleviate these known problems while still providing satisfactory insecticidal activity.
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[7] Bloomquist J. Ion channels as targets for insecticides. Annu Rev Entomol 1996;41:163–90. [8] British Crop Protection Council. Nitenpyram. In: Tomlin C, editor. The pesticide manual, 11th edition. Farharm, UK: British Crop Protection Council; 1997. p. 880–1. [9] Buckingham S, Lapied B, Corrone H, et al: Imidacloprid actions on insect neuronal acetylcholine receptors. J Exp Biol 1997;200:2685–92. [10] Cadiergues M, Steffan J, Tinembart O, et al. Efficacy of an adulticide used alone or in combination with an insect growth regulator for flea infestations of dogs housed in simulated home environments. Am J Vet Res 1999;60:1122–5. [11] Campbell WC. Ivermectin and Abamectin. New York: Springer; 1989. p. 363. [12] 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. [13] Cohen E. Interference with chitin biosynthesis in insects. In: Wright JE, Retnakaran A, editors. Chitin and benzylphenyl ureas, series entomologica, vol. 38. Boston: W. Junk Publishers; 1987. p. 33–42. [14] Cole L, Nicholson R, Casida J. Action of phenylpyrazole insecticides at the GABA-gated chloride channel. Pestic Biochem Physiol 1993;46:47–54. [15] Dobson P, Tinembart O, Fisch R, et al. Efficacy of nitenpyram as a systemic flea adulticide in dogs and cats. Vet Rec 2000;147:709–13. [16] Dominik H, Casida J. Fipronil insecticide: Novel desulfinylation with retention of neurotoxicity. Proc Natl Acad Sci USA 1996;93:12764–7. [17] Dryden M. Denenberg, Bunch S. Control of fleas on naturally infested dogs and cats and in private residences using topical spot applications of fipronil or imidacloprid. Vet Parasitol 2000;93:69–75. [18] EXTONET. Imidacloprid: pesticide information profile, 1999. Available at: http://ace/ orst.edu. Accessed June 2001. [19] Imidacloprid: pesticide tolerances. Federal Register 1997;60(128):34943–5. [20] Godfrey D. Dermatosis and associated systemic signs in a cat with thymoma and recently treated with an imidacloprid preparation. J Small Anim Pract 1999;40:333–7. [21] Hink W, Zakson M, Barnett S. Evaluation of a single oral dose of lufenuron to control flea infestations in dogs. Am J Vet Res 1994;55:822–4. [22] Hurley P. Mode of carcinogenic action of pesticides inducing thyroid follicular cell tumors in rodents. Environ Health Perspect 1998;106:437–45. [23] Krautman M, Novotny M, De Keulenaer K, et al. Safety of selamectin in cats. Vet Parasitol 2000;91:393–403. [24] MacKichan J, Hink W: High performance liquid chromatographic determination of CGA184699 (lufenuron) in dog and cat blood. J Liq Chromatogr 1995;16:2595–2604. [25] Marsella R. Advances in flea control. Vet Clin North Am Small Anim Pract 1999;29:1407–24. [26] Matsuda K, Shimomura M, Kondo Y, et al. Role of loop D of the a 7 nicotinic acetylcholine receptor in its interaction with the insecticide imidacloprid and related neonicotinoids. Br J Pharmacol 2000;130:981–6. [27] Mauer M. Pharmacokinetics of nitenpyram in cats. In: Proceedings of the 24th World Small Animal Veterinary Association Congress, Lyon, France; September 23–26, 1999. p. 16. [28] Mauer M. Pharmacokinetics of nitenpyram in dogs. In: Proceedings of the 24th World Small Animal Veterinary Association Congress, Lyon, France, September 23–26, 1999, p 17 [29] Meister RT. Pesticide dictionary. In: Farm chemical handbook. Willoughby (OH): Meister Publishing; 2001. p. C189, C225, C396. [30] New Animal Drug Application (NADA). Freedom of information summary, Capstar, nitenpyram, NADA 141–175, 2000. Available at: http://www.fda.gov/efoi. Accessed May 2001. [31] New Animal Drug Application (NADA). Freedom of information summary, program suspension for cats, lufenuron suspension, NADA 141–026, 1995. Available at: http:// www.fda.gov/efoi. Accessed June 2001.
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[32] New Animal Drug Application (NADA). Freedom of information summary, program tablets for dogs, lufenuron tablets, NADA 141–035, 1995. Available at: http://www. fda.gov/efoi. Accessed June 2001. [33] New Animal Drug Application (NADA). Freedom of information summary, revolution, selamectin, NADA 141–152, 1999. Available at: http://www.fda.gov/efoi. Accessed June 2001. [34] National Pesticide Telecommunications Network. Imidacloprid fact sheet. Corvalllis (OR): Oregon State University, 1999. [35] Ngim K, Mabury S, Crosby D. Elucidation of fipronil photodegradation pathways. J Agric Food Chem 2000;48:4661–5. [36] Novotny M, Krautman M, Ehrhart J, et al. Safety of selamectin in dogs. Vet Parasitol 2000;91:377–91. [37] Osweiler G, Carson T, Buck W, et al. Insecticides. In: Clinical and diagnostic veterinary toxicology. Dubuque: Kendall/Hunt; 1985. p. 271–320. [38] Pfizer Central Research. Selamectin: an endectocide for companion animal use. Compend Contin Educ Pract Vet 1999;21(Suppl 9I):32–5. [39] Pilla U, Millas W, Stukenbrok H, et al. Distribution of [3H]-selamectin on dog skin following a single topical application. In: Proceedings of the 44th Meeting of the American Association of Veterinary Parasitologists. New Orleans: 1999. p. 55. [40] Schenker R, Tinembart O, Barnett S, et al. A brief introduction to nitenpyram: a new systemic flea adulticide for cats and dogs. Compend Contin Educ Pract Vet 2001;23(Suppl 3A):4–6. [41] Smith R, Paul A, Kitron U, et al. Impact of an orally administered insect growth regulator (lufenuron) on flea infestations of dogs in a controlled simulated home environment. Am J Vet Res 1996;57:502–4. [42] Stansfield D. A review of the safety and efficacy of lufenuron in dogs and cats. Canine Pract 1997;22:34–8. [43] Technical Information Sheet. Frontline TopSpot, fipronil 9.7% w/w, MSDS. Athens (GA): Rhone Merieux, 1997. [44] Technical Information Sheet. Frontline spray treatment, fipronil 0.29% w/w, MSDS. Athens (GA): Rhone Merieux, 1997. [45] Thomas C. Revolution: a unique endectocide providing comprehensive convenient protection. Compend Contin Educ Pract Vet 1999;21(Suppl 9I):2–25. [46] Thomas C. Revolution safety profile. Compend Contin Educ Pract Vet 1999;21(Suppl 9I): 26–31. [47] Thomson W. Insecticides, acaricides, and ovicides. In: Agricultural chemicals, book I. Fresno: Thomson Publications; 1998. p. 133–4. [48] Tinembart O, Tashiro S. Capstar (nitenpyram): a new systemic flea adulticide for dogs and cats. Agrochemical Japan 2000;76:7–10. [49] Tomizawa M, Casida J. Minor structural changes in nicotinoid insecticides confer differential subtype selectivity for mammalian nicotinic acetylcholine receptors. Br J Pharmacol 1999;127:115–22. [50] Tomizawa M, Otsuka G, Miyamoto T, et al. Pharmacological characteristics of insect nicotinic acetylcholine receptor with its ion channel and the comparison of the effect of nicotinoids and neonicotinoids. Journal of Pesticide Science 1995;20:57–64. [51] US Environmental Protection Agency. Imidacloprid pesticide fact sheet. Washington, DC: US Environmental Protection Agency Office of Prevention, Pesticide and Toxic Substances, 1994. [52] US Environmental Protection Agency. New pesticide fact sheet—fipronil. Washington, DC: US Environmental Protection Agency Office of Prevention, Pesticide and Toxic Substances, 1996. [53] Webster M. Product warning. Frontline. Aust Vet J 1999;77:202. [54] Witte S, Luempert L. Laboratory safety studies of nitenpyram tablets for the rapid removal of fleas on cats and dogs. Compend Contin Educ Pract Vet 2001;23(Suppl 3A):7–11. [55] Zhang A, Kayser H, Maeinfisch P, et al. Insect nicotinic acetylcholine receptor: Conserved neonicotinoid specificity of imidacloprid binding site. J Neurochem 2000;75:1294–303.
Toxicology of newer pesticides for use in dogs and cats Lynn R. Hovda, DVM, MSa,*, Stephen B. Hooser, DVM, PhDb,c a
Prosar International Animal Poison Center, 1295 Bandana Boulevard, Suite 335, St. Paul, MN 55108, USA b Toxicology Section, Animal Disease Diagnostic Laboratory, Purdue University, 1175 ADDL, West Lafayette, IN 47907 c Department of Veterinary Pathobiology, Purdue University, 1175 ADDL, West Lafayette, IN 47907, USA
A century ago, many insecticides contained salts of heavy metals such as copper, lead, and arsenic. Acetylcholinesterase-inhibiting organophosphorous and carbamate insecticides such as parathion and carbaryl were introduced in the middle to late 1940s and 1950s [37]. In 1948, Mueller received a Nobel Prize for the discovery of the organochlorine insecticide DDT, which he had developed in 1939. At that time, it was believed that organic insecticides would help to rid the world of arthropod-borne diseases such as malaria and sleeping sickness. The development of organophosphorous, carbamate, and organochlorine insecticides was followed by synthetic pyrethroids (although naturally occurring pyrethrin has been used for centuries) [37]. Although their use is of considerable benefit to society, we have since discovered that significant acute and chronic toxicity can be associated with these older pesticides. As a result, there has been considerable impetus to develop newer insecticides with minimal mammalian and avian toxicity. The last decade of the second millennium witnessed the discovery, development, and use of several new insecticidal and acaricidal pesticides such as fipronil, imidacloprid, lufenuron, nitenpyram, and selamectin. These have been specifically designed by their manufacturers for rapid killing of pests as well as for their safety to pets and people. The mechanisms of action of these pesticides exploit unique physiologic differences between mammals and insects or ticks, resulting in low toxicity in mammals. Specifically, they
* Corresponding author. E-mail address: [email protected] (L.R. Hovda). 0195-5616/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved. PII: S 0 1 9 5 - 5 6 1 6 ( 0 1 ) 0 0 0 1 3 - 4
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prevent the development of flea eggs, larvae, and pupae in the environment. The incidences of pesticide-induced toxicity in dogs and cats associated with the use of these newer pesticides seem to be limited. This article briefly reviews several of these new compounds. Fipronil Fipronil, an N-phenylpyrazole with a trifluoromethylsulfinyl moiety, was introduced in the United States in 1996 for use in animal health, indoor pest control, and commercial turf and crop protection [52]. Currently, it is marketed for veterinary use as Frontline TopSpot for dogs and cats (Merial Labs, Duluth, GA) and Frontline Spray (Merial Labs). Frontline TopSpot contains 9.7% fipronil wt/wt [43], and Frontline Spray contains 0.29% fipronil wt/wt [44]. Veterinary products are labeled for use against fleas and ticks [52]. Products marketed for nonveterinary use contain varying concentrations of fipronil depending on the end use of the product. Technical-grade fipronil contains 95.6% fipronil. Veterinary products carry the signal word ‘‘caution,’’ which means low toxicity [43,44]. All technical grade and most fipronil products formulated for agricultural use in the United States carry the signal word ‘‘warning,’’ which means moderate toxicity [29]. Mechanism of action Fipronil works by disrupting normal function in the central nervous system of target insects. It is believed to act on the c-aminobutyric acid (GABA) receptor as a noncompetitive blocker of the GABA-gated chloride channel [7,14]. There is currently some controversy over whether GABA-gated chloride channels or glutamate-gated channels are actually targeted [7,52]. The GABA receptor system is inhibitory and acts to prevent excess stimulation of nerves. Blockade of the GABA receptors by fipronil results in neural excitation and death in target insects. Fipronil is more toxic to insects than to mammals because of a difference in GABA receptor sensitivity. Toxicity Fipronil products for veterinary use as well as other end-use fipronil products have a low order of toxicity by dermal, oral, or inhalation exposure, except possibly with extralabel use in rabbits [43,44,53]. Fipronil is not a skin sensitizer. It may cause slight skin irritation and mild irritation to the eyes. In rabbits, minimal eye irritation occurred after eye exposure [43]. Signs resolved spontaneously in 3 days. The technical product has a high order of toxicity after oral and inhalation exposure in the rat. Dermal toxicity seems to be low even for the technical-grade product [52]. Chronic feeding studies in rats using the commercial product resulted in seizures, decreased appetite and body weight, liver dysfunction, and change in blood cell counts and biochemistry parameters. Liver dysfunction included
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increased liver weight as well as changes in total protein and bilirubin. In most animal studies, the central nervous system seems to be the target organ of toxicity [52]. Significant oral exposure is expected to cause neurologic problems, including seizures. Other affected organs may include the thyroid and kidney [43,52]. Frontline has been used off label in other species for which there are few registered products. Use in young or small rabbits has been reported to cause anorexia, lethargy, convulsions, and death [53]. No minimal toxic dose LD50 has been established in domestic animals [43,44]. Reported LD50 doses for technical-grade product are 95 mg/kg (rat, oral), greater than 2000 mg/kg (rat, dermal), and 354 mg/kg (rabbit, dermal) [52]. Reported LD50 doses for veterinary product formulations are greater than 5000 mg/kg (rat, oral) and greater than 2000 mg/kg (rabbit, dermal). In multigenerational rat studies, high dosages of fipronil (26.03 mg/kg/d for male rats and 28.4 mg/kg/d for female rats) were associated with reproductive effects, including decreased litter sizes, decreased body weights in litters, decreases in mating percentiles, reduced postimplantation survival, reduced postnatal offspring survival, and a delay in physical development [52]. The results of mutagenic and teratogenic studies were negative. Although a delay in development was noted, there was no evidence that fipronil caused birth defects [43,44,52]. Fipronil has been classified as a group C (possible human) carcinogen based on rat studies showing an increase in thyroid follicular cell tumors in both sexes [43]. In mice fed large daily amounts, there was no evidence of fipronil causing cancer [22,52]. Pharmacokinetics In rat studies, oral fipronil at a rate of 150 mg/kg (single dose) or 4 mg/kg/d for 14 days resulted in significant residual amounts in the carcass, gastrointestinal tract, liver, adrenals and abdominal fat [52]. The half-life ranged from 149 to 200 hours in whole blood at 4 mg/kg, with a shorter half-life at higher doses. Frontline TopSpot applied topically to pets spreads over the skin for 24 hours in a process known as translocation [3,12]. The product is not absorbed through intact skin but is stored in the oil glands of the skin and slowly shed with hair and sebum [3]. Fipronil has a major sulfone metabolite and a desulfinyl photoproduct (trifluormethylsulfinyl moiety) produced by photodegradation [16,35]. In mouse studies, sulfone was the major metabolite found, with the sulfone and desulfinyl photoproduct more persistent than the parent compound. In rat studies, 5% to 25% of the parent compound and metabolites was excreted in the urine, and 45% to 75% was excreted in the feces [52]. Clinical effects and treatment Clinical effects from commercially available veterinary products are expected to be mild and self-limiting. Oral exposure may result in transient
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drooling and intermittent vomiting, but the carrier rather than the active ingredient is often implicated. Treatment is symptomatic and supportive. Animals exhibiting a hypersensitivity reaction to the topically applied product should be bathed in a noninsecticidal shampoo and treated accordingly. Reactions after eye exposures are expected to be mild. Nevertheless, a thorough eye lavage should be performed, followed by a fluorescein dye or slit-lamp examination if signs persist. Animals with oral exposures to the technical-grade product need to be treated aggressively with gastric lavage, followed by activated charcoal with a cathartic. Induction of emesis is not recommended because of the potential for seizures. Additional treatment is symptomatic and supportive, as there is no specific antidote for fipronil. Neurologic and hepatic function should be monitored closely, with seizures expected with ingestion of high doses of the technical-grade product.
Imidacloprid Imidacloprid, a chloronicotinyl nitroguanidine compound, was introduced in the United States in 1994 as a veterinary flea control treatment, structural pest insecticide, crop insecticide, and seed treatment. Chemically, it is 1-[(6-chloro-3-pyridinyl) methyl]-N-nitro-2-imidazolidinimine and is synthesized from the nitromethylene class of compounds [2,34]. Currently, it is marketed as Advantage Topical Solution (Bayer Animal Health, Shawnee Mission, KS) as a 9.1% wt/wt imidacloprid solution for use in dogs and cats [2]. Numerous other commercial products are available with varying concentrations. The technical product contains 94% wt/wt imidacloprid. All veterinary, agricultural, and end-use imidacloprid-containing products carry the label ‘‘caution,’’ which means they are of low-order toxicity [29]. Technicalgrade imidacloprid carries the signal word ‘‘warning,’’ which is associated with moderate toxicity [29]. Mechanism of action Imidacloprid works on the nervous system of the target insect as a competitive inhibitor at nicotinic acetylcholine receptors [1,55]. It binds to nicotinergic receptors in postsynaptic nerves to prevent acetylcholine from binding and transmitting information [9,17]. Receptor blockade results in impairment of normal nerve function and death of the insect. It is not degraded by acetylcholinesterase [1,9]. Imidacloprid is most effective against insects with a large proportion of nicotinergic acetylcholine receptors and has a higher binding strength to specific insect nerve receptors than to mammalian receptors [26]. It has selective activity against fleas and other species of insects but not against ticks [2,9].
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Toxicity Imidacloprid products formulated for veterinary use as well as most other products containing imidacloprid have a low order of toxicity in domestic animals. The technical-grade product has a higher degree of toxicity by ingestion in rats. Inhalation and dermal exposures are associated with lower degrees of toxicity [18]. A reported dermal rat LD50 dose for end-use products is 2000 mg/kg, and oral rat and mice LD50 doses for technical-grade products are 450 mg/kg and 131 mg/kg, respectively [2]. These doses are not toxic to the skin or eyes based on rat studies and are not skin sensitizers based on guinea pig studies [34]. Eye irritation may occur but is generally related to the vehicle or another inert ingredient and not to the active ingredient. In short-term feeding studies, high doses of imidacloprid were associated with thyroid lesions [51]. Chronic feeding studies in rats over a 2-year period showed a decrease in weight gain and increase in thyroid lesions. Dogs fed up to 41 mg/kg for a year showed only increased cholesterol levels and increased ‘‘stress’’ to the liver as measured by increased concentrations of cytochrome P-450 [19]. Signs of significant oral exposure would be expected to mimic toxicity from nicotine, including fatigue, twitching, cramps, and muscle weakness [19]. There is a single case report of a cat developing dermatosis and associated systemic signs shortly after being treated with a topical imidacloprid preparation [20]. Nicotinic signs were not noted. A thymoma was subsequently discovered, which might have been the stimulus for the onset of erythema multiforme. Three-generation, high-dose, reproductive studies in rats resulted in decreased body weight gain in pups and decreased body weight in litters. Higher doses resulted in an increase in skeletal abnormalities and reduced body weights in fetal rats and rabbits [18,34]. Imidacloprid may be weakly mutagenic. In 23 laboratory mutagenic assays, imidacloprid tested negative for all but two effects. Positive test results included genotoxicity in Chinese hamster ovary cells and changes in human lymphocyte chromosomes [51]. Imidacloprid has been classified as a group E compound (evidence of noncarcinogenicity for human beings) [34]. There were no carcinogenic effects noted in a 2-year rat carcinogenicity study. Pharmacokinetics Advantage applied topically to dogs and cats spreads rapidly over the skin by translocation. The product is not absorbed systemically but goes to the hair follicles and glands, where it is shed with hair and sebum [2]. Oral ingestion of imidacloprid is rapid and nearly complete. The product is degraded to 6-chloronicotinic acid (among others), a compound that also acts on the central nervous system [2]. This compound may be conjugated with glycine and eliminated or reduced to guanidine. Elimination primarily occurs in the urine (70%–80%), with 20% to 30% excreted in the feces. Excretion is almost complete in 48 hours [2,34].
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Clinical effects and treatment Clinical effects from Advantage are expected to be mild and caused primarily by the carrier or other ingredients in the formulation. Oral exposure to the veterinary product, especially in self-grooming cats, may result in transient and self-limiting drooling or retching. Animals exhibiting hypersensitivity reactions to the topically applied product should be bathed with a noninsecticidal shampoo and treated symptomatically and supportively. Eye exposures are expected to be mild and caused by the carrier or other inert ingredient. Eyes should be lavaged well, followed by an ophthalmic examination with fluorescein dye or a slit-lamp examination if needed. Animals ingesting technical-grade product or massive doses of end-use products should be treated with gastric lavage followed by activated charcoal with a cathartic. Induction of emesis is controversial because of the expected neurologic and respiratory effects. Signs of toxicity in rats included lethargy, respiratory disturbances, decreased movement, staggering gait, spasms, and occasional trembling. There is no specific antidote for imidacloprid; further treatment is symptomatic and supportive.
Selamectin Approved by the US Food and Drug Administration and introduced to the veterinary market in 2000, selamectin (Revolution; Pfizer Animal Health, Exton, PA) is a semisynthetic avermectin developed specifically for use in dogs and cats. Revolution is a single-entity topical endectocide with broad-spectrum action against endoparasites and ectoparasites [4]. It is marketed for use against fleas (Ctenocephalides felis), heartworms (Dirofiilaria immitis), and ear mites (Otodectes cynotis) in dogs and cats; sarcoptic mange mites (Sarcoptes scabiei) in dogs; ticks (Dermacentor variabilis) in dogs; and hookworms (Ancyclostoma tubaeforme) and roundworms (Toxocara cati) in cats. Selamectin is derived from a precursor avermectin produced from a bioengineered new strain of Streptomyces avermitilis [45]. Chemically, selamectin is (5Z,25S)-25-cyclohexyl-4¢-O-de(2,6-dideoxy-3-Omethyl-a-L-arabino-hexopyranosyl)-5-demethoxy-25-de(1-methylpropyl)22,23-dihydro-5-hydroxyiminoavermectin A1a and contains macrocyclic lactone structures [45,46]. Mechanism of action Similar to other avermectins, selamectin has a mechanism of action that may involve more than one site [11,38]. Selamectin causes neuromuscular paralysis in target species by increasing permeability in neuronal chloride channels primarily through glutamate-gaited channels [4]. There is some controversy regarding the channels, as GABA-gaited channels may also be used. Once selamectin is bound to the receptor, the chloride channel
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remains open, and chloride ions flow into the nerve cell. This increase in permeability and rapid influx of chloride ions inhibits the electric activity of target insects and results in rapid flaccid paralysis with death and elimination from the host. Mammals are less likely to be affected because of less sensitive and less accessible chloride channels [45]. Toxicity Selamectin applied topically in a unit dose of 6 to 12 mg/kg is absorbed systemically into the bloodstream, where it protects against heartworms [40]. Fecal excretion is responsible for its effectiveness against roundworms and hookworms in cats [38]. and perhaps in dogs [6]. Selamectin is selectively distributed from the bloodstream to sebaceous glands of the skin, where it forms reservoirs against fleas, ear mites, and sarcoptes mites [38,39]. Acute and chronic studies have shown selamectin to be safe for topical use in heartworm-positive dogs; Collies with dose-related ivermectin sensitivity; breeding, pregnant, and lactating female dogs and cats; and breeding male dogs and cats [23,36]. It has a wide margin of safety in puppies and kittens greater than 6 weeks of age [38]. Selamectin showed no adverse effects on reproduction in adult male or female cats at three times the recommended dose. Sporadic birth defects occurred, but the distribution was similar to that of a saline control group [23]. In another study, 6-week-old kittens received 10 times the smallest unit dose volume (doses of 237–367 mg/kg of body weight). All measured parameters, including clinical signs, neurologic signs, clinical pathologic values (blood urea nitrogen, creatinine, and liver enzymes), and histopathologic findings, were normal [23]. In adult male and female dogs, selamectin showed no adverse effects on reproduction when administered at three times the recommended dose. In another study, 6-week-old dogs received 10 times the recommended dose (actual doses of 72–114 mg/kg of body weight). All measured parameters, including clinical signs, neurologic signs, clinical pathologic values (blood urea nitrogen, creatinine, and liver enzymes), and histopathologic findings, were normal. No abnormalities were noted when a topical dose of 40 mg/kg was applied to ivermectin-sensitive Collies [36]. Studies of accidental oral dosing of the commercial product in dogs and cats showed no effects in dogs and salivation and intermittent emesis in cats. As with other products, these signs are most likely related to the carrier or another ingredient in the formulation [38]. Pharmacokinetics In cats and dogs, the oral bioavailability of selamectin is reported to be 100% and 62%, respectively [45,46]. Bioavailability after dermal application in cats and dogs is 74% and 4.4%, respectively. Grooming may
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account for the high bioavailability in cats [23,33]. Respective topical and oral Tmax values are reported to be 15 and 7 hours in cats and 3 and 8 hours in dogs [33]. The topical half-life (t1/2) is 8 days in cats and 11 days in dogs [33]. Clinical effects and treatment Clinical effects from selamectin at up to 10 times the normal dose are expected to be mild and self-limiting [23,36]. Minor skin irritation or transient alopecia may occur. Stiff or clumping hair as well as discolored hair or a powdery residue has been reported at the treatment site [33]. Other signs reported in clinical and residential trials include vomiting, loose stool or diarrhea, anorexia, lethargy, tachypnea, and muscle tremors [33]. There is no antidote. Treatment is symptomatic and supportive. Eye exposure should be treated with a thorough lavage, followed by fluorescein dye or a slit-lamp examination if needed. Animals exhibiting a hypersensitivity reaction should be bathed in a noninsecticidal shampoo and treated symptomatically and supportively. Accidental or self-grooming oral exposure in cats is generally self-limiting, and no treatment is needed.
Lufenuron Lufenuron (Program; Novartis Animal Health, Greensboro, NC) is a benzoylphenyl urea insect development inhibitor introduced in the United States in 1990 to control fleas on pets, as a public health insecticide, and on field crops [47]. Currently, it is marketed for veterinary use as once-amonth Program Tablets for dogs and cats and as Program Suspension for cats. Tablets are formulated for dogs from 45 mg to 410 mg per tablet. For cats, they are formulated at 90 mg or 205 mg per tablet or in packs of suspension at 135 mg or 270 mg per pack. The recommended dosage for dogs is 10 mg/kg, and for cats, it is 30 mg/kg [31,32]. Lufenuron is also formulated with milbemycin oxime and marketed as Sentinel (Novartis Animal Health) for heartworm prevention and flea control in dogs and puppies 4 weeks of age and older at 2 lb of body weight or greater. Mechanism of action Lufenuron is an insect development inhibitor that breaks the flea life cycle. The adult female flea is exposed to the drug when it feeds on a treated dog or cat. The drug, which has no deleterious effects on the adult fleas, disrupts the synthesis and deposition of chitin by blocking the enzyme chitin synthetase [13,17]. Because chitin is necessary for the survival of ova and larvae, lufenuron has ovicidal and larvicidal activity. Female fleas that feed on animals given oral lufenuron produce nonviable eggs for 2 weeks. Although a few eggs may hatch, they do not progress to the pupal stage, because the
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flea feces, an important part of the larval diet, contain enough lufenuron to inhibit further growth [21,25]. Toxicity Lufenuron seems to be safe for use in mammals, because they do not have chitin. A search of the literature did not reveal any published reports of lufenuron toxicosis in animals. In several clinical efficacy studies, no adverse effects were noted when lufenuron was used at recommended doses (10 mg/kg in dogs and 30 mg/kg in cats) [5,21,41]. Safety studies have also been performed in over 40 breeds of dogs and 9 breeds of cats, including pregnant female animals, breeding male animals, and puppies and kittens over 6 weeks of age [42]. In these studies, dogs have been given up to 20 times and cats up to 10 times the recommended single oral dose of lufenuron with no or minimal adverse side effects noted [31,32]. In the dogs given 20 times the recommended single oral dose of lufenuron (200 mg/kg), soft stools or diarrhea and lacrimation were noted for several days after administration [32]. Cats given up to 10 times the recommended dose of lufenuron (300 mg/kg) exhibited no adverse effects [31]. In breeding studies, male and female dogs and cats were administered lufenuron daily before, during, and after pregnancy (including lactation). No adverse effects were noted in parents or offspring [31,32]. Lufenuron has also been tested in dogs in combination with carbaryl, permethrin, chlorpyrifos, and cythioate (at their recommended rates) and in cats in combination with carbaryl, pyrethrin, and propoxur (at their recommended rates), with no adverse effects noted for any combination [31,32]. Pharmacokinetics In one pharmacokinetic study, a dog and a cat were administered a single intravenous dose of lufenuron at 10 mg/kg. A half-life of 60 days was reported in both species [24]. Lufenuron concentrates in the milk of lactating bitches. When measured 49 to 56 days after whelping, milk lufenuron concentrations were 14 to 49 times higher than blood concentrations [32]. Blood concentrations in pups measured at the same time that blood concentrations were measured in their dams were four to six times higher in the puppies than in the dams. Elevated levels were detected in the pups 4 to 5 weeks after whelping. This did not seem to have any adverse effects on the pups, however [32]. Clinical effects and treatment Based on numerous safety and efficacy studies in dogs and cats, few adverse reactions are expected even at high doses. If adverse reactions are suspected, symptomatic and supportive therapy should be initiated. Eye exposure should be treated with a thorough lavage, followed by fluorescein dye or a
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slit-lamp examination if needed. Animals exhibiting a hypersensitivity reaction should be bathed in a noninsecticidal shampoo and treated accordingly.
Nitenpyram Nitenpyram (Capstar, Novartis Animal Health, Greensboro, NC) was specifically developed as an oral agent against adult fleas (C. felis) in dogs and cats [40,48]. It was approved by the US Food and Drug Administration as a veterinary drug late in 2000 and introduced to the veterinary market early in 2001 [30]. There are currently no other end-use products marketed or approved for use in the United States. Chemically, nitenpyram is a neonicotinoid with the chemical name (E)-N-(6-chloro-3-pyridylmethyl)-Nethyl-N¢-methyl-2-nitro-vinylidenediamine [40]. It is a systemically active drug, with a minimum recommended dose of 1 mg/kg. Capstar is available in 11.4-mg tablets for cats and dogs weighing up to 11 kg and in 57-mg tablets for dogs weighing between 11 kg and 57 kg. The product can be administered as often as once a day when fleas are seen on the animal. Flea kill is expected to begin in 30 minutes [40]. Mechanism of action Similar to other neonicotinoids, nitenpyram is an agonist to nicotinic acetylcholine receptors in postsynaptic nerve membranes [8,50]. It is insect specific and does not inhibit acetylcholinesterase [49]. Toxicity Nitenpyram has a low acute toxicity. Oral LD50 doses for male and female rats are 1680 mg/kg and 1575 mg/kg, respectively [40]. A dermal LD50 dose for rats is greater than 2000 mg/kg. It is not an irritant to skin or eyes or a dermal sensitizer. It was demonstrated to be neither mutagenic nor teratogenic in clinical and residential studies [10,15]. Target animal safety studies have shown it to be safe in puppies and kittens older than 4 weeks and greater than 2 lb of body weight, in mature dogs and cats, and in reproducing dogs and cats [30]. No adverse reactions were found in acute oral toxicity studies in dogs and cats given 10 times the recommended dose. In addition, no adverse reactions were noted in chronic feeding studies using lower doses (3 and 5 times the recommended dose) or in reproductive toxicity studies [30]. Nitenpyram in cats at 125 mg/kg (125 times the recommended dose) caused some salivation, inactivity, vomiting, and tachypnea. These signs started 1 to 2 hours after treatment, began to resolve by 4 hours after treatment, and were completely gone by 24 hours after treatment [30]. In another study, kittens fed increasing doses from 62.5 mg/kg to 148 mg/kg (62.5–148 times the recommended dose) developed emesis, soft stools, and salivation.
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At the high end of the study, neurologic signs occurred (tremors, tenseness, and decreased activity) [30]. Pharmacokinetics Orally administered nitenpyram has a high bioavailability [27,28,54]. Half-lives in dogs and cats are 2.8 hours and 7.7 hours, respectively. Respective maximum blood concentrations are reached at 1.2 hour and at 0.6 hour in dogs and cats. Excretion is primarily (>90%) via urine [27,28,54]. Clinical effects and treatment Based on safety studies in dogs and cats, few adverse reactions are to be expected even at markedly elevated doses. Because there is no specific antidote, treatment would be symptomatic and supportive. Eye exposure should be treated with a thorough lavage, followed by fluorescein dye or a slit-lamp examination if needed. Animals exhibiting a hypersensitivity reaction should be bathed in a noninsecticidal shampoo and treated accordingly.
Summary The past 10 years have witnessed the development of several new insecticides that have been specifically designed to exploit physiologic differences between insects and mammals. This has resulted in products that seem to have a wide margin of safety when used in dogs and cats. Compared with the more acutely toxic organophosphorous, carbamate, and heavy metal insecticides as well as with the environmental problems of bioaccumulation associated with some of the organochlorine insecticides, these newer insecticides such as fipronil, imidacloprid, selamectin, lufenuron, and nitenpyram seem to alleviate these known problems while still providing satisfactory insecticidal activity.
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