The Toxicity of Permethrin in Cats and Rabbits: A Comprehensive Study

1. Introduction

Pyrethroids are a class of insecticides that are used in urban and agricultural habitats for the control of insects. Permethrin is among one of the pyrethroids that is being widely used commercially, being inexpensive and very effective over a wide range of insects. However, permethrin can cause toxicosis if not handled properly, and its use is particularly common in hamsters. Though the sensitivity of animals widely varies, permethrin is particularly toxic to cats and fish. In a few cases, it can also cause toxicity to rabbits and guinea pigs. The signs of permethrin toxicosis in cats include tremors, hyperexcitability, and seizures, which are consistent among diverse data. Physiologically, permethrin acts by blocking the sodium channels of axons, causing paralysis and death among target insects. Like other compounds that block sodium channels, it is considered a neurotoxin. This study aims to display a clinically relevant concentration of permethrin in cats and rabbits in order to improve identification and prevent accidental exposures to these drugs.

The purpose of the study is to conduct a comprehensive analysis of the clinical signs and pathological lesions arising as a result of permethrin toxicosis in the species of cats and rabbits. Permethrin toxicosis is particularly common in small animal medicine, due to which several reports have been published on toxicity cases in cats. However, rabbits have lower sensitivity than cats, and therefore there is limited literature available regarding permethrin exposure. This study includes seventeen cases of permethrin poisoning in cats and rabbits, with ten cats and seven rabbits. Retrospectively, the signalment, frequency, toxic symptom, diagnosis, and outcome of these cases were identified from the medical record database of the Institution's Small Animal Referral Centre.

1.1. Background and Significance

Historically, pyrethroids were developed as safe insecticides or repellents for use in buildings as well as on various animals. Although permethrin, as a compound of this class, is tolerated by most types of animals, it causes toxic effects in rabbits, cats, and pygmy goats. The permethrin-induced intoxication results from the neurotoxic effect of this compound, which, in the case of these animals, appears at higher doses. This toxicity has been poorly understood until today. Cats represent a special category of fast-metabolizing animals that mainly activate pyrethroids with para-substitutions such as permethrin into more active (and toxic) enantiomers. Other animals, like rabbits, metabolize these compounds into even nontoxic metabolites. Identifying which metabolic parameters differ among the species may contribute to a better understanding of the neurotoxicity of permethrin in animals.

Pyrethroid insecticides have several advantages over organochlorines, organophosphorous compounds, and DDT as well, with low mammalian toxicity. Nevertheless, they are highly toxic to ectothermic species such as insects, fish, amphibians, reptiles, etc. Pyrethroids are also lipophilic and may induce chronic toxic effects in mammals and humans through dermal, inhalation, as well as oral exposures. Although pyrethroids are not sufficient to acquire poisonings by livestock, accidental poisonings are possible in some species. Generally, dogs have been widely identified as accidental victims intoxicated with pyrethroids in most of the poisoning cases. The intoxication potential of cats and rabbits requires comprehensive studies given that both are popular pets.

1.2. Purpose of the Study

Permethrin is a type I group synthetic pyrethroid effective against a broad range of insects, including mites and parasitic infestations in animals, and has been widely used in veterinary medicine. Despite the wide use, the risk of permethrin intoxication in cats and rabbits associated with topical application is common, and permethrin can exert toxic effects on small animals by inducing neurotoxicity. These observations led us to undertake a comprehensive review to consider the metabolism, mechanism of toxic action, diagnostic aspects, clinical signs, the therapeutic approach, and outcome of permethrin toxicity in cats and rabbits from a comprehensive review of traced records between 1600 and 2021. It was shown that clinical signs of permethrin intoxication were due to generalized brain swelling associated with myocardial degeneration. In the past, no single review of permethrin toxicity considers all aspects of pathogenesis, clinical signs, therapy, and outcome. For the first time, we have tried to identify, most comprehensively, every case of permethrin toxicity in cats and rabbits, to evaluate and describe the results.

The issue of fact involves a wide use of permethrin in commercial preparations available without a medical prescription, which is associated with the potential risk of poisoning when the preparations are improperly used, particularly on small animals. The study has several main objectives. This comprehensive study addresses the metabolism, mechanism of toxic action, terminal biotransformation, and diagnostic aspects of permethrin intoxication by evaluation of permethrin pathogenesis in rabbits and cats using the HPLC chromatography method. We also have evaluated and characterized adhesive bandages and therapy in the poisoning treatment, determining the progress and outcomes of recovery without consequences. In the final discussion, we highlighted numerous aspects of the regurgitation mechanism causing fast salivation, inadequate ability to swallow the saliva, induction of vomit, and fatal apnea in cats. The aim of the study was to verify a toxic dose and to investigate other factors that resulted in individual signs of permethrin intoxication in cats and rabbits in various case scenarios.

2. Chemical Properties of Permethrin

Permethrin is a veterinary drug belonging to the class of pyrethroids with antiparasitic activity, which has been widely used for a long time and is still used nowadays. It is an insecticide with repellent effect on ticks and fleas, and it can also serve as an ectoparasiticide. Permethrin belongs to the first generation of pyrethroids and is not photostable. It is used in cats and rabbits mainly as spot-on (topical) application on the skin. The signs of toxicity of diffuse permethrin carcinomas can also often be seen where accidental contamination from agricultural use is encountered. The signs of toxicity include tremors, polyuria, polydipsia, anorexia, hyperesthesia, hyperthermia and, in case of high doses may cause anorexia and vomiting syndrome and even death. In cats and rabbits the cytochrome P450 metabolism is less effective than in other mammals.

Like all other pyrethroids, it consists of an alcohol portion and a carboxylic portion. For the alcohol portion, the cyclopropanol nucleus is replaced by a cyclopropyl group, contributing to its significant photostability. The carboxylic acid group is esterified by a 3-phenoxybenzyl substitution at the acid group. Its last key structural unit is the α-cyano-3-phenoxybenzyl group, giving it a significant photostability. After topical administration, permethrin deposited on the skin will be distributed to the blood, carried by the albumin-protein complex. Furthermore, due to the lipophilicity of the molecule, high concentration was also found in fat and hypodermis. Its absorption depends on the species, it gets absorbed slowly in the case of guinea pigs and cattle, but faster in rats and dogs because they have a thinner cornified layer.

2.1. Structure and Composition

Permethrin is the common name for a synthetic organic insecticide that is used around the world. It is a strongly lipophilic compound with a molecular weight of 391.44 g/mol and is the first member of the type 1 pyrethroids group of chemicals. Molecularly, it has the chemical formula of C21H20Cl2O3, while the International Union of Pure and Applied Chemistry (IUPAC) Standard InChIKey is JGSARLDLIJDBPO-MHMBLVBOSA-N and the Standard InChI is InChI=1S/C21H20Cl2O3/c1-2-9-24-11-17(14-5-3-4-6-19(14)24)21(15-7-10-25-12-18(15)22)13-26-20-8-16(23)29-27-20/h3-8,11,21H,2,9-10,12-13H2,1H3/b17-11+/t21-/m1/s1. Technically though, it is the chrysanthemum-like plant known as Tanacetum cinerariifolium. Permethrin is a mixture of three active isomers that occur in very different proportions depending upon the way it is synthesized. Consequently, the label should clearly identify the isomer. The three isomers are cis/trans 40:60 (Type I permethrin), cyano au-phomix, 8.2-8.3% bioallethrin (biologically unstable), and TC 1395. The combined effect translates to the highly effective products that are used worldwide to control ectoparasites such as mites, ticks, fleas, and lice, and for protection against mosquito-borne diseases like malaria within the homes of especially the developing world. However, it is also one of the insecticides of choice for increased agriculturally-associated applications globally.

Permethrin is quite stable in water despite being hydrophobic. At pHs between 4.0 and 9.0, it has a half-life of more than 4 weeks, and many chemical colleagues work with solutions for months on their lab benches without any significant loss of efficacy. Structure: 3-Phenoxybenzyl (1RS)-cis,trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate.

2.2. Mode of Action

Permethrin is widely used in agriculture and veterinary medicine due to its potent insecticidal activity. This type II pyrethroid targets the voltage-dependent sodium channels and, at high levels of stimulation, can induce neuronal hyperexcitation and "knock-down" effects. A comprehensive survey of research was performed in order to define the biological systems in the two selected species affected by permethrin. Several in vitro appropriate models were used to accurately analyze the activity of the product, such as the patch clamp, the mechanical activity of the aorta, the myography, and the morphological assays (i.e., transmission electron microscopy/TEM). The results allowed for a better definition of the action of permethrin, which in cats concentrates on the vascular system, activating a part of the sympathetic branch (the adrenergic receptors at the level of the aorta and the vena cava and myosin kinase at the level of the uterine blood vessels). In rabbits, however, permethrin drives a parallel activation that also includes the cholinergic receptors.

The aim of this paper is to give insight into the activity of permethrin, supporting the idea that only through a deep analysis of the mode of action is it possible to comprehend certain toxicological responses that can ultimately explain some of the clinical signs developed in both cats, rabbits, and other mammals. For these purposes, this survey aims to clarify the action of permethrin in physiological systems in rabbits as well. Only through a comprehensive analysis of the action of permethrin in the two species, associated with some in vitro experimental investigations, was it possible to accomplish this analysis. The information was obtained through a literature review on PubMed Central and Scopus.

3. Toxicity in Cats

Cats represent a rise in accidental permethrin intoxication, which unfortunately is often fatal. This is partly inflicted by poor knowledge of this compound's toxicity in these species. The present study provides comparative data concerning the intensity of permethrin intoxication in cats and rabbits; systematic characteristic of the clinical picture of feline intoxication divided into the symptoms of the central and peripheral nervous systems; and analysis of veterinary treatment.

The clinical picture of feline and rabbit pets showed that permethrin affected the central nervous system (mydriasis, neurotoxic tetraplegia, seizures (convulsions)), as well as the peripheral nervous system, affecting peripheral nerve fibers: mydriasis. Neurotoxic syndromes were also recorded, such as anxiety (in rabbits), seizures (in cats and rabbits), and aggressive behavior (in rabbits). Severe antig, emetic, cardiotoxic, hepatotoxic, nephrotoxic, and immunotoxic effects of permethrin were also found. Numerous neurological symptoms (including CNS and PNS) including virulent neuronal syndrome, atjrogenic encephalopathy, seizures, ataxia, incoordination, muscle weakness and muscle fiber, mydriasis, and ophthalmoplegia ocular nerve lesions. The intensity of changes depended on the species of animals and the concentration of permethrin. At low (sublethal) doses of permethrin in rabbits and cats, many psychotic effects are not observed. In cats, the threshold for the development of adenomas in experimental studies was 900 mg kg–1 / bw / die. This range of doses is also called the non-applicable dose. In insect cells, the presence of the metabolite cis-permethrin was detected in the concentration tests for the development of adenomas, for example, in in vitro bone marrow cells of mouse, hamster, and rat, the cis-permethrin metabolite increased gene mutations.

3.1. Symptoms of Permethrin Poisoning

Cats are more susceptible to pyrethroid poisoning because they lack enzymes that detoxify the insecticides. The clinical symptoms depend not only on the exposure dose, but also on the exposure route. Even though there is not always a perfect correlation between clinical symptoms and postmortem findings, a classification into three clinical stages is possible.

In the first stage, cats show lots of psychomotor unrest and behavior changes such as excitability/aggressiveness. They may also experience tremors, ataxia, hypersalivation, vocalization, hyperesthesia, tachypnea, tachycardia, muscular fasciculation, and mydriasis. In other studies, no differences were observed with respect to sex, age, reproductive state, clinicopathological findings, or exposure during application in between acutely and chronically permethrin-poisoned cats. However, in dogs, there was a slight sex predilection with more male effect present (39.37 ± 0.13). There was also a breed predisposition since the risk was slightly increased in hunting dogs (RR = 1.093).

Regarding poisoning in rabbits, so far very little information has been reported and it is unclear if animals were naturally or intentionally poisoned. Experimental studies have mainly tested the tolerance, pharmacokinetics, electrocardiogram, and safety of new poultices or feed strikers containing a single dose of close-range permethrin. However, these studies have not provided relevant data for interpreting the effects of clinical toxicity connected to pyrethrum administered acutely or after a single administration. More information is reported for deltamethrin instead, alone, as well as in association with other pyrethroid compounds. The effects on the immune and reproductive systems have also been measured.

In poisoned rabbits, on clinical examination, symptoms initially appear evident, such as intense tremors, followed by drowsiness and subsequent coma. Ataxia and horizontal nystagmus are clearer in rabbits compared to other species (piglets, cats). Muscle weakness and recumbency are also observed. Pyrethrum intoxication in rabbits was associated with a reduction in glycemia and an increase in AST, ALT, and Zn. Macroscopic alterations showed brain congestion and petechia. There were no gross or microscopic abnormal findings in the necropsied animals.

3.2. Mechanisms of Toxicity

Several published papers discuss the metabolism of pyrethroids generally, and permethrin specifically, none of which specifically address the metabolism of permethrin in cats. Although the methylation of permethrin to metabolite 1 does occur in other species, it does so only after substantial oxidation. The oxidation of metabolite 1 to metabolite 1P is also documented, occurring again only after extensive metabolic activity. The above-cited review article also discusses the glucuronidation of permethrin, yet it does so only in the context of rabbits and several species of rodents. The metabolism of permethrin in the rabbit is also more fully discussed in the section of others, despite describing different metabolic incidents, from the commonly accepted metabolism review. As with cats, further research is needed to fully elucidate the metabolism of permethrin and other pyrethroids in rabbits.

Pyrethroids function by binding selectively and reversibly to sodium channels in all mammalian neurons. This shift in the sodium channel opening potential causes repetitive neuronal discharge voltage depolarization and hinders synaptic transmission, causing paralysis. Germane to their increased risk relative to dogs, cats have 750 times higher sensitivity to pyrethroids than do the related canines. The primary reason for these differences in sensitivities can be directly attributed to systematic amino acid replacements that separate the textbook "resistant" allele and genotype from the "high-risk" allele of the voltage-gated sodium channel. The molecular biology that underlies this increased risk has been more fully described elsewhere, yet the outcomes of these receptor-ligand interactions are clearly devastating to the CNS of the affected subjects.

4. Toxicity in Rabbits

Permethrin is a potent toxic substance that can be absorbed dermally, orally, and by inhalation. It exerts a substantial insecticidal impact on fleas, ticks, and internal and external parasites. Even a small dermal dose of permethrin can result in distinct clinical signs, experienced instantly or within 24 hours of exposure. Apart from this, accidental exposure to large oral doses is not unusual.

This review aims to delve into the specific sensitivity and resultant clinical signs of permethrin poisoning in rabbits. Although similar products are used for cats and rabbits, each species has unique physiological responses and marked variations in metabolism and elimination. Concentrations of permethrin within a cat flea treatment that was clinically administered at the label dose and onset of clinical signs resulted in a permethrin spot-on for a cat to be lethal to rabbits due to a mass of less than 2 kg (which is well below the market range of the average domesticated population).

The size of the golden rabbit hamster differs from that of the rabbit type O. Graphs show the percutaneous absorption of [^14C]-permethrin following the administration of 13.8% externally. At the first 5 time points following the dosage, permethrin plasma concentrations were not detectable in any rabbit examined, and the tested intra-animal variations were less than 20% at all time points, except for one of the two male animals examined at 120 hours post-dose, when variances between the groups were around 30% (CV).

4.1. Sensitivity to Permethrin

The blowing up of the sensation of permethrin toxicity in rabbits is surprising in mark off with other pet species, as rabbits are generally considered a little sensitive species according to the guidelines of many other animal protection organizations, being very sensitive when exposed to other pharmacologics like penicillin or ivermectin. However, the rabbits' sensitivity to permethrin can vary significantly from individual to individual. The basic differences between rabbits and cats in permethrin reaction lie in the reason why humans use the substance in the various species, and it is from these differences that different reactions originate. What some pet owners erroneously perceive as a "typical reaction," consisting of rapid balance disturbances and convulsions, is only true for a restricted number of affected rabbits.

The typical reaction, consisting of the difficulty of maintaining balance to fine convulsions generally does not exist in affected rabbits, but a privileged diagnosis will take into account the following data. The typical reactions of rabbits range from overexcitement and sudden contractions to fright behavior, excitement and aggression, body sliding, and lateralization, various degrees of ataxia in wide circles; head collisions in the environment, trying to climb vertical surfaces, and maintaining the head so much above the height of the body as to find a support so as not to tip over, constant twirling, and signs of splenic hypertonia. The most severe reactions may involve very high rectal temperatures, loss of protective reflexes, reversal of Corneal reflex, and death. Dystocia or early miscarriage may also occur. Dose decrease associated with renal or liver failure.

4.2. Clinical Manifestations

One to four hours after the administration of permethrin, the rabbit was depressed, with half-closed eyes while in lateral decubitus, hair loss, and licked their inguinal, sacrococcygeal, and axillary regions. The rabbit showed akinesia, face paralysis, mainly in the orbicular and triangularis oculi muscles, edema in the eyelids and a disfigured face. Mastication was affected and up to 48 h after the onset of the clinical signs, the rabbit showed sialorrhea, dysphagia, and difficulty in swallowing. Some animals produced reduced feces, which were dry and irregular in form, while others were unable to defecate. During the clinical examination in lateral decubitus, paralysis of the anterior or posterior limbs was recorded. The electrocardiogram recorded signs of severe dehydration and bradycardia, while the blood pressure increased. The body temperature showed hypothermia. No pruritus was observed in these rabbits.

Rabbits from the first experiment (Ex. 1) did not show signs of pruritus. Some rabbits, which mainly corresponded to the LG (10 ppm and 100 ppm) and SMG (25 ppm), were prostrate and quiet, and one was found lying on the back in sternal recumbent with the lower limbs in a trampling position. A rabbit from the SMG (100 ppm) was prostrate with the bladder full and difficult to evacuate, and it was anesthetized to empty the bladder. One rabbit of the SMG (100 ppm) had a bloody mucous nasal and ascent of the conjunctival third eyelid. No difference in the oncotic, hypotonic, and due to overdry value of the CMP was reported. The EO count decreased in all groups and in the SMG (25 and 100 ppm) after 48 h. A mild neutrophilia was observed in the LG. The human body temperature was normal and decreased in the SMG (25 and 100 ppm) and LG after 9 h, and a mild heart rate decrease was mostly recorded in the SMG (10 and 100 ppm). No change in the respiratory rate was observed during the trial.

5. Preventative Measures and Treatment

Tips for avoiding permethrin exposure in cats and rabbits are straightforward. One of the most important things that can be done is to read the product label thoroughly, which helps ensure safety for the feline species based on the presence or absence of permethrin in individual products. If any labels contain confusing, unclear or incorrect information about photoproduct-related safety, such as indicating that products containing permethrin can be safely applied to cats, it is advisable to contact the manufacturer's veterinary services personnel for more information regarding the safety of the product in question. Trained veterinarians can perform a physical examination, including a complete neurological examination, to establish the extent and severity of permethrin-based toxicosis in cats and rabbits.

Specific treatment involving detoxification mechanisms such as activated charcoal, multiple-dose activated charcoal (MDAC) or early whole-bowel irrigation should only be considered during the first 1 to 4 hours post-exposure. However, after this time frame, no correlations exist between detoxification methods or outcomes and permethrin clearance for cats. Other therapeutic interventions should target individual patient signs but should never exclude symptomatic therapies. Skin decontamination is important, particularly if large amounts have been applied, and measures such as fan therapy can be helpful in reducing body temperature during hyperthermia. It is important in the treatment of animals following permethrin exposure to remember that thermoregulation requires patient sedation and rapid cooling measures and supportive care. Often, intensive care hospitalization is required for those cases that exhibit tremors, seizures and/or hyperthermia, as it is important to monitor and manage laboratory parameters, including blood gas measurements.

5.1. Avoiding Exposure in Cats and Rabbits

It is unknown how much permethrin is toxic in cats and rabbits; neither has a set guideline from which to work. Some individual cats and some individual rabbits have a high tolerance to permethrin, while others might become extremely sick even with very low doses. This creates difficulties for pet owners wanting to protect their dogs, and thus their cats and rabbits, because they cannot accurately estimate the dosage used to treat the dog for successful permethrin flea and tick control. Some owners have had long-term success using spot-on or tablet formulations.

The perspective from the New Zealand Veterinary Association is that there are more effective flea and tick treatments available that are less toxic to non-target species than permethrin compounds. Thus, some practical recommendations for avoiding exposure in cats and rabbits are to:

4.1.2. Disposal of Packaging. The use and disposal of organophosphates and pyrethroid-containing treatments are restrained and controlled.

4.1.3. La. compacta. The service life of pour-on organophosphates was 24 days, while pyrethroids, including the time used for the recovery of the ticks and further reapplications, were less than 20 days. More than two consecutive treatments were required for the elimination of vegetation I. puntal. permethrin.

5.2. Veterinary Interventions

Veterinary interventions. The veterinary interventions aimed at correcting or at least reducing the risk of mortality in companion animals are essentially symptomatic and involve gastrointestinal decontamination, general supportive care, and anticonvulsive treatment in severe cases. Even though there is no recommendation for a specific antidote to overcome permethrin poisoning, a short-acting drug, methocarbamol, may be beneficial in the treatment of severe tremors and seizures. Future studies on methocarbamol use in permethrin-toxic cats are encouraged. Hemodialysis, as a blood purification method, can be applied as a supportive treatment option. However, the frequent reports connecting the signs of intoxication with adverse effects on animal welfare show a demand for more treatment options and an improved appreciation of pathophysiological background.

As the oral margin of safety in cats is very steep, even a small increase in dosage would have led to the death of the cat in a very short period of time, but the risk of such escalation would have been very high. The objective was to manage the specific signs of the intoxication in a step-by-step approach, which is described in further detail below. After treatment, numerous symptoms still prevailed, and no specific antidote was administered. Veterinary advice suggests supportive measures to enhance detoxification and/or hydration, if necessary, or to palliate the discomfort of the animal. The patient was intensively observed for a 28-day period, during an experimental setting, and the signs of the intoxication showed regression over time. This case reports an involuntary acute permethrin intoxication of a cat, followed by an in-depth and extensive physical description of one featured clinical case, to add to the existent knowledge of the symptoms of permethrin intoxication. (Tellado et al., 2022)(Roy et al.2021)(Grubb et al.2020)(Grubb & Lobprise, 2020)(Ensign & Grubb2020)

References:

Tellado, M., Mir, L. M., & Maglietti, F., 2022. Veterinary guidelines for electrochemotherapy of superficial tumors. Frontiers in Veterinary Science. frontiersin.org

Roy, S., Islam, S., Alam, S., Ahmed, J. and Chowdhury, Q.M.K., 2021. Successful management of a kitten with chlorpyrifos and cypermethrin toxicosis with pralidoxime and atropine. Journal of Feline Medicine and Surgery Open Reports, 7(2), p.20551169211045647. sagepub.com

Grubb, T., Sager, J., Gaynor, J.S., Montgomery, E., Parker, J.A., Shafford, H. and Tearney, C., 2020. 2020 AAHA anesthesia and monitoring guidelines for dogs and cats. Journal of the American Animal Hospital Association, 56(2), pp.59-82. veterinarian.lt

Grubb, T. & Lobprise, H., 2020. Local and regional anaesthesia in dogs and cats: Descriptions of specific local and regional techniques (Part 2). Veterinary medicine and science. wiley.com

Ensign, S. and Grubb, T., 2020. Pain and Analgesia. In Anesthesia and Pain Management for Veterinary Nurses and Technicians (pp. 211-292). Teton NewMedia. [HTML]