Defination of Pesticides:

A pesticide is any substance used to kill, repel, or control certain forms of plant or animal life that are considered to be
pests. Pesticides include herbicides for destroying weeds and other unwanted vegetation, insecticides for controlling a wide
variety of insects, fungicides used to prevent the growth of molds and mildew, disinfectants for preventing the spread of
bacteria, and compounds used to control mice and rats. Because of the widespread use of agricultural chemicals in food
production, people are exposed to low levels of pesticide residues through their diets. Scientists do not yet have a clear
understanding of the health effects of these pesticide residues.

The Food and Agriculture Organization (FAO) has defined pesticide as:

Any substance or mixture of substances intended for preventing, destroying, or controlling any pest, including vectors of
human or animal disease, unwanted species of plants or animals, causing harm during or otherwise interfering with the
production, processing, storage, transport, or marketing of food, agricultural commodities, wood and wood products or
animal feedstuffs, or substances that may be administered to animals for the control of insects, arachnids, or other pests in
or on their bodies. The term includes substances intended for use as a plant growth regulator, defoliant, desiccant, or agent
for thinning fruit or preventing the premature fall of fruit. Also used as substances applied to crops either before or after
harvest to protect the commodity from deterioration during storage and transport.

According to the Environmental Protection Agency (EPA)- the government body that regulates pesticides in the U.S., a
pesticide is any substance or mixture of substances intended for preventing, destroying, repelling or mitigating any pest.
Though often misunderstood to refer only to insecticides, the term pesticide also applies to herbicides, fungicides, and
various other substances used to control pests. Pesticides also include plant regulators, defoliants and desiccants.

Classification of Pesticides:
There are many different types of pesticides, each is meant to be effective against specific pests. The term "-cide" comes
from the Latin word "to kill."

Algaecides: Algaecides are used for killing and/or slowing the growth of algae.

Antimicrobials: Antimicrobials control germs and microbes such as bacteria and viruses.

Biopesticides: Biopesticides are made of living things, come from living things, or they are found in nature.

Desiccants: Desiccants are used to dry up living plant tissues.

Defoliants: Defoliants cause plants to drop their leaves.

Disinfectants: Disinfectants control germs and microbes such as bacteria and viruses.

Foggers: Foggers (total release foggers) are used to kill insects that are in the open and touch the pesticides.

Fungicides: Fungicides are used to control fungal problems like molds, mildew, and rust.

Herbicides: Herbicides kill or inhibit the growth of unwanted plants, aka weeds.

Illegal and Counterfeit Pesticides: Illegal and Counterfeit Pesticides are imported or sold illegally.

Insecticides: Insecticides are used to control insects.

Insect Growth Regulators: Insect Growth Regulators disrupt the growth and reproduction of insects.

Minimum Risk Pesticides: Minimum Risk Pesticides are exempt from EPA registration, but many states require them to be
registered.
Miticides: Miticides control mites that feed on plants and animals. Mites are not insects, exactly.

Molluscicides: Molluscicides are designed to control slugs, snails and other molluscs.

Mothballs: Mothballs are insecticides used to kill fabric pests by fumigation in sealed containers.

Natural and Biological Pesticides: Natural and Biological Pesticides control pests using things found in nature, or man-made
versions of things found in nature.

Ovicides: Ovicides are used to control eggs of insects and mites.

Pheromones: Pheromones are biologically active chemicals used to attract insects or disrupt their mating behavior. The
ratio of chemicals in the mixture is often species-specific.

Plant Growth Regulators: Plant Growth Regulators are used to alter the growth of plants. For example, they may induce or
delay flowering

Repellents: Repellents are designed to repel unwanted pests, often by taste or smell.

Rodenticides: Rodenticides are used to kills rodents like mice, rats, and gophers

Synergists: Synergists make certain pesticides more effective, but they are not effective when used alone.

Treated Seeds: Treated Seeds are coated with a pesticide to limit crop damage from fungus and insects.

Wood Preservatives: Wood Preservatives are used to make wood resistant to insects, fungus and other pests.

Different Types of Pesticides For Veterinary Use in DOGS, CATS, HORSES and LIVESTOCK - cattle,
sheep, goat, pigs, poultry:
NATURAL INSECTICIDES (insecticides, anthelmintics) for veterinary use in DOGS, CATS, HORSES and LIVESTOCK - cattle,
sheep, goat, pigs, poultry:

Natural ANTIPARASITICS compounds are specific chemical molecules, which occur in nature (mostly in plants) and show
some kind of parasiticidal efficacy. "Natural" means that they are not of synthetic origin, although they may be more or less
easily synthesized in the laboratory. Most such products identified so far show insecticidal and/or acaricidal effects, only a
few ones act upon helminths.

The natural origin of such active ingredients does not mean that all commercial products made with them contain only
naturally produced active ingredients. Industrial manufacturing of several natural active ingredients can be done by
extraction and purification of plant extracts, but also by standard synthetic processes. And most inert ingredients are not of
natural origin any way.

Such natural compounds (active ingredients) are not to be mixed up with natural plant extracts or essential oils which
contain more or less well defined mixtures of several compounds.

Flowers of Pyrethrum spp. There are two major types of natural active ingredients: those produced by plants(trees, shrubs,
grasses, etc.) and those produced my microorganisms(bacteria, fungi, yeasts, etc).

Compounds produced by plants can often be obtained by simple (i.e. non synthetic), more or less sophisticated extraction
out of vegetable material (seeds, leaves, bark, etc.) from plants that are conventionally grown and harvested for this
purpose. Many of these plants have been known for centuries and are used in traditional remedies in many cultures and
regions.

Compounds produced by microorganisms are obtained in large scale sophisticated fermentation processes where these
organisms are multiplied, whereby genetically engineered strains may be used. The parasiticidal compounds are then
extracted from such organisms. In contrast with the plants, such microorganisms were not known in the traditional
medicine in the past and are usually not available for preparing home-made remedies.

Only very few antiparasitic compounds of natural (i.e. non-synthetic) origin have such a "crushing" efficacy against
veterinary parasites as most synthetic active ingredients. However, those available can be useful to handle light infestations
or as alternatives to treat weak or young animals.

In addition, there are a few inorganic compounds of mineral origin with certain insecticidal or anthelmintic properties. They
are not produced by living organisms but can be manufactured from naturally ocurring minerals.

Natural active ingredients with antiparasitic efficacy:

Natural organic compounds produced by plants:

Azadirachtin: insecticide & acaricide; very scarce use in domestic animals

Carvacrol: insecticide; not used directly in veterinary products

Citronellal (& citronellol): repellent; scarce use in domestic animals

D-limonene: insecticide, acaricide & repellent; scarce use in domestic animals

Eucalyptol: repellent; very scarce use in domestic animals

Eugenol: insecticide, acaricide & repellent; very scarce use in domestic animals

Geraniol: repellent; very scarce use in domestic animals

Linalool: insecticide, acaricide & repellent: very scarce use in domestic animals

Pyrethrins: insecticides, acaricides & repellents: abundant use in domestic animals

Rotenone: insecticide; scarce use in domestic animals

Thymol: insecticide; very scarce use in domestic animals

These compounds are sometimes used as active ingredients in veterinary antiparasitics, but often also in the form of
essential oils of various plant extracts that contain a more or less variable mixture of some of these and other natural
compounds. These natural compounds or the corresponding plant extracts are often used in OTC (over-the-counter) "soft"
antiparasitics such as shampoos, soaps, sprays, powders, lotions and the like for petsor horses, typically to protect them
against fleas, mosquitoes, flies, etc. The use of such natural compounds on livestock is irrelevant.

Natural organic compounds produced by microorganisms:

Abamectin: insecticide, acaricide & anthelmintic; abundant use in livestock

Spinosad: insecticide & acaricide, abundant use in domestic animals

Natural inorganic compounds of mineral origin:

Sulfur: insecticide; very scarce use in domestic animals

Borax: insecticide; very scarce use in domestic animals

Silica, diatomaceous earth: insecticide, acaricide; scarce use in domestic animals

Copper: anthelmintic, very scarce use in livestock.

Derris elliptica: its roots contain rotenone.

It must be remembered that the natural origin does not guarantee at all that such compounds are less toxic than the
synthetic parasiticides. They are as "chemical" as the synthetic ones. Toxicity is a matter of dose! But as a general rule,
natural compounds are less persistent in the treated animals and in the environment than most classic synthetic
parasiticides. The reason is that they are often sensitive to sunlight and/or are relatively quickly excreted, metabolized or
otherwise broken down in the environment.

Regarding their antiparasitic efficacy, a common feature of most natural compounds is that they are less potent, not as fast-
acting and almost always less persistent than modern synthetic parasiticides. The only exception are abamectin, which is
similar to ivermectin, a semi-synthetic compound, and spinosad. But what may be a disadvantage from the efficacy point of
view can be a benefit from the safety point of view, e.g. in ecological productionwhere the absence of residues (in meat,
milk, eggs, etc.) is a key benefit.

As a rule, products with such natural compounds are often submitted to a much looser authorizationprocess than
veterinary medicines regarding quality (e.g., specifications), proof of efficacy and safety. This is why there are so many
brands: it is quite cheap to develop them.

Many home remedies against veterinary parasites are based on recipes using medicinal plants that contain such natural
compounds.

CHEMICAL CLASSES of VETERINARY PESTICIDES(PARASITICIDES) for use in LIVESTOCK, HORSES, DOGS and CATS:

From a purely chemical point of view almost all active ingredients with parasiticidal activity (either internal or internal
parasiticides) discovered so far are synthetic organic molecules, i.e. they do not occur in nature but have been synthesized
in the laboratory. Very few such active ingredients occur naturally in plants or other organisms. And even fewer are of
mineral (i.e. inorganic) origin.

Most active ingredients can be grouped into chemical classes or families with similar functional groups, i.e. they share a
specific molecular structure. E.g. organophosphates are all derivatives of phosphoric acid.

Active ingredients of the same chemical groups have usually the same mechanism of action at the molecular level. What
differs considerably for active ingredients of the same chemical class is often the spectrum of activity, the toxicity to both
parasitesand non-target organisms, the behavior in the environment, etc.

The most relevant chemical classes of parasiticidesdiscovered so far are the following ones, ordered by spectrum of activity
and by the decade the first compounds were introduced, regardless of whether they are still marketed today or not:

Endectocides

Active against both external and internal parasites

Macrocyclic Lactones (1980s) or endectocides: broad-spectrum systemic ecto and endoparasiticides,

Ectoparasiticides

Active against external parasites (mainly insects, ticks and mites)

Organochlorines (1940s): broad-spectrum insecticides and acaricides, nowadays prohibited in most countries.

Organophosphates (1950s): broad-spectrum insecticides and acaricides. Are being phased out in some countries.

Carbamates (1950s): broad-spectrum insecticides and acaricides. Are being phased out in some countries.

Amidines (1960s): mainly acaricides and tickicides.

Synthetic Pyrethroids (1970s): broad-spectrum insecticides and acaricides.

Benzoylureas (1970s): development inhibitors (= growth regulators).

Juvenile Hormone Analogues (1970s): development inhibitors (= growth regulators).

Neonicotinoids (1990s): broad-spectrum insecticides and acaricides.

Phenylpyrazoles (1990s): broad-spectrum insecticides and acaricides.

Spinosyns (1990s): broad-spectrum insecticides and acaricides, partly systemic.

Isoxazolines (2010s): broad spectrum, systemic insecticides and acaricides.

A few relevant ectoparasiticides do not belong to these chemical classes, e.g. cyromazine, dicyclanil.

Other chemicals frequently used on livestock and pets against external parasites are not properly ectoparasiticides, nor
build an own chemical class, but they share a common funtionality regarding their use against external parasites:

Repellents: do not kill the parasites, but keep them away from the treated animals. They are not properly a chemical class,
but a functional class.

Synergists: enhance the parasiticidal activity of certain active ingredients or help to overcome resistance.

Endoparasiticides = anthelmintics

active against internal parasites mostly parasitic worms (roundworms, tapeworms, flukes)

Benzimidazoles (1960s): broad-spectrum anthelmintics: nematicides, taenicides, flukicides

Imidazothiazoles (1960s): broad-spectrum nematicides (only against roundworms)

Tetrahydropyrimidines (1960s): narrow-spectrum nematicides

Isoquinolines (1970s): taenicides

Salicylanilides (1970s): narrow-spectrum nematicides, taenicides, flukicides

A few relevant endoparasiticides do not belong to these chemical classes, e.g. clorsulon, monepantel, nitroscanate,
nitroxinil, piperazine derivatives.

Other parasiticides

A few parasiticides are of mineral (i.e. non-synthetic) origin, or are directly obtained from plants: Mineral insecticides

Natural plant insecticides

Copper: used mainly as an anthelmintic against a few parasitic roundworms in the stomach of ruminants.

Name & Application Of Different Types Of Pesticides For Veterinary Use in Animal (Small Animal,
Large Animal, Poultry):
Ectoparasiticides Used in Large Animals

Arthropod parasites (ectoparasites) are major causes of livestock production losses throughout the world. In addition, many
arthropod species can act as vectors of disease agents for both animals and people. Treatment with various parasiticides to
reduce or eliminate ectoparasites is often required to maintain health and to prevent economic loss in food animals. Some
ectoparasiticides were derived from pesticides used to protect crops. The choice and use of ectoparasiticides depend to a
large extent on husbandry and management practices, as well as on the type of ectoparasite causing the infestation.
Endectocides are capable of killing both internal and external parasites. Accurate identification of the parasite or correct
diagnosis based on clinical signs is necessary for selection of the appropriate parasiticide. The selected agent can be
administered or applied directly to the animal, or introduced into the environment to reduce the arthropod population to a
level that is no longer of economic or health consequence.

Parasites that live permanently on the skin, such as lice, keds, and mites, can be controlled by directly treating the host.
Some mange mites burrow into the skin and are therefore more difficult to control with sprays than are lice and keds, which
are found on the surface of the skin. However, once these obligate parasites are eradicated, reinfection occurs only from
contact with other infected animals.

Ectoparasites with stages that live off the host (ticks, flies, etc) are less easily controlled. Only a small proportion of the
ectoparasite population can be treated on the host at any one time, and other hosts may maintain them. Some tick species
stay on the host only long enough to feed, which may be as short as 30 min or as long as 21 days. Biting flies, such as the
horn fly, can be found continually on the backs and undersides of cattle, where they suck blood up to 20 times a day; other
biting flies (such as stable flies and horse flies) and mosquitoes feed to repletion, then leave the animal to lay eggs.
Nonbiting flies, such as the face fly or house fly, may visit infrequently but can be very annoying and may transmit disease
agents. Larvae of certain blowflies live on the skin or in tissues of sheep and other animals and cause cutaneous myiasis.
Larvae of other flies spend several months inside animals (eg, nasal bots in the nasal passages of sheep and goats, bots in
the stomach of horses, and cattle grubs or warbles in the back or esophageal tissues).

Many ectoparasite infestations are seasonal and predictable and can be countered by prophylactic use of ectoparasiticides.
For example, in temperate countries, flies are seen predominantly from late spring to early autumn, tick populations often
increase in the spring and autumn, and lice and mite infestations can be more common during the autumn and winter
months. Treatments can be targeted at anticipated times of peak activity as a way to limit parasite populations and disease.

Products are available for parenteral administration or for topical application by various methods, including dips, sprays,
pour-ons, spot-ons, dusting powders, and ear tags. The method used depends on the target parasite and host. Importantly,
most topical ectoparasiticides used in the USA are pesticides regulated by the U.S. Environmental Protection Agency (EPA).
This is an important distinction from products regulated by the U.S. Food and Drug Administration (FDA), because it is illegal
to use an EPA-regulated pesticide product inconsistent with its label directions. The regulating agency should be identifiable
on the product label.

Chemotherapeutic Agents

Most ectoparasiticides are neurotoxins, exerting their effect on the nervous system of the target parasite. Those used in
large animals can be grouped according to structure and mode of action into the organochlorines, organophosphates and
carbamates, pyrethrins and pyrethroids, macrocyclic lactones (avermectins and milbemycins), formamidines, insect growth
regulators, and a number of miscellaneous compounds, including synergists (eg, piperonyl butoxide). There are also a
number of useful compounds with repellent rather than insecticidal activity, including butoxypolypropylene-glycol and N,N-
diethyl-3-methylbenzamide (DEET, previously called N,N-diethyl-metatoluamide).

Organochlorines:

Organochlorine compounds have been withdrawn in many parts of the world because of concerns regarding environmental
persistence.

Organochlorines fall into three main groups:

1)Chlorinated ethane derivatives, such as DDT (dichlorodiphenyltrichloroethane), DDE

(dichlorodiphenyldichloroethane), and DDD (dicofol, methoxychlor);

2)Cyclodienes, including chlordane, aldrin, dieldrin, hepatochlor, endrin, and toxaphene

3) Hexachlorocyclohexanes such as benzene hexachloride (BHC), which includes the γ-isomer, lindane.
  Chlorinated ethanes cause inhibition of sodium conductance along sensory and motor nerve fibers by holding
sodium channels open, resulting in delayed repolarization of the axonal membrane. This state renders the nerve
vulnerable to repetitive discharge from small stimuli that would normally cause an action potential in a fully
repolarized neuron.
 The cyclodienes appear to have at least two component modes of action: inhibition of γ-aminobutyric acid (GABA)-
stimulated Cl– flux and interference with Ca 2+ flux. The resultant inhibitory postsynaptic potential leads to a state
of partial depolarization of the postsynaptic membrane and vulnerability to repeated discharge. A similar mode of
action has been reported for lindane, which binds to the picrotoxin side of GABA receptors, resulting in an
inhibition of GABA-dependent Cl– ion flux into the neuron.
 DDT and BHC were used extensively for flystrike control but subsequently replaced in many countries by more
effective cyclodiene compounds, such as dieldrin and aldrin. Both the development of resistance and
environmental concerns led to their withdrawal. DDT and lindane were widely used in dip formulations to control
sheep scab, but they have mostly been replaced by the organophosphates and subsequently the synthetic
pyrethroids.

Organophosphates and Carbamates:

 The organophosphates comprise a large group of chemicals, many of which are available for topical application
and in ear tags as well as for premise control of parasites. There have been many products available worldwide for
use in domestic animals, although only a few of the available compounds continue to be used for on-animal
treatment.
 Organophosphates are neutral esters of phosphoric acid or its thio analogue that inhibit the action of
acetylcholinesterase (AChE) at cholinergic synapses and at muscle endplates. The compound mimics the structure
of acetylcholine (ACh); when it binds to AChE, it causes transphosphorylation of the enzyme. The transphorylated
AChE is unable to break down accumulating ACh at the postsynaptic membrane, leading to neuromuscular
paralysis. The degree of transphorylation of the enzyme helps to determine the activity of the organophosphate.
Eventually, the AChE is metabolized by oxidative and hydrolytic enzyme systems.
 Organophosphates can be extremely toxic in animals and people, inhibiting AChE and other cholinesterases (see
Organophosphates (Toxicity)). Chronic toxicity results from inhibition of an enzyme known as neuropathy target
esterase (NTE) or neurotoxic esterase and is associated with particular compounds. NTE hydrolyzes the fatty acids
from the membrane lipid, phosphotidylcholine, and inhibition of NTE appears to cause structural changes in
neuronal membranes and a reduction in conduction velocity, which may be manifest as posterior paralysis in some
animals. Cases of organophosphate toxicity are treated with oximes or atropine.
 Organophosphates used topically include coumaphos, diazinon, dichlorvos, malathion,
tetrachlorvinphos,trichlorfon, phosmet, and pirimiphos. Ear tags containing chlorpyrifos, coumaphos, diazinon, or
pirimiphos are available. These compounds are generally active against fly larvae, flies, lice, ticks, and mites on
domestic livestock, although activity varies between compounds and differing formulations. Chlorpyrifos can be
used in microencapsulated form for residual activity and improved safety. Diazinon and propetamphos have been
available in dip formulations to control psoroptic mange in sheep. Both eliminate mites and protect in a single
application when correctly applied. Diazinon provides longer residual protection than propetamphos. In cattle, a
number of compounds have been used for systemic control of warble fly grubs and lice as pour-on applications or
in hand sprays, spray races, or dips for tick control.
 Carbamate insecticides are closely related to organophosphates and are anticholinesterases. Unlike
organophosphates, they appear to cause a spontaneously reversible block on AChE without changing it. The main
carbamate compound used in veterinary medicine is propoxur. Carbaryl, another carbamate previously used in
veterinary medicine, has been withdrawn from the veterinary market.

Pyrethrins and Synthetic Pyrethroids:

  A number of pyrethroids are available in many countries as pour-on, spot-on, spray, and dip formulations with
activity against biting and nuisance flies, lice, and ticks on domestic livestock. Flumethrin and high cis-cypermethrin
are also active against mites and have been used to treat psoroptic mange of sheep.
 Natural pyrethrins are derived from pyrethrum, a mixture of alkaloids from the Chrysanthemum plant. Pyrethrum
extract, prepared from the pyrethrum flower head, contains several molecules collectively known as pyrethrins
(pyrethrin I and II, cinerin I and II, and jasmolin I and II). Pyrethrins are lipophilic molecules that generally undergo
rapid absorption, distribution, and excretion. They provide excellent knockdown (rapid kill) but have poor residual
activity because of instability. Pyrethrin I is the most active ingredient for kill, and pyrethrin II for rapid insect
knockdown.
 Pyrethroids are synthesized chemicals modeled on the natural pyrethrin molecule. They are more stable, thus have
longer residual activity, and have a higher potency than natural pyrethrins.
 The mode of action of pyrethrins and synthetic pyrethroids appears to be interference with sodium channels of the
parasite nerve axons, resulting in delayed repolarization and eventual paralysis. Synthetic pyrethroids can be
divided into two groups (types I and II, depending on the presence or absence of an α-cyano moiety). Type I
compounds have a mode of action similar to that of DDT, involving interference with the axonal Na+ gate leading
to delayed repolarization and repetitive discharge of the nerve. Type II compounds also act on the Na+ gate but do
so without causing repetitive discharge. The lethal activity of pyrethroids seems to involve action on both
peripheral and central neurons, while peripheral neuronal effects alone probably produce the knockdown effect.
Some preparations contain a synergist (eg, piperonyl butoxide), which inhibits breakdown of pesticides by
microsomal mixed-function oxidase (cytochrome P450) systems in insects.
 Pyrethroids are generally safe in mammals and birds but are highly toxic to fish and aquatic invertebrates.
Concerns have been expressed over their environmental effects, particularly in relation to the aquatic
environment, leading to their withdrawal as sheep dips in some countries.
 Some of the more common pyrethroids used include β-cyfluthrin, bioallethrin, cyfluthrin, cypermethrin,
deltamethrin, fenvalerate, flumethrin, lambda cyhalothrin, phenothrin, permethrin, prallethrin, and tetramethrin.
The content of some synthetic pyrethroids is also expressed in terms of the drug isomers, eg, cypermethrin
preparations may contain varying proportions of their cis and trans isomers. Thus, cypermethrin (cis:trans 60:40)
2.5% is equivalent to cypermethrin (cis:trans 80:20) 1.25%. In general, cis isomers are more active than the
corresponding trans isomers.

Macrocyclic Lactones (Avermectins and Milbemycins):

 Avermectins and the structurally related milbemycins, collectively referred to as macrocyclic lactones, are
fermentation products of Streptomyces avermitilis and S cyanogriseus, respectively. Avermectins differ from each
other chemically in side chain substitutions on the lactone ring, whereas milbemycins differ from the avermectins
through the absence of a sugar moiety from the lactone skeleton. A number of macrocyclic lactone compounds are
available for use in animals and include the avermectins abamectin, doramectin, eprinomectin, ivermectin, and
selamectin, and the milbemycins moxidectin and milbemycin oxime. These compounds are active against a wide
range of nematodes and arthropods and are often referred to as endectocides.
 Endectocidal activity, particularly against ectoparasites, is variable and depends on the active molecule, the
product formulation, and the method of application. Macrocyclic lactones can be given PO, parenterally, or
topically (as pour-ons and spot-ons). The method of application depends on the host and, to some degree, on the
target parasites. In cattle, for example, available endectocide products can be given PO, by injection, or topically
using pour-on formulations. The latter are generally more effective against lice (Linognathus, Haematopinus, and
to some extent Bovicola) and headfly (Haematobia/Lyperosia) infestations than equivalent compounds
administered parenterally. In sheep, PO administration of some endectocides has little effect against psoroptic
mite infestations (Psoroptes ovis), but parenteral administration increases activity, providing both protection and
control depending on the product used.
  The route of administration and product formulation influence the rates of absorption, metabolism, excretion, and
subsequent bioavailability and pharmacokinetics of individual compounds. Avermectins and milbemycins are
highly lipophilic, a property that varies with only minor modifications in molecular structure or configuration. After
administration, these compounds are stored in fat, from which they are slowly released, metabolized, and
excreted. Ivermectin is absorbed systemically after PO, SC, or dermal administration; it is absorbed to a greater
degree and has a longer half-life when given SC or dermally. Excretion of the unaltered molecule is mainly via the
feces, with <2% excreted in urine of ruminants. In cattle, the reduced absorption and bioavailability of ivermectin
given PO may be due to its metabolism in the rumen. The affinity of these compounds for fat explains their
persistence in the body and the extended periods of protection afforded against some species of internal and
external parasites. The prolonged half-life of these compounds also determines residue levels in meat and milk and
the subsequent compulsory withdrawal periods after treatment in food-producing animals.
 Macrocyclic lactones bind to glutamate receptors of glutamate-gated chloride channels, triggering Cl– ion influx
and hyperpolarization of parasite neurons, leading to flaccid paralysis. These molecules have low affinity for
mammalian ligand-gated chloride channels and do not readily cross the blood-brain barrier.

Persistent Efficacy

A single therapeutic dose of an avermectin can persist in concentrations sufficient to be effective against susceptible
nematode infections for prolonged periods. The clinical significance of prolonged efficacy is important. Sustained availability
protects animals from reinfection by some nematode (and arthropod) species for several weeks, which helps control pests
that intermittently or constantly challenge livestock. Large variations in the persistent efficacy of a particular macrocyclic
lactone against a particular worm species have been reported. Potential reasons for these variable results include study
design and host- and parasite-related factors. Persistent efficacy has been investigated mainly against the three major cattle
nematodes Ostertagia ostertagi, Cooperia oncophora, and Dictyocaulus viviparus, and the sheep nematodes Haemonchus
contortus and Teladorsagia circumcincta. The duration of persistent efficacy varies according to the macrocyclic lactone and
formulation used and may be (excluding specific long-acting formulations) 14–45 days for Ostertagia, 0–35 days for
Cooperia, and 21–42 days for Dictyocaulus. The persistent efficacy of oral moxidectin (2–5 wk) gives it a special role in
control of haemonchosis and T circumcincta in sheep and in resistance development.

Cattle:

Ivermectin, eprinomectin, abamectin, doramectin, and moxidectin are variously available as PO, SC, and pour-on
formulations for use in cattle. The SC and PO formulations are given at 0.2 mg/kg, whereas the pour-on formulation is used
at 0.5 mg/kg. Topical administration (ie, pour-on formulations) is more convenient but results are more variable between
animals than when administration is SC or PO. Grooming behavior of cattle has a major influence on the plasma disposition
of topical macrocyclic lactones. Undesirable subtherapeutic concentrations in both treated and untreated cattle may
contribute to development of drug resistance.

An oil-based, long-acting formulation of ivermectin (3.15% w/v ivermectin) is available in Brazil and most Latin American
and African countries. One low-volume SC dose (1 mL/50 kg, equivalent to ivermectinat 630 mcg/kg) effectively treats and
prophylactically controls many internal and external parasites of cattle for up to 77 days. A long-acting parenteral
formulation for moxidectin has also been developed. The injectable solution (1 mg/kg, SC, behind the ear) is an oil-based
formulation containing 10% moxidectin; it is registered in Latin America, Australasia, and some European countries. In
controlled studies, the periods of protection against some nematode infections using this long-acting moxidectin
formulation were 90–150 days according to the species. Recently, a long-acting injectable formulation of eprinomectin (1
mg/kg, SC, in front of the shoulder) was registered for use in cattle. Treatment provides persistent parasite control for 100–
150 days, depending on parasite species.

The macrocyclic lactones have a very high (>98%) efficacy against all stages (including inhibited forms) of the common cattle
nematodes. The least susceptible nematodes are Cooperia and Nematodirusspp. Because of their high potency and
elimination through milk, the macrocyclic lactones are not recommended for use in animals that produce milk for human
consumption. Eprinomectin and moxidectin pour-ons are exceptions and have no milk withdrawal time in many countries.

A wide range of effective chemoprophylactic systems has been developed to prevent outbreaks of parasitic gastroenteritis
and control infections in first-season grazing calves. Strategic anthelmintic medication during the first half of the grazing
season, using carefully timed administration of macrocyclic lactones, has proved to be highly effective in western Europe for
the control of GI nematodes of grazing calves during their first year. Because of differences in management, pasture
infectivity, and climate, it is difficult to identify which program is most effective. Any chemoprophylactic program should be
beneficial, as long as it is adapted to the epidemiologic situation and farm management.

Small Ruminants:

Ivermectin, doramectin, and moxidectin are variously available as PO, SC, and IM formulations for use in small ruminants.
As for cattle, the macrocyclic lactones have a very high (>98%) efficacy against all stages, including inactive forms, of the
common sheep and goat nematodes. However, because of management practices leading to selection for resistance to
macrocyclic lactones among nematodes of small ruminants, mainly in the southern hemisphere, their use is more
problematic (see Resistance to Anthelmintics). Although moxidectin, at its recommended dose rate, can initially be effective
against some parasite strains resistant to ivermectin, there is side-resistance between the avermectins and the
milbemycins, so this efficacy is temporary. Oral moxidectin has a persistent efficacy of up to 5 wk for Haemonchus
contortus and Teladorsagia circumcincta. Ivermectin controlled-release capsules have been used by sheep producers. The
delivery rate, maintained for 100 days, is 0.8 mg ivermectin/day for sheep 20–40 kg in weight and 1.6 mg/day for sheep
weighing 41–80 kg.

Swine:

In pigs, ivermectin and doramectin are given at 0.3 mg/kg body wt, SC, or ivermectin is given in feed for 7 days at 0.1 mg/kg
body wt/day for the treatment of all adult and larval stages of the common swine parasites, including the kidney worm
Stephanurus. The exception is Trichuris suis, in which efficacy is ~80%.

Horses:

Ivermectin and moxidectin are the two most common macrocyclic lactones available for use in horses. In certain regions,
abamectin is also available. Ivermectin and abamectin are used in horses at a dosage of 200 mcg/kg, whereas moxidectin is
used at 400 mcg/kg. Ivermectin, abamectin, and moxidectin are effective against a broad range of adult and migrating larval
stages of nematode (including large and small strongyles) and arthropod (Gasterophilusspp) parasites. The only reported
difference in efficacy of the two products is that at therapeutic dosages, ivermectin has not shown significant efficacy
against the arrested stages and intramucosal developing stages of the cyathostomes, and moxidectin appears less potent
against stomach bots (Gasterophilus spp). The persistence of moxidectin in circulation can provide horses with 2–3 wk of
protection from infective cyathostome larvae. Moxidectin and ivermectin may not be the drugs of choice to treat infections
with Parascaris equorum because of emerging resistance.

Dogs and Cats:

Ivermectin, selamectin, moxidectin, and milbemycin oxime may be used in dogs for the prevention of heartworm disease
and control of GI roundworms. Many canine parasites are susceptible to ivermectin at the dosages used in other animals;
however, because some dogs are adversely affected at these levels, ivermectin is used in dogs at 6 mcg/kg body wt, PO,
given at 1-mo intervals, to prevent development of Dirofilaria immitis, the cause of heartworm disease. At higher dosages
(>100 mcg/kg), some Collies and individual dogs of other breeds are adversely affected by ivermectin. At a dosage of 0.5
mg/kg, PO, milbemycin oxime is used for prevention of heartworm infection and for treatment of hookworms, ascarids, and
whipworms in dogs. Moxidectin is also effective for prevention of heartworm infection at a dose rate of 3 mcg/kg, PO. The
safety of milbemycin and moxidectin in dogs, including those sensitive to macrocyclic lactones, appears to be similar to that
of ivermectin.
Selamectin, an avermectin monosaccharide, and moxidectin are available in topical formulations. Selamectin and
moxidectin are also true endectocides at their recommended dosages, because their activity encompasses common
intestinal nematodes (eg, Toxocara), heartworms,

Formamidines:

 Amitraz is the only formamidine used as an ectoparasiticide. It appears to act by inhibition of the enzyme
monoamine oxidase and as an agonist at octopamine receptors. Monoamine oxidase metabolizes amine
neurotransmitters in ticks and mites, and octopamine is thought to modify tonic contractions in parasite muscles.
Amitraz has a relatively wide safety margin in mammals; the most frequently associated adverse effect is sedation,
which may be associated with an agonist activity of amitraz on α2-receptors in mammalian species.
 Amitraz is available as a spray or dip for use against mites, lice, and ticks in domestic livestock. It controls lice and
mange in pigs and psoroptic mange in sheep. In cattle, it has been used in dips, sprays, or pour-ons for control of
single-host and multihost tick species. In dipping baths, amitraz can be stabilized by the addition of calcium
hydroxide and maintained by standard replenishment methods for routine tick control. An alternative method
involves the use of total replenishment formulations in which the dip bath is replenished with full concentration of
amitraz at weekly intervals before use. Amitraz is contraindicated in horses.

Chloronicotinyls and Spinosyns:

Imidacloprid is a chloronicotinyl insecticide, a synthesized chlorinated derivative of nicotine. Spinosad is a fermentation

product of the soil actinomycete Saccharopolyspora spinosa. Both compounds bind to nicotinic acetylcholine receptors (but
at different sites) in the insect’s CNS, leading to inhibition of cholinergic transmission, paralysis, and death. Spinosad has
been developed in some countries for use on sheep to control blowfly strike and lice.

Insect Growth Regulators:

 Insect growth regulators (IGRs) are used throughout the world and represent a relatively new category of insect
control agents. They constitute a group of chemical compounds that do not directly kill the adult parasite but
interfere with growth and development. Because they act mainly on immature parasite stages, IGRs are not usually
suitable for rapid control of established adult parasite populations. Where parasites show a clear seasonal pattern,
IGRs can be applied before any anticipated challenge as a preventive measure. They are widely used for blowfly
control in sheep but have limited use in other livestock.
 Based on their mode of action, IGRs can be divided into chitin synthesis inhibitors (benzoylphenyl ureas), chitin
inhibitors (triazine/pyrimidine derivatives), and juvenile hormone analogues (S-methoprene, pyriproxyfen). Several
benzoylphenyl ureas have been introduced to control ectoparasites. Chitin is a complex aminopolysaccharide and a
major component of the insect’s cuticle. During each molt, it has to be newly formed by polymerization of
individual sugar molecules. The exact mode of action of the benzoylphenyl ureas is not fully understood. They
inhibit chitin synthesis but have no effect on the enzyme chitin synthetase. It has been suggested that they
interfere with the assembly of the chitin chains into microfibrils. When immature insect stages are exposed to
these compounds, they are not able to complete ecdysis and die during molting. Benzoylphenyl ureas also appear
to have a transovarial effect. Exposed adult female insects produce eggs in which the compound is incorporated
into the egg nutrient. Egg development proceeds normally, but the newly developed larvae are incapable of
hatching. Benzoylphenyl ureas show a broad spectrum of activity against insects but have relatively low efficacy
against ticks and mites. The exception is fluazuron, which has greater activity against ticks and some mite species.
 Benzoylphenyl ureas are highly lipophilic molecules. When administered to the host they build up in body fat, from
which they are slowly released into the bloodstream and excreted largely unchanged. Diflubenzuron and
flufenoxuron are used to prevent blowfly strike in sheep. Diflubenzuron is available in some countries as an
emulsifiable concentrate for use as a dip or shower. It is more efficient against first-stage larvae than second and
third instars and is therefore recommended as a preventive, providing protection for 12–14 wk. It may also have
potential to control a number of major insect pests such as tsetse flies. Fluazuron is available in some countries for
 use in cattle as a tick development inhibitor. When applied as a pour-on, it provides longterm protection against
the 1-host tick, Rhipicephalus (Boophilus) microplus.
 Triazine and pyrimidine derivatives are closely related compounds that are also chitin inhibitors. They differ from
the benzoylphenyl ureas both in chemical structure and mode of action, ie, they appear to alter the deposition of
chitin into the cuticle rather than its synthesis.
 Cyromazine, a triazine derivative, is effective against blowfly larvae on sheep and lambs and also against other
Dipterasuch as houseflies and mosquitoes. At recommended dose rates, cyromazine shows only limited activity
against established strikes and must therefore be used preventively. Blowflies usually lay eggs on damp fleece of
treated sheep. Although larvae are able to hatch, the young larvae immediately come into contact with
cyromazine, which prevents the molt to second instars. The efficacy of a pour-on preparation of cyromazine does
not depend on factors such as weather, fleece length, and whether the fleece is wet or dry. Control can be
maintained for up to 13 wk after a single pour-on application, or longer if cyromazine is applied by dip or shower.
 Dicyclanil, a pyrimidine derivative, is highly active against dipteran larvae. A pour-on formulation, available in some
countries for blowfly control in sheep, provides up to 20 wk of protection.
 The juvenile hormone analogues mimic the activity of naturally occurring juvenile hormones and prevent
metamorphosis to the adult stage. Once the larva is fully developed, enzymes within the insect’s circulatory system
destroy endogenous juvenile hormones, prompting development to the adult stage. The juvenile hormone
analogues bind to juvenile hormone receptor sites, but because they are structurally different, are not destroyed
by insect esterases. Metamorphosis and further development to the adult stage does not proceed. S-Methoprene
is a terpenoid compound with very low mammalian toxicity that mimics a juvenile insect hormone and is used as a
feed-through larvicide for hornfly (Haematobia) control on cattle.

Miscellaneous Compounds:

Piperonyl butoxide and MGK 264 (N-octyl bicycloheptene dicarboximide) are used as synergistic additives in the control of
arthropod pests. They are commonly formulated together with insecticides such as natural pyrethrins. The degree of
potentiation of insecticidal activity is related to the ratio of components in the mixture; as the proportion of piperonyl
butoxide or MGK 264 increases, the amount of natural pyrethrins required to evoke the same level of kill decreases. The
insecticidal activity of other pyrethroids, particularly of knockdown agents, can also be enhanced by the addition of
piperonyl butoxide or MGK 264. Piperonyl butoxide inhibits the microsomal enzyme system of some arthropods and is
effective against some mites. In addition to having low mammalian toxicity and a long record of safety, it rapidly degrades
in the environment.

Various products from natural sources, as well as synthetic compounds, have been used as insect repellents. Such
compounds include cinerins, pyrethrins and jasmolins, citronella oil, di-N-propyl isocinchomeronate, butoxypolypropylene
glycol, picaridin, DEET, and DMP (dimethylphthalate). The use of repellents is advantageous as legislative and regulatory
authorities become more restrictive toward the use of conventional pesticides. They are used mainly to protect horses
against blood-sucking arthropods, particularly midges (Culicoides).

Insecticides may be used to provide environmental control of some insects by application to premises. The insect
pheromone (Z)-9-tricosene is incorporated into some products to attract insects to the site of application.

Ectoparasiticides Used in Small Animals:

Flea and tick infestation is a major health problem in dogs and cats, and control presents an economic burden to their
owners. Traditionally, a wide array of ectoparasiticides has been available, and switching among brands was frequent,
leading to problems in achieving acceptable external parasite control. Veterinarians are uniquely qualified to explain the
host/parasite interrelationships and advise owners on selection of the most suitable control program. However, many pet
owners still purchase flea and tick products in supermarkets or pet supply shops where professional advice is not available.
Recent advances in product technology have greatly expanded the available options for veterinarians and pet owners.
However, this wide array of available parasiticides can lead to confusion. Veterinarians should become familiar with these
technologic improvements in both insecticidal chemistry and delivery systems and encourage client education by their staff.

Active Chemical Ingredients:

Nomenclature can be confusing if the shorter approved name is not used and the full chemical name is written (eg,
chlorpyrifos versus 0,0-diethyl 0-[3,5,6 trichloro 2 pyridyl] phosphorothioate). The use of trade names can cause added
confusion. Although most commercial products contain only one active ingredient, it is not uncommon for two or more to
be combined to provide enhanced efficacy or broader spectrum of activity. All labels should be read carefully for
ingredients, age and species restrictions, and directions for use.

Macrocyclic Lactones:

Currently, three macrocyclic lactones are used for control of internal and external parasites in dogs and cats: selamectin
and aprinomectin, which are semisynthetic avermectins, and moxidectin, a semisynthetic milbemycin. Although the exact
mode of action of macrocyclic lactones is not fully elucidated, it is believed that they bind to glutamate-gated chloride
channels in the parasites’ nervous system, increasing their permeability and allowing for the rapid and continued influx of
Cl– into the nerve cell. This inhibits nerve activity and causes paralysis of the parasite. Selamectin is presented as a single
active ingredient; moxidectin is combined with imidacloprid (see Neonicotinoids, below); and eprinomectin has been
combined with fipronil (see Phenylpyrazoles, below), S-methoprene (see Insect Growth Regulators, below), and
praziquantel. These macrocyclic lactones are applied topically, rapidly absorbed through the skin, and distributed via the
blood. They have activity against a variety of internal and external parasites.

Cholinesterase Inhibitors:

Two groups of compounds, organophosphates and carbamates, share the same mechanism of action—inhibition of
acetylcholinesterase. This enzyme normally is responsible for acetylcholine (neurotransmitter) destruction. Applications of
organophosphates or carbamates to insects produce spontaneous muscular contractions followed by paralysis. The binding
of organophosphates to acetylcholinesterase is more persistent, if not permanent, whereas the interaction with
carbamates is reversible. These compounds were once very popular for their prolonged action and potency. However, the
use of organophosphates has declined because their low margin of safety and slight variance from approved use or
continued use may lead to toxicity. When these compounds are used for flea or tick control, it should be determined before
treatment whether any other cholinesterase inhibitor has been used on the animal or in its environment.
Organophosphates for small animal therapy include chlorpyrifos, dichlorvos, malathion, diazinon, phosmet, fenthion,
chlorfenvinphos, and cythioate. Carbamates include carbaryl and propoxur.

Chlorinated Hydrocarbons:

These compounds are becoming less popular because of their persistence in the environment, although this factor brought
the benefit of prolonged action. Lindane and methoxychlor are still occasionally used. (Also see Chlorinated Hydrocarbon
Compounds (Toxicity).)

Neonicotinoids:

The neonicotinoids are a class of insecticides referred to as nitroquanidines, neonicotinyls, chloronicotines, and recently as
chloronicotinyls. The neonicotinoids are modeled after natural nicotine. Three compounds in this category are currently
available for veterinary use: dinotefuran, imidacloprid, and nitenpyram. All neonicotinoids act as agonists on the
postsynaptic acetylcholine receptors in insects. This inhibits cholinergic transmission, resulting in paralysis and death.
Imidacloprid is applied as a spot-on topical product and is used primarily to control fleas on both dogs and cats. It also has
excellent activity against lice. Although it has potent residual activity, it is readily soluble in water, so swimming and
repeated bathing may compromise its duration of activity. Nitenpyram is administered PO in pill form to kill fleas in both
dogs and cats. It is absorbed rapidly, with maximal blood concentrations reached within 1.2 hr in dogs and 0.6 hr in cats.
Fleas begin to die within 20–30 min of administration, with 100% flea mortality within 3–4 hr. The compound is rapidly
eliminated, with >90% excreted in the urine within 24–48 hr, primarily as unchanged nitenpyram. Even though imidacloprid
and nitenpyram are classified similarly, their mechanisms of action appear to be different. Although imidacloprid is
described as a paralytic, nitenpyram produces hyperexcitability in fleas before death.

The newest addition to the neonicotinoids is dinotefuran, considered a third-generation neonicotinoid. The structure of
dinotefuran is unique in that it was derived from that of the acetylcholine molecule rather than nicotine. It has been
proposed that dinotefuran does not bind to the same sites as imidacloprid and other neonicotinoids but at a different site in
the nerve synapse. Dinotefuran is applied as a topical spot-on with different formulations for dogs and cats. The cat
formulation is combined with the insect growth regulator pyriproxyfen and is used primarily to control fleas. The dog
formulation contains pyriproxyfen and permethrin and is labeled for control of fleas, ticks, and mosquitoes.

Formamidines:

This small group of acaricidal compounds has the proposed mode of action of binding to octopamine receptors, a specific
group of receptors found in Acari. In veterinary medicine, the only approved formamidine is amitraz. It is used primarily as
an acaricide to control ticks and mites. It is available as a dip for control of canine demodicosis, and it will also control
scabies. An amitraz-impregnated collar is also marketed for control of ticks on dogs. Amitraz is not approved for use on cats.

Oxadiazines:

Oxadiazine insecticides can control a broad spectrum of insects. Indoxacarb is the only member of this group currently
being used in veterinary medicine. It is considered a pro-insecticide that is metabolized within the insect to a more active
form, which is an N-decarbomethoxylated metabolite that is at least 40 times more potent than parent indoxacarb. This
metabolic conversion of indoxacarb, known as bioactivation, is attributed to actions of esterase and amidase enzymes
within the insect. The active metabolite exerts its effect by blocking the voltage-gated sodium ion channels in insects.
Indoxacarb is administered topically in a spot-on formulation for control of fleas on dogs and cats. Indoxacarb has also been
combined with permethrin for control of ticks on dogs.

Isoxazolines:

Isoxazolines are a new class of compounds that have both potent insecticidal and acaricidal activities. Isoxazolines have a
novel mode of action and specifically block arthropod ligand-gated chloride channels. Afoxolaner and fluralaner are
currently the only two compounds approved for use in veterinary medicine. Both are unique in that they were the first oral
flea and tick products. The compounds are readily absorbed after oral administration and provide 4–12 wk of insecticide
and acaricide activity.

Insect Growth Regulators:

These compounds inhibit the development of immature stages of insects. They are generally classified as either juvenile
hormone mimics (insect growth regulators) or as chitin synthesis inhibitors (insect development inhibitors). Methoprene,
fenoxycarb, and pyriproxyfen are similar in structure to insect juvenile hormone and are classified as juvenile hormone
mimics. When these compounds are applied to flea larvae or into their environment, they are absorbed by the larvae and
act like natural insect juvenile hormone. Juvenile hormone analogues bind to juvenile hormone receptor sites; larvae are
prevented from completing metamorphosis and subsequently die. These compounds also have ovicidal and embryocidal
activity against flea eggs when applied topically to dogs and cats. Female fleas in the hair coat absorb the juvenile hormone
analogue, which affects viability of developing eggs. These compounds are active against a wide range of insects, including
mosquito larvae; methoprene is used as a larvicide in the strategic control of mosquito-borne diseases. For flea control,
their outdoor use should be limited to specific flea habitats to avoid adverse effects on beneficial insect species.

Lufenuron, a benzoylphenyl urea, inhibits the formation of chitin (a polymer of N-acetyl glucosamine), which is a major
component of insect exoskeletons. During each larval molt, chitin is reformed by polymerization. Lufenuron interferes with
polymerization and deposition of chitin, killing developing larvae either within the egg or after hatching. Lufenuron is
administered PO to dogs or cats or by injection to cats. Female fleas feeding on treated animals are prevented from
producing viable eggs or larvae. Other insect development inhibitors, such as diflubenzuron (another chiton inhibitor) and
cyromazine (a moulting disruptor), also have considerable activity against developing fleas. Insect growth regulators and
insect development inhibitors affect many insect species that undergo complete metamorphosis, but they have little or no
activity against ticks or other Acari, which undergo incomplete metamorphosis.

Phenylpyrazoles:

This group of compounds has broad-spectrum activity that is both insecticidal and acaricidal. The members of this group
currently available for use in veterinary medicine worldwide include fipronil and pyriprole. These compounds bind to γ-
aminobutyric acid and glutamate-gated receptor sites of insect nervous systems, inhibiting the flux of Cl– into nerve cells,
which results in hyperexcitability. These compounds have broad-spectrum activity against fleas, ticks, mites, and lice.
Numerous fipronil-containing formulations are available worldwide, including an alcohol-based fipronil-only spray, several
spot-on formulations that contain only fipronil, a spot-on combination with the insect growth regulator methoprene, and
numerous combination formulations that contain fipronil and various pyrethroids. Fipronil is very lipophilic; it accumulates
in the sebaceous glands, has very low solubility in water, and has prolonged residual activity on both dogs and cats.

Pyrethrins and Pyrethroids:

These compounds rapidly disrupt sodium and potassium ion transport in nerve membranes, resulting in spontaneous
depolarizations, augmented neurotransmitter secretion, and neuromuscular blockade, causing paralysis. Although the
activity is rapid, without sufficient exposure paralyzed insects can also recover rapidly. The synergists piperonyl butoxide
and N-octyl bicycloheptene dicarboxymide interfere with the insect detoxification mechanism and can potentiate the
activity of pyrethroids. Natural pyrethrum is extracted from chrysanthemum flowers and is notable for its rapid but brief
action and relative lack of toxicity in dogs and cats.

Synthetic pyrethroids are pyrethrum-like compounds that generally have greater potency and residual effects but are less
well tolerated in cats. Some pyrethroids, such as permethrin, can be highly toxic to cats. Pyrethroids are generally classified
by developmental generation. First-generation pyrethroids are generally unstable in heat and sunlight (eg, allethrin);
second-generation are more photostable, isomeric mixtures (eg, cypermethrin, permethrin); third-generation are
photostable and more neurologically active isomers obtained by isomeric enrichment (eg, λ-cyhalothrin, β-cyfluthrin); and
fourth-generation are nonester pyrethroids (eg, MTI 800, flufenprox, etofenprox).

Spinosyns:

Spinosyns are a novel family of insecticides derived from the fermentation of the actinomycete, Saccharopolyspora spinosa.
The two most abundant products derived from the fermentation process are spinosyns A and D, which are the major active
components of spinosad. Spinosad is used to control a wide variety of insects, including flies and fleas. Spinosyns have a
novel mode of action, primarily targeting binding sites on nicotinic acetylcholine receptors distinct from other insecticides
such as neonicotinoids. Spinosyns also affect γ-aminobutyric acid receptor function, which may contribute further to their
insecticidal activity. These actions cause excitation of the insect nervous system, leading to involuntary muscle contractions,
prostration with tremors, and finally paralysis. Spinosad has activity against fleas and is formulated as a chewable tablet for
dogs and cats. A topical spot-on spinosyn formulation called spinetoram has been developed for cats.

Repellents:

N,N-diethyl-3-methylbenzamide (DEET, previously called N,N-diethyl-meta-toluamide) remains the most effective among
currently available insect repellents for people. It is a broad-spectrum repellent effective against mosquitoes,biting flies,
chiggers, fleas, and ticks. However, the effectiveness of DEET formulations for dogs and cats has not been proved, and
safety is a concern because concentrated formulations containing DEET have caused weakness, paralysis, liver disease, and
seizures in pets. DEET should not be administered to dogs or cats.
The synthetic pyrethroid permethrin is a rapidly acting neurotoxicant that can produce what is termed a “hot-foot” effect
and is often described as a repellency. Various permethrin formulations are labeled as repellents for ticks, mosquitoes, and
fleas.

Synergists:

Synergists are generally not considered toxic or insecticidal but are used with insecticides to enhance their activity. They are
used primarily to potentiate the activity of pyrethrum or pyrethroids. Synergists inhibit cytochrome P450–dependent
monooxygenases or glutathione S-transferases, enzymes produced by microsomes in insect tissues. They bind the oxidative
enzymes that would normally break down the insecticide and prevent them from degrading the toxicant. Piperonyl
butoxide and N-octyl bicycloheptene dicarboxamide are common synergists.

Toxicity Of Different Types Of Pesticides For Veterinary Use (Small Animal, Large Animal, Poultry):
Overview of Insecticide and Acaricide (Organic) Toxicity:

Insecticides are any substance or a mixture of substances intended to prevent, destroy, repel, or mitigate insects. Similarly,
acaricides are substances that can destroy mites. A chemical can exert both insecticidal and acaricidal effects. Based on
their properties, these chemicals can be classified into four groups:

1) Organophosphates,

2) Carbamates,

3) Organochlorines, and

4) Pyrethrins and pyrethroids.

 Because of worldwide use, these chemicals pose health risks to nontarget species, including people, domestic and
companion animals, wildlife, and aquatic species. In large animals, poisoning is often due to inadvertent or
accidental use, whereas in small animals (particularly dogs) poisoning is often due to malicious intent.
 Pesticide labels must carry warnings against use on unapproved species or under untested circumstances. These
warnings may pertain to acute or chronic toxicity, or to residues in meat, milk, or other animal products. Because
labels change to meet current government regulations, it is important to always read and follow all label directions
accompanying the product.
 Each exposure, no matter how brief or small, results in some of the compound being absorbed and perhaps stored.
Repeated short exposures may eventually result in intoxication because of cumulative effect. Every precaution
should be taken to minimize human exposure. This may include frequent changes of clothing with bathing at each
change, or if necessary, the use of respirators, rain gear, and gloves impervious to pesticides. Respirators must
have filters approved for the type of insecticide being used (eg, ordinary dust filters will not protect the operator
from organophosphorus insecticide fumes). Such measures are generally sufficient to guard against intoxication.
Overexposure to chlorinated hydrocarbon insecticides is difficult to measure except by the occurrence of overt
signs of poisoning.
 Organophosphate and carbamate insecticides produce their toxicity by inactivation of acetylcholinesterase (AChE)
enzyme at the synapses in nervous tissue and neuromuscular junctions, and in RBCs. Therefore, the cholinesterase-
inhibiting property of organophosphates or carbamates may be used to indicate degree of exposure if the activity
of the blood/RBC-AChE is determined during an early period of exposure.
 Organic pesticides are known to exert deleterious effects on fish and wildlife as well as on domestic species. In no
event should amounts greater than those specifically recommended be used, and maximal precautions should be
taken to prevent drift or drainage to adjoining fields, pastures, ponds, streams, or other premises outside the
treatment area.
  The safety and exposure level of these compounds in target species has been carefully established, and application
recommendations and regulations must be followed. Individuals, including veterinarians, have been prosecuted for
failure to follow label directions or to heed label warnings and for failure to warn animal owners of the necessary
precautions.
 An ideal insecticide or acaricide should be efficacious without risk to livestock or persons making the application
and without leaving residues in tissues, eggs, or milk. Only a few compounds may meet all these requirements.
 Poisoning by organic insecticides and acaricides may be caused by direct application, by ingestion of contaminated
feed or forage treated for control of plant parasites, or by accidental exposure. This discussion is limited to only
those insecticides or acaricides most frequently hazardous to livestock or likely to leave residues in animal
products.
 Chemical synthesis rarely yields 100% of the product of interest, and normally there are, in variable proportions,
structurally related compounds that have biologic effects different from those of the compound sought. A prime
example is dichlorodiphenylethane (DDD): the p,p′-isomer is an effective insecticide of low toxicity for most
mammals; the o,p′-isomer causes necrosis of the adrenal glands of people and dogs and is used to treat certain
adrenal malfunctions.
 In general, products stored under temperature extremes or held in partially emptied containers for long periods
may deteriorate. But during storage, malathion produces isomalathion, which is many times more toxic than
malathion. In addition to isomalathion, two other technical impurities of malathion (malaoxon and trimethyl
phosphorodithioate) can be formed and can potentiate the toxicity of malathion by several fold. Similar impurities
can be formed and potentiate the toxicity of another organophosphate insecticide, phenthoate. Storing a chemical
in anything but the original container is hazardous, because in time its identity may be forgotten. Accidental
contact with animals or people may then have disastrous consequences. Consumer-mixed and unapproved
combinations can be very dangerous and should never be used. For example, simultaneous administration of two
organophosphate insecticides can result in potentiation of malathion toxicity by a hundredfold.
 A number of cholinesterase-inhibiting carbamate and organophosphate insecticides (eg, carbaryl, dichlorvos,
methiocarb, carbofuran, paraoxon, mevinophos, aldicarb, and monocrotophos) are also immunotoxic. Impaired
macrophage signaling through interleukins 1 and 2 appears to be involved, and the insecticide levels that cause
this effect are very low. This can lead to subtle but damaging influences on the health of exposed animals.

Carbamate Insecticides (Toxicity):

The carbamates are esters of carbamic acid. Unlike organophosphates, carbamates are not structurally complex. Presently,
the volume of carbamates used exceeds that of organophosphates, because carbamates are considered to be safer than
organophosphates.

Aldicarb:

The oral LD50 in rats is 0.9 mg/kg, and the dermal LD50 in rabbits is 5 mg/kg. Dogs are frequently poisoned with malicious
intent.

Carbaryl:

The oral LD50 in rats is 307 mg/kg, and the dermal LD50 in rabbits is 2,000 mg/kg. A 2% spray is nontoxic to calves; 4% is
nontoxic to mature cattle when applied dermally.

Carbofuran:

The oral LD50 in rats, dogs, chickens, ducks, pheasants, quails, and wild birds is 8, 19, 6.3, 0.415, 4.2, 5, and 0.42 mg/kg,
respectively. Dogs are commonly poisoned with malicious intent by tainting food. The minimum toxic dose in cattle and
sheep is 4.5 mg/kg, becoming lethal at 18 and 9 mg/kg, respectively. Cattle and other domestic animals are often poisoned
by accidental exposure. Pigs have been poisoned after drinking water contaminated by this compound. In Africa, wildlife
populations (including deer, lions, and birds) are declining because of malicious use of carbofuran. The dermal LD50 in
rabbits is 2,550 mg/kg.

Methomyl:

The oral LD50 in rats is 17 mg/kg, and the dermal LD50 in rabbits is >2,000 mg/kg. Dogs have been commonly poisoned with
malicious intent by tainting food. Cattle have been reported to be poisoned after consumption of forage inadvertently
sprayed with methomyl.

Propoxur:

The oral LD50 is 95 mg/kg in rats and >800 mg/kg in goats. The dermal LD50 in rabbits is >1,000 mg/kg.

Clinical Findings:

The carbamate insecticides act similarly to the organophosphates (see Organophosphates (Toxicity)) in that they inhibit
acetylcholinesterase (AChE) at nerve synapses and neuromuscular junctions. This inhibition is reversible because the
inhibiting bond is much less durable; thus, the inhibition of blood AChE frequently is not evident at the laboratory. Signs
include hypersalivation, GI hypermotility, abdominal cramping, vomiting, diarrhea, sweating, dyspnea, cyanosis, miosis,
muscle fasciculations (in extreme cases, tetany followed by weakness and paralysis), and convulsions. In brief, the acronym
SLUD (salivation, lacrimation, urination, and diarrhea) describes the overall clinical features of carbamate poisoning. Death
usually results from respiratory failure and hypoxia due to bronchoconstriction leading to tracheobronchial secretion and
pulmonary edema.

Organophosphates Toxicity:

The organophosphates (OPs) are derivatives of phosphoric or phosphonic acid. OPs have replaced the banned
organochlorine compounds and are a major cause of animal poisoning. They vary greatly in toxicity, residue levels, and
excretion. Many have been developed for plant and animal protection, and in general, they offer a distinct advantage by
producing little tissue and environmental residue. Some of the OPs developed initially as pesticides are also used as
anthelmintics. Five such compounds include dichlorvos, trichlorfon, haloxon, naphthalophos, and crufomate. The first two
are primarily used against parasitic infestations in horses, dogs, and pigs; the latter three are used against parasites in
ruminants.

Many of the OPs now used as pesticides (eg, chlorpyrifos, diazinon, fenitrothion, malathion, parathion, etc) are not potent
inhibitors of cholinesterase until activated in the liver by microsomal oxidation enzymes; they are generally less toxic, and
intoxication occurs more slowly. Certain OP preparations are microencapsulated, and the active compound is released
slowly; this increases the duration of activity and reduces toxicity, but the toxic properties are still present.

Organophosphate Insecticides

Azinphos-methyl (or -ethyl):

The maximum nontoxic oral dose is 0.44 mg/kg for calves, 2.2 mg/kg for cattle and goats, and 4.8 mg/kg for sheep. The oral
LD50 in rats is 5 mg/kg, and the dermal LD50 in rabbits is 220 mg/kg.

Carbophenothion:

Carbophenothion has been used as a spray for fruit trees and as a dip or spray for sheep blowfly, keds, and lice. Dairy calves
<2 wk old sprayed with water-based formulations showed poisoning at concentrations ≥0.05%, and adult cattle were
poisoned by spraying with 1%. Sheep and goats have been poisoned by 22 mg/kg, PO, but not by 8 mg/kg. In sheep, 0.1% as
a dip produces no signs of poisoning. The LD50 for rats is ~31 mg/kg; a daily dosage of 2.2 mg/kg for 90 days produced
poisoning. Dogs tolerated a diet containing 32 ppm for 90 days. A single application of a powder containing 1% of
carbophenothion is lethal to cats.

Chlorfenvinphos:

Adult cattle were poisoned by 5% or higher sprays, whereas young calves were poisoned at concentrations of 2%. The
minimum oral toxic dose appears to be ~22 mg/kg for cattle of all ages. The acute oral LD50 for rats is 12 mg/kg, and the
dermal LD50 in rabbits is 3,200 mg/kg.

Chlorpyrifos:

The oral LD50 is 500 mg/kg in goats and 941 mg/kg in rats. In comparison with calves, steers, and cows, bulls (particularly of
the exotic breeds) are highly susceptible to a single dose of chlorpyrifos. The maximum tolerated dose of chlorpyrifos in
sheep is 750 mg/kg. Sheep given 850 mg/kg died 5 days after dosing, those given 900 mg/kg died on the third day, and a
dose of 1,000 mg/kg was lethal within 30 hours. Onset of poisoning signs is usually delayed compared with that of many
other commonly used organophosphates because of the conversion of chlorpyrifos to the active cholinesterase inhibitor
chlorpyrifos-oxon. Chlorpyrifos produces reproductive and developmental toxicity.

Coumaphos:

Coumaphos is used against cattle grubs and a number of other ectoparasites and for treatment of premises. The maximum
concentration that may be safely used on adult cattle, horses, and pigs is 0.5%. Young calves and all ages of sheep and goats
must not be sprayed with concentrations >0.25%; 0.5% concentrations may be lethal. Adult cattle may show mild toxicity at
1% concentrations. The minimum lethal dose for calves appears to be between 10 and 40 mg/kg. A dose of 25 mg/kg is
usually fatal in sheep. The oral LD50 in rats is 13 mg/kg.

Crotoxyphos:

Crotoxyphos is used as a spray or powder for the control of ectoparasites on cattle and pigs. Crotoxyphos is of rather low
toxicity; however, Brahman cattle are markedly more susceptible than European breeds. Cattle (except as above), sheep,
goats, and pigs all tolerate sprays containing crotoxyphos at 0.5% levels or higher. Crotoxyphos is safe at a level of 1%,
although skin lesions have been found in pigs. Toxic doses appears to be in the 2% range, except for in Brahman cattle, in
which 0.144%–0.3% may be toxic.

Demeton:

Demeton is used as a systemic insecticide against sucking insects and mites. Demeton is used mainly as a foliage spray and
has a relatively long residual life. It is a mixture of demeton-O and demeton-S and is highly toxic to mammals. The oral LD50
is 8 mg/kg in goats and 2 mg/kg in rats; the dermal LD50 in rats and rabbits is 8 mg/kg. Demeton-O poisoning developed in
several hundred cattle grazing near cotton treated with this insecticide. The corresponding analogues of demeton
(demeton-O-methyl and demeton-S-methyl) are also used for similar purposes but are less toxic than demeton.

Diazinon:

Young calves appear to tolerate 0.05% spray but are poisoned by 0.1% concentrations. Adult cattle may be sprayed at
weekly intervals with 0.1% concentrations without inducing poisoning. Young calves tolerate 0.44 mg/kg, PO, but are
poisoned by 0.88 mg/kg. Cattle tolerate 8.8 mg/kg, PO, but are poisoned by 22 mg/kg. Sheep tolerate 17.6 mg/kg but are
poisoned by 26 mg/kg. The oral LD50 in rats is 300 mg/kg, and the dermal LD50 in rabbits is 379 mg/kg.

Dichlorvos:

Dichlorvos has many uses on both plants and animals. It is rapidly metabolized and excreted, and residues in meat and milk
are not a problem if label directions are followed. It is of moderate toxicity, with a minimum toxic dose of 10 mg/kg in
young calves and 25 mg/kg in horses and sheep. The oral LD50 in rats is 25 mg/kg, PO, and the dermal LD50 in rabbits is 59
mg/kg. A 1% dust was not toxic to cattle. Flea collars containing dichlorvos may cause skin reactions in some pets. Cats
wearing dichlorvos-impregnated collars can develop signs of ataxia-depression syndrome, followed by death.

Dimethoate:

Dimethoate is used extensively in horticulture as a systemic insecticide, but it also kills insects by contact. When
administered PO, the minimum toxic dose for young dairy calves was ~48 mg/kg, while 22 mg/kg was lethal for cattle 1 yr
old. Daily doses of 10 mg/kg for 5 days in adult cattle lowered blood cholinesterase activity to 20% of normal but did not
produce poisoning. Horses have been poisoned by doses of 60–80 mg/kg, PO. When applied topically, 1% sprays have been
tolerated by calves, cattle, and adult sheep. The oral LD50 in rats is 215 mg/kg, and the dermal LD50 in rabbits is 400 mg/kg.

Dioxathion:

Dioxathion is a nonsystemic acaricide and insecticide for the control of ticks. Dioxathion is a mixture of cis- and trans-
isomers, usually in the ratio of 1:2. The cis-isomer is more toxic than the trans-isomer. Used on both plants and animals, it is
rapidly metabolized and not likely to produce residues in meat greater than the 1 ppm official tolerance. Concentrations of
≥0.15% are generally used on animals. The minimum toxic dose in calves is 5 mg/kg. Sprays of 0.5% in cattle and sheep or
0.25% in goats and pigs are nontoxic. Sprays at concentrations up to 0.1% are usually safe for calves and lambs. Twice this
concentration may produce signs of poisoning. Dioxathion at 8.8 mg/kg, PO, has killed young calves, and it produced
intoxication at 4.4 mg/kg. Emaciated cattle with severe tick infestation are more frequently poisoned than healthy animals.
Maximum residues of dioxathion in adipose tissue of cattle occur 2–4 days after dipping. The elimination half-life, after
obtaining maximum concentrations, is ~16 days.

Disulfoton:

The maximum nontoxic oral dose is 0.88 mg/kg for young calves, 2.2 mg/kg for cattle and goats, and 4.8 mg/kg for sheep.
Poisoning has occurred in cattle after consuming harvested forages previously sprayed with this insecticide. The oral LD50in
rats is 2 mg/kg, and the dermal LD50 in rabbits is 6 mg/kg. Chronic exposure to disulfoton may result in tolerance to
toxicity.

Ethyl 4-Nitrophenyl Phenylphosphonothioate (EPN):

EPN is a nonsystemic insecticide and acaricide structurally related to parathion. The acute oral LD50 in rats is 8–36 mg/kg.
EPN at a dosage of 10 mg/kg was found to be nontoxic to adult cattle and sheep. The minimum oral toxic dose of EPN is 2.5
mg/kg in calves and 25 mg/kg in sheep and yearling cattle. Sprays containing 0.025%–0.05% EPN are toxic to young calves,
and 0.25% EPN is lethal. Dogs were not poisoned at dosages >100 mg/kg.

Famphur:

The oral LD50 in rats is 35 mg/kg, and the dermal LD50 in rabbits is 2,730 mg/kg. The maximum nontoxic dose is 10 mg/kg
in calves and 50 mg/kg in cattle, sheep, and horses. In general, Brahman cattle are especially susceptible to famphur
toxicity. This compound is effective against warbles in cattle, but (as for all grubicides) directions must be followed as to
time of application; larvae killed while migrating and the resultant local reaction can cause serious problems. In several
instances, famphur poisoning occurred in birds (mainly magpies and robins) shortly after cattle had been treated with a
pour-on preparation containing famphur.

Fenitrothion:

Fenitrothion, also known as sumithion, is used as a contact insecticide in agriculture and horticulture. The oral LD50 in rats
is 250 mg/kg, and the dermal LD50 in rabbits is 1,300 mg/kg. When applied to cattle, its metabolites are excreted at low
levels in milk and urine. Fenitrothion produces reproductive and developmental toxicity in chickens.

Fenthion:
Fenthion is commonly applied topically to control warble infestation in cattle and fleas in dogs. The minimum toxic dose,
PO, is 25 mg/kg for cattle; 50 mg/kg is lethal to sheep. The oral LD50 in rats is 255 mg/kg, and the dermal LD50 in rabbits is
330 mg/kg.

Malathion:

Malathion is one of the safest organophosphates because of its selective toxicity; it is highly toxic to insects but much less
toxic to mammalian species. The oral LD50 in rats is 885 mg/kg, and the dermal LD50 in rabbits is 4,000 mg/kg. The oral
acute toxic dose in calves is 10–20 mg/kg and in adult cattle and sheep is 50–100 mg/kg. In a chronic study in buffalo calves
(6–9 mo old), daily oral administration of malathion at 0.5 mg/kg for 1 yr produced no biochemical or clinical effects.
Dosages >1 mg/kg inhibited blood acetylcholinesterase (AChE) activity and increased liver enzymes (ALT and AST). A 20
mg/kg dose produced clinical signs after 10 days. The acute oral LD50 in buffalo calves is 53 mg/kg. Dermal application by
spray containing 0.5% or 1% of malathion had no apparent effect on calves, but 5% spray caused death within 75 hr.
Malathion at 0.5% or 1% should not be sprayed on calves for more than 3 consecutive days. Malathion is excreted in cow’s
milk.

Methyl parathion:

Methyl parathion is less toxic than parathion (diethyl parathion). The LD50 in rats from a single oral dose is 9–25 mg/kg, and
the dermal LD50 in rabbits is 63 mg/kg. Methyl parathion at 2.5 mg/kg had no ill effect, but 10 mg/kg daily quickly led to
toxic signs. The lethal dose in cattle is 100 mg/kg. Methyl parathion is excreted in cow’s milk. Methyl parathion produces
reproductive and developmental toxicity.

Mevinphos:

The LD50 in rats is 3 mg/kg, and the dermal LD50 in rabbits is 16 mg/kg. Mevinphos has been commonly used to control the
population of birds, and thereby caused poisoning in nontarget species. Mevinphos at 200 ppm in the diet is lethal in dogs.

Naled:

Naled is essentially a dibrominated dichlorvos, which has the ability to act as a contact insecticide. It has a broad spectrum
of insecticidal action. Because it has a short residual life, it poses relatively little hazard to fish and wildlife. The oral LD50 in
rats is 191 mg/kg, and the dermal LD50 in rabbits is 390 mg/kg.

Oxydemeton-methyl:

The maximum nontoxic oral dose is 0.88 mg/kg for young calves, 2.2 mg/kg for cattle, and 4.8 mg/kg for sheep and goats.

Parathion:

Parathion (diethyl parathion) is widely used for control of plant pests and is approximately one-half as toxic as tetraethyl
pyrophosphate (see Tetraethyl pyrophosphate (TEPP)). The oral LD50 in rats is 3 mg/kg, and the dermal LD50 in rabbits is
6.8 mg/kg. It is used as a dip and spray for cattle in some countries (not in the USA). Most cases of occupational insecticide
poisonings in people have been attributed to parathion or its degradation products. The minimum toxic dose in calves is
0.25–0.5 mg/kg and in cattle is 25–50 mg/kg. The minimum oral lethal dose in sheep is 20 mg/kg and in goats is 50 mg/kg.
The LD50 in dogs is 23–35 mg/kg and in cats is 15 mg/kg. Dermal sprays containing 0.02%, 1%, and 1% of parathion are
lethal to calves, sheep, and goats, respectively. Parathion is used extensively to control mosquitoes and insects in orchards
and on market garden crops. Normally, because so little is used per acre, it presents no hazard to livestock. However,
because of the potency of parathion, care should be taken to prevent accidental exposure. Parathion does not produce
significant residues in animal tissues.

Phorate:
Phorate is closely related to demeton (see Demeton). It is a systemic insecticide and miticide. The oral LD50 in rats is 1.6
mg/kg, and the dermal LD50 in rabbits is 2.5 mg/kg. The minimum toxic dose PO is 0.25 mg/kg in calves, 0.75 mg/kg in
sheep, and 1 mg/kg in cattle.

Phosmet:

Phosmet is a nonsystemic acaricide and insecticide. The minimum oral toxic dose is 25 mg/kg in cattle and calves and 50
mg/kg in sheep. Spraying with a 0.5% solution has no toxic effect, but a 1% solution of phosmet produces intoxication in
cattle. Phosmet is not excreted in milk.

Ronnel (Fenchlorphos):

Ronnel is an excellent oral systemic insecticide. It is effective against many ecto- and endoparasitic arthropods, including
cattle grubs, screw worms, and sucking lice. Ronnel is also used as a residual spray insecticide to control flies, fleas, and
cockroaches. The oral LD50 in rats is 1,250 mg/kg, and the dermal LD50 in rabbits is 2,000 mg/kg. Ronnel produces mild
signs of poisoning in cattle at 132 mg/kg, but severe signs do not appear until the dosage is >400 mg/kg. The minimum toxic
dose in sheep is 400 mg/kg. Concentrations as high as 2.5% in sprays have failed to produce poisoning of cattle, young dairy
calves, or sheep. Poisoning usually occurs in two stages. The animal first becomes weak and, although able to move about
normally, may be placid. Diarrhea, often flecked with blood, may also be seen. Salivation and dyspnea then appear if the
dose was high enough. Blood cholinesterase activity declines slowly over 5–7 days. Ronnel produces residues in meat and
milk; strict adherence to label restrictions is essential. The residues may be removed by giving the animal activated charcoal
for several days.

Ruelene:

Ruelene is active both as a systemic and contact insecticide in livestock, has some anthelmintic activity, and has rather low
toxicity. Dairy calves have been poisoned by 44 mg/kg, PO, while adult cattle require 88 mg/kg for the same effect. Sheep
are moderately intoxicated by 176 mg/kg; Angora goats are about twice as sensitive. Pigs have been poisoned by 11 mg/kg
and horses by 44 mg/kg. Most livestock tolerate a 2% topical spray.

Temephos:

Temephos is used as an insecticide against mosquitoes and midges. It is of low toxicity to mammalian species. The oral LD50
for rats is 1 g (or more)/kg, while the dermal LD50 is >4 g/kg. Daily exposure of cattle for 1 yr at 1–1.5 mg/kg is known to
produce clinical signs of poisoning and affect fertility in heifers.

Terbufos:

This soil insecticide is used to control corn rootworms. The oral LD50 in rats is 1.6 mg/kg. The minimum oral toxic dose is
~1.5 mg/kg for sheep and cattle. Cases of intoxication in cattle have occurred. Ingestion of 7.5 mg/kg was lethal to heifers.

Tetrachlorvinphos:

Tetrachlorvinphos has low toxicity in dogs; chronic feeding studies indicate the lowest effect level was 50 mg/kg/day, and
the no observed effect level (NOEL) was 3.13 mg/kg/day. The minimum toxic dose in pigs is 100 mg/kg.

Tetraethyl pyrophosphate (TEPP):

Tetraethyl pyrophosphate (TEPP) is one of the most acutely toxic insecticides. Although not used on animals, accidental
exposure occurs occasionally. One herd of 29 cattle (including calves and adults) was accidentally sprayed with 0.33% TEPP
emulsion; all died within 40 min.

Trichlorfon:
Trichlorfon is used as a systemic insecticide and anthelmintic in domestic animals. It is also used as an acaricide in sheep at
the dose rate of 80 mg/kg at weekly intervals for not more than 4 wk. The oral LD50 in rats is 630 mg/kg, and the dermal
LD50 in rabbits is >2,000 mg/kg. As a spray, trichlorfon at a 1% concentration is tolerated by adult cattle; given PO, it is
tolerated by young dairy calves at 4.4 mg/kg but produces poisoning at 8.8 mg/kg. Adult cattle, sheep, and horses appear to
tolerate 44 mg/kg, while 88 mg/kg produces poisoning. Dogs were unaffected when fed 1,000 ppm of trichlorfon for 4 mo.
Administration of trichlorfon at 75 mg/kg, PO, produces adverse clinical signs in dogs. Trichlorfon is metabolized rapidly.

Clinical Findings:

In general, OP pesticides have a narrow margin of safety, and the dose-response curve is quite steep. Signs of OP poisoning
are those of cholinergic overstimulation, which can be grouped into three categories: muscarinic, nicotinic, and central.
Muscarinic signs, which are usually first to appear, include hypersalivation, miosis, frequent urination, diarrhea, vomiting,
colic, and dyspnea due to increased bronchial secretions and bronchoconstriction. Nicotinic effects include muscle
fasciculations and weakness. The central effects include nervousness, ataxia, apprehension, and seizures. Cattle and sheep
commonly show severe depression. CNS stimulation in dogs and cats usually progresses to convulsions. Some OPs (eg,
amidothioates) do not enter the brain easily, so that CNS signs are mild. Onset of signs after exposure is usually within
minutes to hours but may be delayed for >2 days in some cases. Severity and course of intoxication is influenced principally
by the dosage and route of exposure. In acute poisoning, the primary clinical signs may be respiratory distress and collapse
followed by death due to respiratory muscle paralysis. In addition to brain and skeletal muscles, OPs are known to adversely
affect other organ systems, including the cardiovascular, respiratory, hepatic, reproductive and developmental, and
immune systems.

Diagnosis:

An important diagnostic aid for OP poisoning is the determination of acetylcholinesterase (AChE) activity in blood and brain.
Unfortunately, the depression of blood cholinesterase does not necessarily correlate with the severity of poisoning; signs
are seen when brain AChE activity is inhibited >70%, and the enzyme in blood reflects, only in a general way, the levels in
nervous tissue. The key factors appear to be the degree and rate at which the enzyme activity is reduced. Analyses
performed after exposure may be negative, because OPs do not remain long in tissues as the parent compounds.
Chlorinated OP compounds have greater potential for tissue residue. Frozen stomach and rumen contents should be
analyzed for the pesticide, using GC-MS for identification, confirmation, and quantitation. Blood/serum and urine can also
be analyzed for residue of OPs or their metabolites. More than 70% of OPs produce one or more of the six
dialkylphosphates (dimethyl phosphate, diethyl phosphate, dimethyl thiophosphate, diethyl thiophosphate, dimethyl
dithiophosphate, and diethyl dithiophosphate).

Lesions:

Animals with acute OP poisoning have nonspecific or no lesions. Pulmonary edema and congestion, hemorrhages, and
edema of the bowel and other organs may be found. Animals surviving >1 day may become emaciated and dehydrated.

Chlorinated Hydrocarbon Compounds (Toxicity):

Because of persistent tissue residues and chronic toxicity, use of chlorinated hydrocarbon compounds has been drastically
curtailed. Only lindane and methoxychlor are approved for use on or around livestock. Detectable residues of some
chlorinated hydrocarbon insecticides, including BHC, heptachlor, heptachlor epoxide, lindane, and oxychlordane, can be
found in fatty tissue after acute or chronic exposure.

Aldrin:

Aldrin is a potent insecticide similar to dieldrin with the same order of toxicity (see Dieldrin). It is no longer registered in the
USA but was used for termite control. The oral LD50 in rats is 39 mg/kg, and the dermal LD50 in rabbits is 65 mg/kg. In farm
animals, the toxic dose is ~15–30 mg/kg.
Benzene Hexachloride (BHC, HCH, Hexachlorocyclohexane):

Benzene hexachloride (BHC) is composed of 12%–45% γ isomer. BHC was a useful insecticide for large animals and dogs but
is highly toxic to cats in the concentrations necessary for parasite control. Only the γ isomer (γ−BHC, lindane) is a useful
insecticidal agent; the other isomers are stored for excessively long periods in body tissues. Lindane, which contains >99%
of the γ isomer, should be used in preference to the technical grade of BHC, which contains several isomers. The oral LD50
of lindane in rats is 76 mg/kg, and the dermal LD50 in rabbits is 500 mg/kg. Presently, BHC is not sold in the USA.

Cattle in good condition have tolerated 0.2% lindane applications, but stressed, emaciated cattle have been poisoned from
spraying or dipping in 0.075% lindane. Horses and pigs appear to tolerate 0.2%–0.5%, and sheep and goats ordinarily
tolerate 0.5% applications. Emaciation and lactation increase the susceptibility of animals to poisoning by lindane; such
animals should be treated with extreme caution. Young calves are very susceptible to lindane and are poisoned by a single
oral dose of 4.4 mg/kg. Mild signs appear in sheep given 22 mg/kg, and death occurs at 100 mg/kg. Adult cattle have
tolerated 13 mg/kg without signs. BHC is stored in body fat and excreted in milk.

Chlordane:

Chlordane is no longer registered as an insecticide in the USA. Exposure occurs when livestock consume treated plants or
when they come in direct contact through carelessness and accidents. The lethal dose of chlordane for most species is in
the range of 200–300 mg/kg. Very young calves have been killed by doses of 44 mg/kg, and the minimum toxic dose for
cattle is ~88 mg/kg. Cattle fed chlordane at 25 ppm of their diet for 56 days showed 19 ppm in their fat at the end of the
feeding. Topical emulsions and suspensions have been used safely on dogs at concentrations up to 0.25%, provided freshly
diluted materials were used; dry powders up to 5% have been safe. The no-effect level in dogs in a 2-yr feeding study was 3
mg/kg. Pigeons and Leghorn cockerels and pullets suffered no effects after 1–2 mo exposure to vapors emanating from
chlordane-treated surfaces. The oral LD50 in rats is 283 mg/kg, and the dermal LD50 in rabbits is 580 mg/kg.

Dieldrin:

Dieldrin is not a registered pesticide in the USA. Residues limit its application, and it is one of the most toxic chlorinated
hydrocarbon insecticides. The oral LD50 in rats is 40 mg/kg, and the dermal LD50 in rabbits is 65 mg/kg. Young dairy calves
are poisoned by 8.8 mg/kg, PO, but tolerate 4.4 mg/kg, whereas adult cattle tolerate 8.8 mg/kg and are poisoned by 22
mg/kg. Pigs tolerate 22 mg/kg and are poisoned by 44 mg/kg. Horses are poisoned by 22 mg/kg. Because of its effectiveness
against insect pests on crops and pasture and the low dosage per acre, dieldrin is not likely to poison livestock grazing the
treated areas. Diets containing 25 ppm of dieldrin have been fed to cattle and sheep for 16 wk without harmful effects
other than residues in fat, which are slow to disappear. Great care must be exercised in marketing animals that have grazed
treated areas or consumed products from previously treated areas. There is a zero tolerance level for residues in edible
tissues.

Statements pertaining to dieldrin also apply, in general, to endrin, the most toxic of the three chlorinated cyclodiene
insecticides

Endosulfan:

Endosulfan is widely used to control insect and mite pests on a variety of crops and orchards. It is heavily used on tobacco.
Endosulfan is very toxic to mammalian species. The oral LD50 in rats is 18 mg/kg, and the dermal LD50 in rabbits is 74
mg/kg. The LD50 of endosulfan in dogs is 77 mg/kg. Its lethal dose in cattle is 8 g. Generally, cattle are poisoned by
accidental exposure, and dogs are poisoned by malicious intent. Exposure of cattle to endosulfan produces residues in the
liver, kidneys, muscle, and milk.

Heptachlor:

Heptachlor is not currently registered in the USA and is not recommended for use on livestock in the USA. Among its few
agricultural applications, heptachlor is used for residual control of subterranean termites. The oral LD50 in rats is 40 mg/kg,
and the dermal LD50 in rabbits is 119 mg/kg. Because it is very effective against certain plant-feeding insects, it is
encountered from time to time in some geographic areas grazed by livestock. Young dairy calves tolerate dosages as high as
13 mg/kg but are poisoned by 22 mg/kg. Sheep tolerate 22 mg/kg but are poisoned by 40 mg/kg. Diets containing 60 ppm
of heptachlor have been fed to cattle for 16 wk without harmful effects other than residues in fat. Heptachlor is converted
to heptachlor epoxide by animals and stored in body fat. For this reason, a specific analysis performed for heptachlor
usually yields negative results, while that for epoxide is positive.

Toxaphene:

Toxaphene is no longer under active registration in the USA. It has been used with reasonable safety if recommendations
were followed, but it can cause poisoning when applied or ingested in excessive quantities. The oral LD50 in rats is 40
mg/kg, and the dermal LD50 in rabbits is 600 mg/kg. Dogs and cats are particularly susceptible. Young calves have been
poisoned by 1% toxaphene sprays, while all other farm animals except poultry can withstand 1% or more as sprays or dips.
Chickens have been poisoned by dipping in 0.1% emulsions, and turkeys have been poisoned by spraying with 0.5%
material. Toxaphene is primarily an acute toxicant and does not persist long in the tissues. Adult cattle have been mildly
intoxicated by 4% sprays and severely affected by 8%. Adult cattle have been poisoned from being dipped in emulsions that
contained only 0.5% toxaphene (an amount ordinarily safe) because the emulsions had begun to break down, allowing the
fine droplets to coalesce into larger droplets that readily adhere to the hair of cattle. The resultant dosage becomes
equivalent to that obtained by spray treatments of much higher concentrations. Toxaphene is lethal to young calves at 8.8
mg/kg but not at 4.4 mg/kg. The minimum toxic dose for cattle is ~33 mg/kg, and for sheep between 22 and 33 mg/kg.
Spraying Hereford cattle 12 times at 2-wk intervals with 0.5% toxaphene produced a maximum residue of 8 ppm in fat.
Cattle fed 10 ppm of toxaphene in the diet for 30 days had no detectable toxaphene tissue residues, whereas steers fed 100
ppm for 112 days stored only 40 ppm in their fat (this amount was eliminated 2 mo after the toxaphene was discontinued).

Natural Pesticides Toxicity For Veterinary Use (Small Animal, Large Animal, Poultry ):
Insecticides Derived from Plants (Toxicity)

Most insecticides derived from plants (eg, rotenone from Derris and pyrethrins from Chrysanthemum or Pyrethrum) have
traditionally been considered safe for use on animals. Nicotine in the form of nicotinesulfate is an exception. Unless it is
carefully used, poisoning may result. Pets are exposed to tobacco by ingesting commercial tobacco products (eg, cigarettes
or chewing tobacco), whereas livestock may consume discarded tobacco stalks or hay contaminated with tobacco plant
drippings in the barn. The minimum lethal dose of nicotine is 1 g in cattle, 0.2–0.3 g in horses, 0.1–0.2 g in sheep, and 0.02–
0.1 g in dogs and cats. Affected animals show tremors, incoordination, nausea, disturbed respiration, muscle paralysis, and
finally coma and death. Nicotine and related alkaloids from tobacco can cross the placenta and produce teratogenic effects.
Recovery from sublethal doses is usually complete within 3 hr. Death occurs within a matter of hours from paralysis of
thoracic respiratory muscles and cardiac arrest. Necropsy may reveal parts of tobacco leaves or stalks in the rumen
contents. Lesions include pale mucous membranes, dark blood, hemorrhages on the heart and in the lungs, and congestion
of the brain. Treatment consists of removing the material by washing or by gastric lavage with tannic acid, administering
activated charcoal, providing artificial respiration, and treating for cardiac arrest and shock.

Pyrethrins:

Pyrethrins are insecticides obtained from the flowers of C cinerariaefolium and have been used as insecticides for many
years. Pyrethrins and pyrethroids produce toxicity affecting primarily the sodium channel, but also chloride and calcium
channels of nerve cells. These insecticides also interact with nicotinic acetylcholine receptors. Synergists, such as piperonyl
butoxide, sesamex, piperonyl cyclonene, etc, are added to increase stability and effectiveness. This is accomplished by
inhibiting mixed function oxidases, enzymes that detoxify pyrethrins and pyrethroids; unfortunately, this also potentiates
mammalian toxicity.

Pyrethroids:
Pyrethroids are synthetic derivatives of natural pyrethrins. There are two types of pyrethroids. Type I compounds that lack
an α-cyano substituent include pyrethrin I, allethrin, tetramethrin, kadethrin, resmethrin, phenothrin, and permethrin. Type
II compounds that contain a stabilizing α-cyano-3-phenoxybenzyl component include cyfluthrin, cypermethrin,
fenpropanthrin, deltamethrin, cyphenothrin, fenvalerate, and fluvalinate. Type I pyrethroids produce a neurologic
syndrome through their effects on both the central and peripheral nervous systems, with signs including tremors,
incoordination, prostration, seizures, and death. Type II pyrethroids work primarily by CNS mechanisms to exert the
choreoathetosis/salivation syndrome, characterized by hyperactivity, hunched back, salivation, tremors, and incoordination
progressing to sinuous writhing movements.

Diagnosis of pyrethrin/pyrethroid poisoning is based on clinical signs, history of exposure, and determination of insecticide
residue in body tissues and fluids. These insecticides do not produce characteristic pathologic lesions.

Generally, symptomatic and supportive treatment is required after ingestion of a dilute pyrethrin or pyrethroid preparation.
Toxicity may also be due to the solvent. Induction of emesis may be contraindicated. A slurry of activated charcoal at 2–8
g/kg may be administered, followed by a saline cathartic (magnesium or sodium sulfate [10% solution] at 0.5 mg/kg).
Vegetable oils and fats, which promote the intestinal absorption of pyrethrum, should be avoided. If dermal exposure
occurs, the animal should be bathed with a mild detergent and coolwater. The area should be washed very gently so as not
to stimulate the circulation and enhance skin absorption. Initial assessment of the animal’s respiratory and cardiovascular
integrity is important. Further treatment involves continuing symptomatic and supportive care. Seizures should be
controlled with either diazepam(administered to effect at 0.2–2 mg/kg, IV) or methocarbamol (55–220 mg/kg, IV, not
exceeding 200 mg/min). Phenobarbital or pentobarbital (IV), to effect, can be used if diazepam or methocarbamol are too
short-acting.

d-Limonene:

d-Limonene is the major component of the oil extracted from citrus rind. It is used for the control of fleas on cats and for
other insect pests. Adult fleas and eggs appear to be most sensitive to d-limonene, which is more effective if combined with
the synergist piperonyl butoxide. At recommended dosages, the solution containing d-limonene appears to be safe, but
increasing the concentration 5–10 fold in sprays or dips increases the severity of toxic signs, which include hypersalivation,
muscle tremors, ataxia, and mild to severe hypothermia. The inclusion of piperonyl butoxide in the formulation potentiates
the toxicity in cats. Allergies have also been reported in people in contact with d-limonene, and it appears to increase
dermal absorption of some chemicals. When orally administered to dogs, d-limonene causes vomiting (median effective
dose 1.6 mL/kg). No antidote is available.