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VetBooks.ir Chapter 40

Neonicotinoids

Steve M. Ensley

INTRODUCTION BACKGROUND
Neonicotinoids are a relatively new class of insecticides The neonicotinoids were developed in the late 1970s by
with widespread use in veterinary medicine and crop chemists at Shell Chemical Company doing research with
production. The neonicotinoid insecticides include imida- the heterocyclic nitromethylenes for use as insecticides
cloprid, acetamiprid, dinotefuran, thiamethoxam, and (Soloway et al., 1978; Schroeder and Flattum, 1984).
clothianidin. In the last decade neonicotinoid insecticides The neonicotinoids and chloronicotinyls are a separate
have been the fastest growing class of insecticides in mod- class of compounds from the nicotinoids (Tomizawa and
ern crop protection because of the widespread use against Yamamoto, 1993). Chemists at Nihon Bayer Agrochem
a broad spectrum of sucking and certain chewing pests discovered imidacloprid in 1984 when the 3-pyridylmethyl
(Jeschke et al., 2010). Neonicotinoids have a relatively group was added to the nitromethylene heterocyclic parent
low risk for nontarget organisms and the environment, a molecule. This addition to nitromethylene greatly
high-target specificity to insecticide, and versatility in increased the insecticidal activity and reduced mammalian
application methods (Cresswell, 2011). The neonicotinoids toxicity. After imidacloprid was discovered several other
have been implicated in the Colony Collapse disorder in analogs with the 6-chloro-3-pyridylmethyl moiety have
bees but this has not been proven definitively (Lundin been developed, such as acetamiprid, nitenpyram and thia-
et al., 2015). Neonicotinoids have been shown to affect cloprid (Takahashi et al., 1992; Minamida et al., 1993;
the immunocompetence of honey bees (Brandt et al., Yamada et al., 1999). Fig. 40.1 shows the structure of
2016). Recently, some concerns have also been raised imidacloprid.
about adverse effects of imidacloprid in birds and aquatic
life (Zeng et al., 2013; Sa ´nchez-Bayo, 2014). PHARMACOKINETICS/TOXICOKINETICS
Imidacloprid is a neonicotinoid compound that is
used as an insecticide for dermal application on animals, When administered orally, imidacloprid is rapidly
for termite and grub control and as an insecticide for absorbed, metabolized primarily in the liver and excreted
crop protection. The neonicotinoids act on nicotinic primarily in urine. Absorption and distribution of imida-
receptors in insects and vertebrates. To reduce toxicity cloprid in rats occurs within 1 h following oral adminis-
to mammals and increase toxicity to insects, neonicotinic tration. Imidacloprid is not distributed to the central
compounds have been selected that are highly specific nervous system (CNS), fatty tissues or bone. This indi-
for subtypes of nicotinic receptors that occur in insects cates that the BBB allows little distribution to the CNS
(Kagabu, 2011; Tomizawa et al., 2011). The neonicoti- for imidacloprid in particular and the neonicotinoids in
noids do not readily pass the blood brain barrier (BBB), general. There are two routes of imidacloprid metabolism
further reducing the potential for mammalian toxicity in mammals. The first route of metabolism involves
(Yamamoto et al., 1995). oxidative cleavage of imidacloprid to imidazolidine and
Imidacloprid does not accumulate in the body, and it 6-chloronicotinic acid. The imidazolidine moiety is
is not carcinogenic, mutagenic, teratogenic nor a repro- excreted in the urine. The 6-chloronicotinic acid is further
ductive toxicant. Imidacloprid has a high margin of safety degraded by glutathione conjugation to a derivative of
due to the high insecticidal specificity and low mamma- mercapturic acid, then to methyl mercaptonicotinic acid.
lian toxicity (Nagata et al., 1999). This chapter describes The mercaptonicotinic acid is then conjugated with gly-
toxicity of neonicotinoids in animals. cine to form a hippuric acid conjugate that is excreted.

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