Page 559 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

526 SECTION | VI Insecticides

VetBooks.ir sometimes mediated solely through α 2 receptors and some-
times through both receptor types. It is also predicted that
the signs related to α 1 adrenergic receptors expected to
appear during poisoning could be masked by α 2 -agonist
effects (Del Pino et al., 2015).
Amitraz blocks H1 receptors in the ileum of guinea
pig strongly in vitro (Pass and Mogg, 1991), but in rat
FIGURE 41.1 The chemical structure of amitraz.
brains weakly in vivo (Costa et al., 1988). A strong hista-
minergic effect was achieved with BTS-27271 in the
transforms into 4-formamido-3-methylbenzoic acid (BTS-
ileum of guinea pigs (Pass and Mogg, 1991). Besides this,
39098), BTS-28369 and some unknown metabolites that
the fact that the intestinal stagnation obtained by intrave-
contain DMA rings, where all of these metabolites can be
nous delivery of amitraz and BTS-27271 to separate
found in urine (Knowles and Benezet, 1981). BTS-27271
sheep was partially reversed by an H1 agonist, and it was
and BTS-27919 are the primary metabolites of amitraz,
completely reversed by an α 2 -adrenergic receptor antago-
and they are a cause of concern because they may have
nist suggests that amitraz is a weak inhibitor of H1 recep-
developmental or genotoxic effects and because they con-
tors and that this effect is a seconder result of amitraz’s
tain a 2,4-dimethylaniline ring (USEPA, 1996).
stimulation of α 2 -adrenergic receptors (Pass and Mogg,
When amitraz is administered orally, it is absorbed in
1991).
significant levels, and it has a long excretion half-life in
The behavioral disorders (Godar et al., 2014), infertil-
dogs (Hugnet et al., 1996). It has been shown that the
ity (Mihalik et al., 2010), and neurotoxic signs (Del Pino
concentration of amitraz and clinical signs are strongly
et al., 2011) that develop in amitraz poisoning are
associated in both cats (Marafon et al., 2010) and dogs
explained by its effect on the monoamine oxidase (MAO)
(Hugnet et al., 1996). In dogs, the clinical signs of amitraz
enzyme. Studies indicate that amitraz mainly inhibits
poisoning usually start 1 h after oral intake and/or when it
MAO-A and BTS-27271 inhibit MAO-B (Moser and
reaches a plasma concentration of 5 mg/L which lasts
MacPhail, 1989).
until the concentration of amitraz drops below this level
(Hugnet et al., 1996).
In an experimental study (Pass and Mogg, 1995), it TOXICITY
was shown that the metabolism rate of amitraz to BTS-
27271 and/or the excretion rate of unmetabolized amitraz Acute Toxicity
is higher in sheep than it is in ponies and that amitraz can
The acute lethal dose-50 (LD 50 ) or lethal concentration-
remain in the plasma of ponies for longer. This study is
50 (LC 50 ) values of amitraz and some of its metabolites
an important indicator of the sensitivity of horses to
delivered by inhalation, orally, or dermal routes are
amitraz.
described in Table 41.1 (Krieger, 2010; Del Pino et al.,
2015; CALEPA, 1995). USEPA has classified amitraz as
MECHANISM OF ACTION class III mildly toxic by the oral or inhalation route, as
class II, moderately toxic by dermal route, and as class
Amitraz shows its effects in mammals mainly by activat- IV, nonirritating to the skin and only mildly irritating if it
ing α 2 -adrenergic receptors (Costa et al., 1988). Both ami- contacts the eyes, and as “nonsensitizing to skin”
traz and BTS-27271 change the secretion of insulin and (USEPA, 1996). However, because amitraz poisoning
glucagon by stimulating the pancreatic α 2 -adrenergic mostly occurs due to contact with products that contain, it
receptors of rats in vitro (Abu-Basha et al., 1999). With would be more appropriate to provide the toxicity data of
the stimulation of α 2 -adrenergic receptors, the intracellular these products. In a risk assessment performed by
adenylate cyclase enzyme is also inhibited, and the cAMP California EPA, amitraz formulated with 50% of a soil-
levels were found to decrease (Chen and Hsu, 1994). derived carrier (Mitac 50% WP), a surfactant and a dis-
Amitraz was also found to activate α 1 -adrenergic recep- persive agent and a 12.5% amitraz product prepared using
tors in vitro in the forebrain of mice (Costa et al., 1988), a petrol distillate (Taktic 12.5% EC) were found to be
andin vivo indogs (Cullen and Reynoldson, 1990) slightly less poisonous in rats. Twenty percent amitraz product
through partial agonist effects. Therefore, vascular α 1 and prepared with a petrol distillate (Mitac 20% EC) caused
α 2 -adrenergic receptors contribute to the vasopressor effect more toxicity (Table 41.1) (CALEPA, 1995). The acute
of amitraz causing hypotension and central nervous system oral LD 50 of an amitraz formulation that contains xylene
(CNS) depression through the stimulation of the central prepared in the laboratory (12.5% EC) was found to be
α 2 -adrenergic receptors (Cullen and Reynoldson, 1990). higher than the LD 50 of technical amitraz. In this case, it
All of this data indicate that the effects of amitraz are was concluded that xylene increased the toxicity of