Amitraz

Amitraz is particularly effective against acarids, but it is used as a pesticide in many different fields. Therefore, amitraz is available in many different forms, such as a wettable powder, an emulsifiable concentrate, a soluble concentrate/liquid, and an impregnated collar (for dogs). It is characterized as an insect repellent, insecticide, and pesticide synergist. These are the properties which make it especially useful as a pesticide: • The repellent effect causes insects to turn away from their target as this is treated with amitraz. For agricultural purposes amitraz is primarily used to control the pear psylla (Cacopsylla pyricola) on Oregon pear crops and whiteflies and mites on cotton or pear crops. Territorial differences in amitraz use depend on the species of mites that infest the crops/trees/etc., the local practice, and the number and size of the pear trees. An infestation e.g. by Tetranychus spp. requires higher rates of amitraz. Taking those factors into consideration the application volumes of amitraz have been standardized in terms of maximum spray concentration and in the rate of amitraz per hectare. In combination with additional agents it can be used against flea-infestation as well. For the treatment of dogs amitraz is available as a collar or as a spray- or wash-solution and has an immediate effect against tick infestation as well as a preventive effect. In some countries amitraz emulsions are also applied to treat demodicosis of cats or dogs, an exceeding infestation of mites of the family Demodicidae. For the treatment of cattle, sheep, goats and pigs amitraz is available as spray- or wash-solution, to treat or prevent infestations by mites, lice, flies and ticks. Thereby pigs and cattle should be sprayed and sheep and goats bathed. Other animal species — horses or Chihuahuas, for example — should not be treated with amitraz because adverse effects may occur. == Adverse effects ==

Adverse effects in mammals are caused by amitraz' alpha-adrenergic agonist activity. Symptoms can include low blood pressure and pulse, hypothermia, lethargy, absence of appetite, vomiting, increased blood sugar and digestive problems. Furthermore, skin- or mucosa-irritations may occur in dogs as a response to an amitraz containing collar. This can lead to itching, eczema, alopecia or conjunctivitis. == Toxicity ==

Human toxicity In 2006 the United States Environmental Protection Agency (USEPA) re-assessed the classification for amitraz to a non-quantifiable "Suggestive Evidence of Carcinogenicity" descriptor, and in 2013 determined that quantification of risk using a non-linear approach for amitraz will adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to amitraz and its metabolites. Accidental exposure of men to greater amounts of amitraz can lead to death due to respiratory failure, mainly after oral uptake or inhalation. In Turkey during 1989, 41 cases of deadly amitraz intoxications have been detected. Initially it is important to remove the patient from the amitraz contaminated area. When amitraz has been inhaled the patient should first get respiratory protection. Additionally the patient should be supplied with 4 L oxygen per minute. In case of an intoxication via skin-contact, contaminated clothes should be removed first. Affected areas need to be washed with water. If eyes have been exposed to amitraz, anesthesia should be administered and the eyes carefully washed. After the oral intake of amitraz it is important to make the patient drink ca. 0.3 L water to reduce amitraz' irritating effect on the gullet. Furthermore, it is important to prevent the patient as much as possible from vomiting, to reduce the risk of further aspiration of amitraz. Subsequently, the patient need to be observed for at least 24 hours to ensure that the symptoms do not recur. Non-human toxicity == Synthesis ==

Since its discovery by Boots Co. in 1969 three main synthesis routes for amitraz has been developed, which stand out in terms of facility and generality. One of the first amitraz-manufacturing plants used this reaction scheme (figure 1). This yields an intermediate, which reacts further as its catalyzed by p-toluene acid to N, N'-[(methylimino) dimethylidyne] di-2,4-xylidine (amitraz). Alternatively, the aniline in the first step can be replaced by an arylformamide. In addition the replacement of the dialkylformamide with an N-alkylpyrrolidone can be used to obtain products of the clenpyrin group from this reaction. route 3: arylisocyanate + formamide: To achieve this reaction a mixture a suitable arylisocyanate and formamide is heated and marked by the evolution of CO2, to yield the desired formamidine. == Metabolism ==

Since amitraz most common use is as a pesticide, it is important to consider that between animals and plants often different pathways for biotransformation occur. Most animal species, including humans can metabolize amitraz rapidly to form six metabolites during biotransformation, N-methyl-''''-(2,4-xylyl)formamide, Form- 2'4'xylidine, 4-N-Methyl-formidoyl) amino-meta-toluix acid, 4-Formamido-meta-toluic acid, 4- Acetamido- meta-toluic acid and 4- Amino- meta- toluic acid. In rats the metabolic pathway (figure 3) has been examined after oral administration of C-labelled amitraz, which was found to be effectively metabolized, degraded and excreted to four of the metabolites in urine and six in faeces. Under basic conditions (pH>6) amitraz is metabolized to 2,4-dimethylphenylformamide. Followed by hydrolysis to 2,4-dimethylaniline, which also benefits from a basic pH. At very acidic pH (pH<3) 2,4-dimethylaniline has been observed as the main degradation product. Under less acidic conditions (pH 3–6) mainly N-(2,4-dimethylphenyl)--methylformamidine and already amounts of 2,4-dimethylphenylformamide occur. == Mechanism of action ==

Amitraz is used as a pesticide. Therefore, amitraz exposure to humans occurs mainly through inhalation or dermal contact with the compound during its use or production. The toxic effects to humans following on amitraz-uptake include loss of consciousness, vomiting, respiratory failure, miosis, hypothermia, bradycardia, hyperglycemia and central nervous system depression. When an amitraz poisoning is lethal, death results from respiratory depression. Xylene present in amitraz formulations additionally induces central nervous system depression. Consequently, a dose-dependent delay of gastrointestinal transit in conscious mice occurs. This effect could be antagonized by alpha2-adrenergic blocking agents, but administration of other antagonists did not reduce the depressant effect on the gastrointestinal transit. This interaction is probably the reason for increased nervous activity of ticks as a response on amitraz. Usual activation of the receptors may lead to changes in the concentration of intracellular second messengers such as cyclic nucleotides cyclic AMP (cAMP) and cyclic GMP, inositol-1,4,5-trisphosphate and Ca2+. Influencing this signal transduction system can lead to various events depending on the celltype. However, in vivo it has been observed that only at high doses of amitraz or its main metabolite N-2,4-dimethylphenyl-N-methyl-formamide monoamine oxidase inhibition occurs. In a dose of 5 to 80 mg/kg body weight, given intraperitoneally to rats, amitraz reduces yeast-induced fever and antagonizes the carrageenin-induced swelling of the hind paw. Some of the physiological effects of amitraz probably go back to this aspirin-like activity and occur due to inhibition of prostaglandin synthesis. ==References ==