Amitraz (development code BTS27419) is a non-systemic acaricide and insecticideCorta, E., Bakkali, A., Berrueta, L. A., Gallo, B., & Vicente, F. (1999). Kinetics and mechanism of amitraz hydrolysis in aqueous media by HPLC and GC-MS. Talanta, 48(1), 189-199 and has also been described as a scabicide. It was first synthesized by the Boots Co. in England in 1969.Harrison, I. R., et al. (1973). 1,3,5-Triazapenta-1, 4-dienes: Chemical aspects of a new group of pesticides. Pestic. Sci. 4: 901 Amitraz has been found to have an insect repellent effect, works as an insecticide and also as a pesticide synergist.PubChem Substance. Amitraz – Substance Summary. retrieved from https://pubchem.ncbi.nlm.nih.gov/substance/24868774 Its effectiveness is traced back on alpha-adrenergic agonist activity, interaction with octopamine receptors of the central nervous system and inhibition of monoamine oxidases and prostaglandin synthesis. Therefore, it leads to overexcitation and consequently paralysis and death in insects. Because amitraz is less harmful to mammals, amitraz is among many other purposes best known as insecticide against mite- or tick-infestation of dogs. It is also widely used in the beekeeping industry as a control for the Varroa destructor mite, although there are reports of resistance.
Use
Amitraz is particularly effective against acarids,Brown, P. M. (1977). Toxicological problems associated with the manufacture of triazapentadienes. Proceedings of the Royal Society of Medicine, 70(1), 41-43 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).Environmental Protection Agency. (1996). R.E.D. Facts – Amitraz. Prevention, Pesticides And Toxic Substances (7508W), November 1996 retrieved from It is characterized as an insect repellent, insecticide, and pesticide synergist. These are the properties which make it especially useful as a pesticide:Bonsall, J. L., & Turnbull, G. J. (1983). Extrapolation from safety data to management of poisoning with reference to amitraz (a formamidine pesticide) and xylene. Human Toxicology The repellent effect causes insects to turn away from their target as this is treated with amitraz. It acts as an insecticide, which means that it can be used to control insects that are directly or indirectly harmful to man. As a pesticide synergist it also increases the effect of some other pesticides if they are combined with amitraz. These can be traced back to the mechanisms of action, which lead to a wide field of effects, including direct lethality, excitant-repellant behavioral effects, and chemosterilization for the target species. In addition, it generally causes low damage to nontarget species, which is one of the advantages of amitraz. Furthermore, amitraz is especially effective against insects such as spider mites and ticks in their juvenile and resistant forms.Hollingworth, R. M. (1976). Chemistry, biological activity, and uses of formamidine pesticides. Environmental Health Perspectives, 14(April), 57-69 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. It's also applied to pome fruit, citrus fruit, cotton, stone fruit, bush fruit, strawberries, hops, cucurbits, aubergines, capsicums, tomatoes and ornamental plants to control all stages of tetranychid and eriophyid mites, pear suckers, scale insects, mealybugs, whiteflies, aphids and eggs and first instar larvae of lepidoptera. To apply amitraz, various techniques can be used such as an airblast and concentrate spray to pears or by ground boom and aircraft to cotton.IPCS INCHEM. (1984). Pesticide residues in food – 1984. retrieved from http://www.inchem.org/documents/jmpr/jmpmono/v84pr03.htm 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.
Besides its application as pesticide on plants, amitraz is also used as an animal ectoparasiticide on cattle, goats, sheep, pigs and dogs. In these applications, it is exclusively applied externally. It achieves special efficiency against mites (first of all Demodex canis), but it also works against lice, flies, and all development stages of ticks.Peter R., de Bruin C., Odendaal D., Thompson P.N. The use of a pour-on and spray dip containing Amitraz to control ticks (Acari: Ixodidae) on cattle. J S Afr Vet Assoc, 2006, 77(2), 66-9Tarallo V.D., Lia R.P., Sasanelli M., Cafarchia C., Otranto D. Efficacy of Amitraz plus Metaflumizone for the treatment of canine demodicosis associated with Malassezia pachydermatis. Parasit Vectors, 2009, 2(1) 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.Grossman M.R. Amitraz toxicosis associated with ingestion of an acaricide collar in a dog. J Am Vet Med Assoc, 1993, 203(1), 55-7 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.Federal Register Volume 78, Number 54 (Wednesday, March 20, 2013) Rules and Regulations Pages 17123-17130 [FR Doc No: 2013-06191]. 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. The observed toxic dose in about 50% of these patients has been 0.3 g to 1.25 g of 12.5% amitraz formulations and 0.5 to 2 g of 20% formulations. The remaining patients took doses up to 10 g. Other frequently occurring symptoms after massive amitraz intoxication are CNS depression, respiratory depression, miosis, hypothermia, hyperglycemia, loss of consciousness, vomiting and bradycardia.
Treatment
In case of an amitraz overdose in humans atipamezole or yohimbine, which act as α2-antagonists, can be used as antidote.Gifte.de. (2007) Amitraz. retrieved from http://www.gifte.de/Chemikalien/amitraz.htm 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
Species Method of administration DoseHayes W.J. et al. (1991). Handbook of Pesticide Toxicology. Volume 3 Classes of Pesticides. pg.1487Lewis, R. J. (1996). Sax's Dangerous Properties of Industrial Materials. 9th edition, Volume 1-3, pg. 2227 Rat oral 400 mg/kg dermal >1600 mg/kg intraperitoneal 800 mg/kg Mouse oral 1600 mg/kg intraperitoneal >100 mg/kg Rabbit oral >100 mg/kg dermal >200 mg/kg Baboon oral 150–250 mg/kg Dog oral 100 mg/kg Guinea pig oral 400–800 mg/kg
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.
Route 1: 2,4-Xylidine + triethyl orthoformate + methylamine (imine formation/amine formation): PubChem Substance. Amitraz – Substance Summary. Retrieved from https://pubchem.ncbi.nlm.nih.gov/substance/13178
One of the first amitraz-manufacturing plants used this reaction scheme (figure 1). Therefore, the reactions has been carried out in an enclosed area, to recycle unused reagents. The first step of this route is the reaction of an aniline with triethyl orthoformate. In the named manufacturing plant 2,4-Xylidine has been used as the aniline. The reaction yields an intermediate formimidate ester. In the next step methylamine is added, which combines with the formimidate ester to yield the desired formamidine. As the formamidines forms, ethanol is set free from the chemical reaction and is recycled. This is probably the most suitable method for the synthesis of amitraz, because this second step yields -2,4-dimethyl-N-methylformamidine. The free -NH groups of these molecules react with each other to finally yield amitraz. The last steps of the manufacturing process include crystalisation out from isopropyl alcohol, filtering and drying. These last steps need to be carried out by instructed personnel, who wear full protective clothing with a positive-pressure breathing apparatus.
Route 2: Substituted formamide + aniline:
The first step of this synthesis route to an N-arylformamidine as amitraz is the reaction of a substituted formamide, usually a dialkylformamide, with an aniline. To gain amitraz N-methyl formamide and 2,4 dimethyl aniline hydrochloride can be used (figure 2). This reaction is catalyzed by the presence of acid halides, such as POCl3, SOCl2, COCl2, or an arylsulfonylhalide, as p-toluene sulfonyl chloride (figure 2).Thomas A. Unger, T.A.U. (1996). Pesticide synthesis handbook. New Jersey: Noyes Publications, pp. 836. 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