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Material Safety Data Sheet(MSDS)

Questions And Answer

• Overview

  Amitraz is a formamidine pesticide widely used as an insecticide and acaricide. Formamidine pesticides were developed in the late 1950s and early 1960s due to the development of resistances to conventional insecticides. The two formamidines primarily marketed and most widely used are chlordimeform and amitraz. Amitraz (1,5-di (2,4-dimethylphenyl)-3-methyl-1, 3, 5-triazapenta1,4-diene) (Figure 1) was first patented in 1971, registered as a pesticide of technical grade in 1975^[1] and marketed in 1981.
  Amitraz is an insecticide used to prevent tick and mite infestation and is in common use around the world. Amitraz is applied to cattle^[2] and sheep in dip baths at concentrations of 0.025%^[3], to dogs from collars impregnated with 0.025% amitraz, or by topical application in a bath of 0.05% amitraz^[4], to pigs in sprays containing 12.5%, and to cotton and hops^[5] by spraying 20% solutions of amitraz from aeroplanes and ground sprinklers. In addition, amitraz is used to control psylla infestations of pears^[6]. Human exposure to amitraz occurs when diluting the concentrate obtained from the manufacturer, when applying the amitraz to crops or animals, and when working in amitraz-treated areas, for example pear orchards or cotton fields^[1].
  Different agencies have evaluated amitraz toxicity and the lethal dose 50 (LD50) or lethal concentration 50(LC50) values on acute toxicity studies^{[1, 7]}. The EPA (Environmental Protection Agency), according to acute toxicity studies, classifies amitraz as Class III-slightly toxic by the oral and inhalation routes, as Class II-moderately toxic by the dermal route, and as Class IV-not a dermal irritant and only slightly irritant to the eyes and not a dermal sensitizer^[1].
  Amitraz is rapidly absorbed, distributed, metabolized, and eliminated primarily via urine when administered orally to mammals.^{[1, 7]} No differences have been described between species and genders in the rates and routes of excretion. In all species studied, 55−74% of the dose was excreted in the urine within the first 24 h after dosing^{[1, 7]}. The degradation products present in the urine include N′-[2,4-dimethylphenyl]-Nmethylformamidine (BTS-27271), 2,4-dimethylformanilide (BTS-27919), 2,4-dimethylaniline (BTS-24868), 4-formamido3-methylbenzoic acid (BTS-39098), 4-amino-3-methylbenzoic acid (BTS-28369), and several unknown metabolites.^[8] Moreover, the spectrum of metabolites observed was similar in all species studied. BTS-27271 and BTS-27919 are the main metabolites of amitraz and a cause of concern due to the content of the 2,4-dimethylaniline moiety, which could lead to developmental and genotoxic effects.^{[1, 2]} Furthermore, BTS-27271 has been found to be more potent than amitraz with regard to its miticidal activity and mammalian toxicity. The action of these metabolites has been described only for some of the mechanisms and effects of amitraz; thus, further studies are needed to determine their participation in the rest of the mechanisms and effects^{[9, 10]}.
  
  Figure 1 the chemical structure of amitraz;

• Indication and contradiction

  Amitraz is indicated for animal use against mites, lice and ticks for cattle, swine and sheep. For dogs, it is used against ticks and mite^[11]. It was reported as the drug of choice in the treatment of localized and generalized demodicosis in dogs^[11]. Along with macrocyclic lactones such as milbemycin oxime, ivermectin, moxidectin, and doramectin, amitraz is still recommended for the treatment of generalized canine demodicosis, although it is not very efficient in adult-onset demodicosis cases^[12]. Chesney (1989) also reported the use of amitraz in the treatment of demodicosis in cats[13]. Gunaratnam et al. (1983)^[14] evaluated amitraz toxicity in cats, and concluded that low concentrations, around 0,0125% are capable of generating moderate toxic effects, especially anorexia. The toxic effects are even more evident in cats, due to their licking habit, resulting in a higher intake of the product. However, it is possible to use amitraz topically in healthy cats, respecting the appropriate contraindications common to the other species, which is to avoid the use in diabetic, hypothermic, and cardiac patients.
  Amitraz is contraindicated in horses due to the risk of hypomotility and intestinal atony, leading to severe intestinal impaction^{[13, 14]}. It has been also observed, besides the intestinal symptoms, the occurrence of neurologic signs as drowsiness, decreased cranial nerve reflexes and ataxia in horses submitted to the experimental use of amitraz. This substance is contraindicated for patients with extended skin injuries, which could lead to an over absorption, favoring intoxication. ;

• Pharmacokinetics and pharmacodynamic

  Amitraz is quickly hydrolyzed in an acid environment when it is orally administrated, due to its instability in this environment. The hydrolysis in a low pH generates the compound 2,4-dimethylphenyl formamide, which is stable in an acid environment. This substance can still be hydrolyzed, generating 2,4-dimethylaniline^[15]. Absorption is effective through the skin, which may be major or minor depending on its integrity, the occurrence of injuries, and inflammation. After reaching the blood stream, the drug reaches the highest plasmatic level in up to two hours. The biotransformation occurs in the liver, generating the active metabolite BTS 27271, the most important pharmacologically, because it acts directly in the regulation of the insulin and glucagon secretion by binding to the α2A and α2D-adrenergic receptors, inhibiting insulin and stimulating glucagon secretion, resulting in hyperglycemia. Metabolites are excreted in bile and urine.
  In insects, formamidines such as chlordimeform and amitraz operate its toxic effects by interacting with octopaminergic receptors in the central nervous system^[16]. The mechanisms by which the deleterious effects of amitraz in mammals are determined are based on its agonistic action on α2-adrenergic receptors and inhibitory action over the monoamine oxidase (MAO), but there are reports of various action pathways, such as: H1 histamine receptor inhibition, prostaglandin synthase inhibition, adenylyl cyclase inhibition, voltage-gated calcium channels activation, reactive oxygen species generation, cell death induction and endocrine disruptions. Amitraz is also related to the emergence of neurotoxic effects and modifications in the reproductive sphere in rats^[17]. ;

• Reference

  1. USEPA (United States Environmental Protection Agency) (1996)
  2. McDougall K and Lewis I (1984). Aust Vet J 61,137–140.
  3. Eamens G, Spence S and Turner M (2001) Aust Vet J 79,703–706.
  4. Shaw S and Foster A (2000) Aust Vet J 78,243–244.
  5. Weichel L and Nauen R (2003) Pest Manage Sci 59,991–998.
  6. Schaub L, Sardy S and Capkun G (2002) Pest Manage Sci 58,959–963.
  7. JMPR. Pesticide Residues in Food−1998, Evaluations Part II: Toxicological WHO/PCS/99.18, 1998
  8. Knowles, C. O., and Benezet, H. J. (1981) J. Environ. Sci. Health, Part B 16, 547−555.
  9. Schuntner, C. A., and Thompson, P. G. (1978) Aust. J. Biol. Sci. 31, 141−148.
  10. Pass, M. A., and Mogg, T. D. (1991) Comp. Biochem. Physiol., Part C: Pharmacol., Toxicol. Endocrinol. 99, 169−172.
  11. Folz, S.D et al. Veterinary Parasitology, 16(3-4): 335–341, 1984.
  12. Mueller, R.S. Veterinary Dermatology, 15: 75-89, 2004
  13. Chesney, C.J. Journal of Small Animal Practice, 30(12): 689-695, 1989
  14. Gunaratnam, P.; Wilkinson, G.T.; Seawright, A.A. Australian Veterinary Journal, 60(9): 278–279, 1983.
  15. Pierpoint, A.C.; Hapeman, C.J.; Torrents, A. Journal of Agricultural and Food Chemistry's. 45(5): 1937-1939,1997.
  16. Chen, A.C.; He, H.; Davey, R.B. Veterinary Parasitology, 148: 379-383, 2007.
  17. Del Pino, J.; et al Chemical Research in Toxicology, 28(6): 1073-1094, 2015.
  18. Costa, L. G., Wu, D. S., Olibet, G., and Murphy, S. D. (1989) Neurotoxicol. Teratol. 11, 405−411.
  19. Douglas, W. W. (1980) Histamine and 5-Hydroxytryptamine (Serotonin) and Their Antagonist, in The Pharmacological Basis of Therapeutics., pp 609−646, Macmillan, New York.
  20. Levitt, P., et al. (1997) Trends Neurosci. 20, 269−274.
  21. Fajardo, A. M., et al (2014) Cancers 6, 436−458.
  22. Shin, D. H., and Hsu, W. H. (1994) Toxicol. Appl. Pharmacol. 128, 45−49.
  23. Radakovic, M., et al J. Biosci. (New Delhi, India) 38, 53−62.
  24. Gregorc, A., and Bowen, I. D. (2000) Cell Biol. Int. 24, 319−324.
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