- Email: [email protected]
Amitraz
Amitraz VC Moser, Toxicity Assessment Division, NHEERL/ORD, US Environmental Protection Agency, Research Triangle Park, NC, USA Ó 2014 Elsevier Inc. All rights reserved. This article is a revision of the previous edition article by Jamaluddin Shaikh, volume 2, pp 99–100, Ó 2005, Elsevier Inc. The views expressed in this paper are those of the author and do not necessarily reflect the views or policies of the US Environmental Protection Agency.
IUPAC Name: N,N0 -[(methylimino)dimethylidyne]di-2,4xylidine l Synonyms: BTS 27419, BAAMÒ, TakticÒ, MitacÒ, PreventicÒ, OvasynÒ l Molecular Formula: C19H23N3 l Chemical Structure: l
Background Amitraz has been used as an insecticide and acaricide on crops, livestock, and pets since the mid-1970s. While there are a number of synthesized formamidine chemicals, only a few are marketed as pesticides. These chemicals stimulate the light organ of the firefly, causing it to glow, confirming their actions as octopamine receptor agonists in insects.
Uses Amitraz is a contact insecticide and acaricide used to control psylla, whiteflies, and mites on cotton and pear crops; and mites, lice, and ticks on livestock, wildlife, and pets. It is applied via spray-dip machines, low-pressure ground sprayers, dip or hand spray, or in impregnated dog collars. The registrant has canceled the use of amitraz on cotton and pear in the United States.
Environmental Fate and Behavior Amitraz is rapidly degraded (aerobic soil t1/2 of about 1 day) to several transformation products, and contamination of ground or surface waters is not a concern. On the other hand, the degradates are moderately persistent in aquatic and terrestrial environments, and are relatively immobile in soil.
Toxicokinetics Amitraz is rapidly and well-absorbed via oral exposure. After a single dose, onset of effects is rapid (within hours of dosing). A major metabolite, N0 -(2,4-dimethylphenyl)-Nmethylformamidine (BTS-27271), has been shown to have the same biological activity of amitraz in mammalian systems. Several subsequent metabolites include hydrolysis and conjugated products that are excreted primarily in urine, and to lesser extent in feces. Metabolism is similar across species, including humans. Kinetic studies of single, low doses indicate that amitraz is eliminated within hours after a single dose, but behavioral and pharmacological studies suggest dose dependency. Following a low dose (5 mg kg1), greater than half of a dose is gone within 24 h, whereas higher doses (50–75 mg kg1) require several days. Similarly, behavioral studies show that effects of lower doses are reversible within hours to days, whereas higher doses produced effects that were still evident after 8 days.
Mechanisms of Toxicity Formamidines produce behavioral changes in target pests, including altered feeding and mating behaviors, representing a novel mode of pesticidal and pestistatic actions. Similarity between the target insect octopamine receptors and mammalian a2-adrenoreceptors gives support for the mechanism of toxicity produced by amitraz, which is mediated through the noradrenergic nervous system. Specifically, amitrazinduced bradycardia, mydriasis, sedation, intestinal stasis, hyperglycemia, and even lethality were blocked using pharmacological antagonists of the a2-adrenoreceptors (e.g., yohimbine, piperoxan, atipamezole), but not by blockers of the a1-adrenoreceptors, or of other neurotransmitter receptors. This relative selectivity has been confirmed both in vivo and in vitro using receptor binding assays. Monoamine oxidase inhibition, a known action of other formamidine chemicals, was only measured at highly toxic doses of amitraz. In addition to these neurological actions, amitraz and other formamidines are anti-inflammatory and antipyretic by means of blocking prostaglandin E2 synthesis.
Acute and Short-Term Toxicity Exposure and Exposure Monitoring
Animal
Humans may be exposed to amitraz residues in foods or occupationally; however, the highest potential for residential exposures involves its use as a tick dip and in pet collars resulting in dermal or incidental oral ingestion.
200
Amitraz is moderately toxic by dermal exposure and slightly toxic by oral exposure or inhalation. It is nonirritating and does not cause skin sensitization. Dogs and baboons are the most sensitive with oral LD50 values around 100–250 mg kg1,
Encyclopedia of Toxicology, Volume 1
http://dx.doi.org/10.1016/B978-0-12-386454-3.00097-X
Amitraz
rats are somewhat less sensitive with LD50 values around 500–800 mg kg1, and mice are least sensitive with LD50 values >1600 mg kg1. Acute neurotoxic signs include hypothermia, periods of excitability and aggression, ataxia, and decreased spontaneous activity. High doses produce tremors, convulsions, and signs of hypothalamic depression. Other pharmacological actions include slowed gastrointestinal transit, which can exacerbate colic in horses. In addition to laboratory animal studies, there are a number of reports on adverse effects following amitraz use in dogs and horses, which appear to be very sensitive.
Human Studies in human volunteers reported nervous system effects, including excitation followed by sedation, disorientation, hypothermia, and decreased heart rate and blood pressure: these signs mirror those observed in laboratory animal studies. Humans appear to be the most sensitive species.
Chronic Toxicity Animal Neurotoxic effects (central nervous system (CNS) depression, hyperexcitable and aggressive behaviors, and hypothermia) were evident in subchronic and chronic studies in rodents and nonrodents; indeed, these signs are similar across species, sexes, and routes of administration. The effects at low doses do not appear to accumulate with repeated exposure, but repeated higher doses intensify the hyperreactivity syndrome. Higher doses in several species also produce decreased weight gain, hyperglycemia, and liver and kidney toxicity. Dosing for just a few days induced hepatic microsomal enzyme levels and activities. Altered hormone levels (e.g., 17b-estradiol, testosterone) may result from altered metabolism; decreased hormone release and weak antiestrogenic activity have also been reported in vitro.
Human Little is known regarding the chronic effects of amitraz in humans.
Immunotoxicity Dosing for 1 month increased adrenal weight, decreased splenic plaque-forming cells, and attenuated delayed-type hypersensitization reaction in rats.
201
study showed reduced litter size and pup survival in all three generations. Special reproductive studies indicated prolonged estrus cycling in rats but not in mice, although changes in hormone levels and relative lengths of proestrus to diestrus were noted in the latter species. Decreased male fertility, increased resorptions, and changes in reproductive organ weights were indicative of adverse effects on fertility and reproductive systems in mice. Prenatal exposure of rats resulted in altered ages of physical developmental landmarks (vaginal opening, fur development, incisor eruption, righting reflex) and changes in open-field behavior in the offspring for up to 1 month of age. Pre- and postnatal exposures also resulted in long-term changes in noradrenergic, serotonin, and dopamine neurochemistry.
Genotoxicity The results of several studies indicate that amitraz is not mutagenic and does not cause DNA damage.
Carcinogenicity Mouse studies have reported lymphoreticular, lung, or liver tumors at the highest dose tested, which produced considerable toxicity, in females only. No findings of carcinogenicity have been reported in rats. The data are generally noncompelling, and the US Environmental Protection Agency (US EPA) has classified it as ‘suggestive evidence of carcinogenicity.’
Clinical Management With dermal exposure, areas exposed to amitraz should be washed with soap and water. Eyes should be washed with copious amounts of clean water. Symptoms include skin rashes, eye and oral irritation, coughing, nausea, headache, sore throat, and sweating. These minor effects are rapidly reversible. Accidental ingestion of sufficient amounts leads to depressed respiration, hypotension, bradycardia, miosis, gastric stasis, hyperglycemia, and coma. These signs and symptoms are somewhat similar to cholinesterase inhibitor poisoning and have sometimes been misdiagnosed as such. Gastric lavage or activated charcoal is indicated immediately. Symptomatic treatments and supportive care (intubation and assisted ventilation) are usually effective. Although a2-antagonists (e.g., yohimbine) have been shown to block amitraz effects in animal studies, this treatment has not been explored in clinical cases.
Ecotoxicity Reproductive Toxicity In rat and rabbit developmental studies, embryotoxicity (increased fetal death, decreased size), and teratogenicity (fetal visceral and skeletal abnormalities) were observed at doses lower than or equal to those producing maternal toxicity (clinical signs, decreased weight gain). A rat multigenerational
The parent amitraz is only slightly toxic to several avian species (8-day LD50 values >1000 ppm in diet), but causes reproductive toxicity (eggshell cracking, decreased viability of embryos and chicks). On the other hand, amitraz is highly toxic to fish (96-h LC50 values 1–10 ppm) and aquatic invertebrates. The degradates of amitraz, which are more environmentally stable, tend to have the reverse toxicity pattern. Amitraz is practically nontoxic to bees.
202
Amitraz
Exposure Standards and Guidelines The US EPA dietary reference dose (RfD) for amitraz is 0.0125 mg kg1 day1, based on an acute no-effect level (NOEL) of 0.125 mg kg1 in a human neurotoxicity study; with the inclusion of an additional factor to assure safety to infants and children, the US EPA population adjusted dose becomes 0.00125 mg kg1 day1. Due to the reversibility of acute doses, the US EPA determined that this endpoint is appropriate for exposures of all durations. The Joint FAO/ WHO Meeting on Pesticide Residues established an acute RfD value of 0.01 mg kg1, based on the same human study, as well as an acceptable daily intake (ADI) value of 0.01 mg kg1 day1, based on the NOEL of 1.3 mg kg1 day1 for developmental effects in rats.
See also: Behavioral Toxicology; Developmental Toxicology; Neurotoxicity; Pesticides.
Costa, L.G., Olibet, G., Wu, D., Murphy, S.D., 1989. Acute and chronic effects of the pesticide amitraz on a2-adrenoceptors in the mouse brain. Toxicol. Lett. 47, 135–143. Evans, P.D., Gee, J.D., 1980. Action of formamidine pesticides on octopamine receptors. Nature 287, 60–62. Hollingworth, R.M., 1976. Chemistry, biological activity, and uses of formamidine pesticides. Environ. Health Perspect. 14, 57–69. Hollingworth, R.M., Murdock, L.L., 1980. Formamidine pesticides: Octopamine-like actions in a firefly. Science 208, 74–76. Institoris, L., Banfi, H., Lengyel, Z., Papp, A., Nagymajtenyi, L., 2007. A study on immunotoxicological effects of subacute amitraz exposure in rats. Hum. Exp. Toxicol. 26, 441–445. Kim, J.C., Shin, J.Y., Yang, Y.S., Shin, D.H., Moon, C.J., Kim, S.H., Park, S.C., Kim, Y.B., Kim, H.C., Chung, M.K., 2007. Evaluation of developmental toxicity of amitraz in Sprague-Dawley rats. Arch. Environ. Contam. Toxicol. 52, 137–144. Knowles, C.O., Benezet, H.J., 1981. Excretion balance, metabolic fate and tissue residues following treatment of rats with amitraz and N 0 -(2,4-dimethylphenyl)N-methylformamidine. J. Environ. Sci. Health, Part B. Pesticides, Food Contam. Agric. Wastes B16, 547–555. Moser, V.C., 1991. Investigations of amitraz neurotoxicity in rats: IV. Assessment of toxicity syndrome using a functional observational battery. Fundam. Appl. Toxicol. 17, 7–16. Palermo-Neto, J., Sákaté, M., Flório, J.C., 1997. Developmental and behavioral effects of postnatal amitraz exposure in rats. Braz. J. Med. Biol. Res. 30, 989–997. Smith, B.E., Hsu, W.H., Yang, P.C., 1990. Amitraz-induced glucose intolerance in rats: Antagonism by yohimbine but not by prazosin. Arch. Toxicol. 64, 680–683.
Further Reading
Relevant Websites
Avsarogullari, L., Ikizceli, I., Sungur, M., Sözüer, E., Akdur, O., Yücei, M., 2006. Acute amitraz poisoning in adults: Clinical features, laboratory findings, and management. Clin. Toxicol. (Philadelphia) 44, 19–23. Costa, L.G., Olibet, G., Murphy, S.D., 1988. Alpha 2-adrenoceptors as a target for formamidine pesticides: In vitro and in vivo studies in mice. Toxicol. Appl. Pharmacol. 93, 319–328.
http://www.epa.gov/pesticides/reregistration/amitraz/ – background and recent regulatory actions in US. http://www.inchem.org/documents/jmpr/jmpmono/v098pr02.htm – information from the International Programme on Chemical Safety. http://www.cdpr.ca.gov/docs/risk/rcd/amitraz.pdf – risk characterization document from California Environmental Protection Agency.
IUPAC Name: N,N0 -[(methylimino)dimethylidyne]di-2,4xylidine l Synonyms: BTS 27419, BAAMÒ, TakticÒ, MitacÒ, PreventicÒ, OvasynÒ l Molecular Formula: C19H23N3 l Chemical Structure: l
Background Amitraz has been used as an insecticide and acaricide on crops, livestock, and pets since the mid-1970s. While there are a number of synthesized formamidine chemicals, only a few are marketed as pesticides. These chemicals stimulate the light organ of the firefly, causing it to glow, confirming their actions as octopamine receptor agonists in insects.
Uses Amitraz is a contact insecticide and acaricide used to control psylla, whiteflies, and mites on cotton and pear crops; and mites, lice, and ticks on livestock, wildlife, and pets. It is applied via spray-dip machines, low-pressure ground sprayers, dip or hand spray, or in impregnated dog collars. The registrant has canceled the use of amitraz on cotton and pear in the United States.
Environmental Fate and Behavior Amitraz is rapidly degraded (aerobic soil t1/2 of about 1 day) to several transformation products, and contamination of ground or surface waters is not a concern. On the other hand, the degradates are moderately persistent in aquatic and terrestrial environments, and are relatively immobile in soil.
Toxicokinetics Amitraz is rapidly and well-absorbed via oral exposure. After a single dose, onset of effects is rapid (within hours of dosing). A major metabolite, N0 -(2,4-dimethylphenyl)-Nmethylformamidine (BTS-27271), has been shown to have the same biological activity of amitraz in mammalian systems. Several subsequent metabolites include hydrolysis and conjugated products that are excreted primarily in urine, and to lesser extent in feces. Metabolism is similar across species, including humans. Kinetic studies of single, low doses indicate that amitraz is eliminated within hours after a single dose, but behavioral and pharmacological studies suggest dose dependency. Following a low dose (5 mg kg1), greater than half of a dose is gone within 24 h, whereas higher doses (50–75 mg kg1) require several days. Similarly, behavioral studies show that effects of lower doses are reversible within hours to days, whereas higher doses produced effects that were still evident after 8 days.
Mechanisms of Toxicity Formamidines produce behavioral changes in target pests, including altered feeding and mating behaviors, representing a novel mode of pesticidal and pestistatic actions. Similarity between the target insect octopamine receptors and mammalian a2-adrenoreceptors gives support for the mechanism of toxicity produced by amitraz, which is mediated through the noradrenergic nervous system. Specifically, amitrazinduced bradycardia, mydriasis, sedation, intestinal stasis, hyperglycemia, and even lethality were blocked using pharmacological antagonists of the a2-adrenoreceptors (e.g., yohimbine, piperoxan, atipamezole), but not by blockers of the a1-adrenoreceptors, or of other neurotransmitter receptors. This relative selectivity has been confirmed both in vivo and in vitro using receptor binding assays. Monoamine oxidase inhibition, a known action of other formamidine chemicals, was only measured at highly toxic doses of amitraz. In addition to these neurological actions, amitraz and other formamidines are anti-inflammatory and antipyretic by means of blocking prostaglandin E2 synthesis.
Acute and Short-Term Toxicity Exposure and Exposure Monitoring
Animal
Humans may be exposed to amitraz residues in foods or occupationally; however, the highest potential for residential exposures involves its use as a tick dip and in pet collars resulting in dermal or incidental oral ingestion.
200
Amitraz is moderately toxic by dermal exposure and slightly toxic by oral exposure or inhalation. It is nonirritating and does not cause skin sensitization. Dogs and baboons are the most sensitive with oral LD50 values around 100–250 mg kg1,
Encyclopedia of Toxicology, Volume 1
http://dx.doi.org/10.1016/B978-0-12-386454-3.00097-X
Amitraz
rats are somewhat less sensitive with LD50 values around 500–800 mg kg1, and mice are least sensitive with LD50 values >1600 mg kg1. Acute neurotoxic signs include hypothermia, periods of excitability and aggression, ataxia, and decreased spontaneous activity. High doses produce tremors, convulsions, and signs of hypothalamic depression. Other pharmacological actions include slowed gastrointestinal transit, which can exacerbate colic in horses. In addition to laboratory animal studies, there are a number of reports on adverse effects following amitraz use in dogs and horses, which appear to be very sensitive.
Human Studies in human volunteers reported nervous system effects, including excitation followed by sedation, disorientation, hypothermia, and decreased heart rate and blood pressure: these signs mirror those observed in laboratory animal studies. Humans appear to be the most sensitive species.
Chronic Toxicity Animal Neurotoxic effects (central nervous system (CNS) depression, hyperexcitable and aggressive behaviors, and hypothermia) were evident in subchronic and chronic studies in rodents and nonrodents; indeed, these signs are similar across species, sexes, and routes of administration. The effects at low doses do not appear to accumulate with repeated exposure, but repeated higher doses intensify the hyperreactivity syndrome. Higher doses in several species also produce decreased weight gain, hyperglycemia, and liver and kidney toxicity. Dosing for just a few days induced hepatic microsomal enzyme levels and activities. Altered hormone levels (e.g., 17b-estradiol, testosterone) may result from altered metabolism; decreased hormone release and weak antiestrogenic activity have also been reported in vitro.
Human Little is known regarding the chronic effects of amitraz in humans.
Immunotoxicity Dosing for 1 month increased adrenal weight, decreased splenic plaque-forming cells, and attenuated delayed-type hypersensitization reaction in rats.
201
study showed reduced litter size and pup survival in all three generations. Special reproductive studies indicated prolonged estrus cycling in rats but not in mice, although changes in hormone levels and relative lengths of proestrus to diestrus were noted in the latter species. Decreased male fertility, increased resorptions, and changes in reproductive organ weights were indicative of adverse effects on fertility and reproductive systems in mice. Prenatal exposure of rats resulted in altered ages of physical developmental landmarks (vaginal opening, fur development, incisor eruption, righting reflex) and changes in open-field behavior in the offspring for up to 1 month of age. Pre- and postnatal exposures also resulted in long-term changes in noradrenergic, serotonin, and dopamine neurochemistry.
Genotoxicity The results of several studies indicate that amitraz is not mutagenic and does not cause DNA damage.
Carcinogenicity Mouse studies have reported lymphoreticular, lung, or liver tumors at the highest dose tested, which produced considerable toxicity, in females only. No findings of carcinogenicity have been reported in rats. The data are generally noncompelling, and the US Environmental Protection Agency (US EPA) has classified it as ‘suggestive evidence of carcinogenicity.’
Clinical Management With dermal exposure, areas exposed to amitraz should be washed with soap and water. Eyes should be washed with copious amounts of clean water. Symptoms include skin rashes, eye and oral irritation, coughing, nausea, headache, sore throat, and sweating. These minor effects are rapidly reversible. Accidental ingestion of sufficient amounts leads to depressed respiration, hypotension, bradycardia, miosis, gastric stasis, hyperglycemia, and coma. These signs and symptoms are somewhat similar to cholinesterase inhibitor poisoning and have sometimes been misdiagnosed as such. Gastric lavage or activated charcoal is indicated immediately. Symptomatic treatments and supportive care (intubation and assisted ventilation) are usually effective. Although a2-antagonists (e.g., yohimbine) have been shown to block amitraz effects in animal studies, this treatment has not been explored in clinical cases.
Ecotoxicity Reproductive Toxicity In rat and rabbit developmental studies, embryotoxicity (increased fetal death, decreased size), and teratogenicity (fetal visceral and skeletal abnormalities) were observed at doses lower than or equal to those producing maternal toxicity (clinical signs, decreased weight gain). A rat multigenerational
The parent amitraz is only slightly toxic to several avian species (8-day LD50 values >1000 ppm in diet), but causes reproductive toxicity (eggshell cracking, decreased viability of embryos and chicks). On the other hand, amitraz is highly toxic to fish (96-h LC50 values 1–10 ppm) and aquatic invertebrates. The degradates of amitraz, which are more environmentally stable, tend to have the reverse toxicity pattern. Amitraz is practically nontoxic to bees.
202
Amitraz
Exposure Standards and Guidelines The US EPA dietary reference dose (RfD) for amitraz is 0.0125 mg kg1 day1, based on an acute no-effect level (NOEL) of 0.125 mg kg1 in a human neurotoxicity study; with the inclusion of an additional factor to assure safety to infants and children, the US EPA population adjusted dose becomes 0.00125 mg kg1 day1. Due to the reversibility of acute doses, the US EPA determined that this endpoint is appropriate for exposures of all durations. The Joint FAO/ WHO Meeting on Pesticide Residues established an acute RfD value of 0.01 mg kg1, based on the same human study, as well as an acceptable daily intake (ADI) value of 0.01 mg kg1 day1, based on the NOEL of 1.3 mg kg1 day1 for developmental effects in rats.
See also: Behavioral Toxicology; Developmental Toxicology; Neurotoxicity; Pesticides.
Costa, L.G., Olibet, G., Wu, D., Murphy, S.D., 1989. Acute and chronic effects of the pesticide amitraz on a2-adrenoceptors in the mouse brain. Toxicol. Lett. 47, 135–143. Evans, P.D., Gee, J.D., 1980. Action of formamidine pesticides on octopamine receptors. Nature 287, 60–62. Hollingworth, R.M., 1976. Chemistry, biological activity, and uses of formamidine pesticides. Environ. Health Perspect. 14, 57–69. Hollingworth, R.M., Murdock, L.L., 1980. Formamidine pesticides: Octopamine-like actions in a firefly. Science 208, 74–76. Institoris, L., Banfi, H., Lengyel, Z., Papp, A., Nagymajtenyi, L., 2007. A study on immunotoxicological effects of subacute amitraz exposure in rats. Hum. Exp. Toxicol. 26, 441–445. Kim, J.C., Shin, J.Y., Yang, Y.S., Shin, D.H., Moon, C.J., Kim, S.H., Park, S.C., Kim, Y.B., Kim, H.C., Chung, M.K., 2007. Evaluation of developmental toxicity of amitraz in Sprague-Dawley rats. Arch. Environ. Contam. Toxicol. 52, 137–144. Knowles, C.O., Benezet, H.J., 1981. Excretion balance, metabolic fate and tissue residues following treatment of rats with amitraz and N 0 -(2,4-dimethylphenyl)N-methylformamidine. J. Environ. Sci. Health, Part B. Pesticides, Food Contam. Agric. Wastes B16, 547–555. Moser, V.C., 1991. Investigations of amitraz neurotoxicity in rats: IV. Assessment of toxicity syndrome using a functional observational battery. Fundam. Appl. Toxicol. 17, 7–16. Palermo-Neto, J., Sákaté, M., Flório, J.C., 1997. Developmental and behavioral effects of postnatal amitraz exposure in rats. Braz. J. Med. Biol. Res. 30, 989–997. Smith, B.E., Hsu, W.H., Yang, P.C., 1990. Amitraz-induced glucose intolerance in rats: Antagonism by yohimbine but not by prazosin. Arch. Toxicol. 64, 680–683.
Further Reading
Relevant Websites
Avsarogullari, L., Ikizceli, I., Sungur, M., Sözüer, E., Akdur, O., Yücei, M., 2006. Acute amitraz poisoning in adults: Clinical features, laboratory findings, and management. Clin. Toxicol. (Philadelphia) 44, 19–23. Costa, L.G., Olibet, G., Murphy, S.D., 1988. Alpha 2-adrenoceptors as a target for formamidine pesticides: In vitro and in vivo studies in mice. Toxicol. Appl. Pharmacol. 93, 319–328.
http://www.epa.gov/pesticides/reregistration/amitraz/ – background and recent regulatory actions in US. http://www.inchem.org/documents/jmpr/jmpmono/v098pr02.htm – information from the International Programme on Chemical Safety. http://www.cdpr.ca.gov/docs/risk/rcd/amitraz.pdf – risk characterization document from California Environmental Protection Agency.