Toxicol Rev 2003; 22 (2): 71-74

REVIEW ARTICLE 1176-2551/03/0002-0071/$30.00/0

 2003 Adis Data Information BV. All rights reserved.

Poisoning with Amitraz

Alex T. Proudfoot
National Poisons Information Service (Birmingham Centre), City Hospital, Birmingham, UK

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
1. Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
2. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
3. Mechanisms of Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
4. Toxicokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
5. Dose/Response Relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
6. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
6.1 Ingestion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
6.2 Dermal Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
7. Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
7.1 Supportive Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
7.2 Confirmation of the Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
7.3 α2-Adrenoceptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

Abstract Amitraz, an insecticide and veterinary medicine, has been available in many countries since 1974 but reports
of poisoning with it have only become prominent in the last 7 years. The vast majority of cases have occurred in
Turkey and have involved children. The data available, both human and animal, do not allow clear separation of
the features of toxicity of amitraz from those of the hydrocarbon solvents in which it is commonly dissolved.
Amitraz stimulates α2-adrenoceptors resulting in impairment of consciousness, respiratory depression, convul-
sions, bradycardia, hypotension, hypothermia and hypoglycaemia. Even the most severely poisoned patients
recover with nothing more than intensive care; only one possible death has been documented. Animal studies
indicate that the α2-adrenoceptor antagonists, yohimbine and atipamezole, can reverse amitraz-induced toxicity
but they have not been assessed in poisoned humans.

1. Uses Poisoning with amitraz is uncommon and most cases have emanat-
ed from Turkey.[3,5-10] Ready availability in the community would
Amitraz (figure 1) is a formamidine insecticide, acaricide and
appear to be the principal reason for the comparatively high
veterinary medicine that is commonly formulated in xylene[1,2] or
number of reports from this country. In turn, this is because most
petroleum distillate.[3,4] Various emulsifiable concentrates and so-
families in its rural regions raise a few cattle that they treat with
lutions containing 20–200 g/L are available worldwide. Amitraz is
amitraz, which can be obtained without prescription.[8] However,
used particularly on fruit trees and in cattle, sheep, pigs and honey-
single or very small numbers of cases have been reported from
bee hives. It was first marketed in 1974.[2]
Belgium,[1] China,[11] France,[4] Italy (unpublished report quoted
by Larsen[12]), The Netherlands,[13] Japan[2] and the UK.[2]
2. Epidemiology
Ingestion is the most common route of exposure and deliberate
There are no reports of poisoning by amitraz alone; all have self-poisoning[2,4,6,11] and accidental ingestion by adults[1,2,6] and
involved products that also contained hydrocarbon solvents. children[2-5,7-10,13-15] have all been reported. Less frequently, chil-
72
CH3 CH3 CH3
N N N
C C
H H
CH3 CH3
Fig. 1. Chemical structure of amitraz.
dren have become poisoned after dermal contact with amitraz,[3,7,8]
in some cases when it has been used to treat scabies or some other
ectoparasitic infestation.[8] Only one death is thought to have
resulted from amitraz intoxication.[2] The assertion that there was a
second[10] is not confirmed by the reference given.[16]
3. Mechanisms of Toxicity
The CNS and cardiac toxicity of amitraz result from its α2-ad-
renoceptor agonist activity, in which respect it is similar to cloni-
dine. These actions reduce insulin secretion and heat production.
Amitraz also inhibits monoamine oxidase in vitro but not in vivo.[2]
It is widely agreed that any gastrointestinal or pulmonary features
that develop are more probably caused by the solvents in the
commercial formulations of the pesticide. They may also contrib-
ute to CNS toxicity.
4. Toxicokinetics
Peak plasma concentrations of amitraz are attained in poisoned
patients as early as 2 hours post-ingestion suggesting that absorp-
tion is rapid.[1,17] Animal studies indicate that the agent is metabol-
ised extensively, mainly to N-2,4-dimethylphenyl-N-methyl
formamidine and 2,4-dimethylaniline then to 3-methyl-4-ami-
nobenzoic acid, the principal urinary metabolite.[2] Data from two
volunteers given single oral doses of 0.25 mg/kg bodyweight
indicate that humans produce the same metabolites (unpublished
report quoted by Larsen[12]). Of the dose given, 58–68% was
excreted in the urine in the first 24 hours and 77–87% within 72
hours. A plasma half-life of 4 hours was calculated in one case.[1]
There are no data on dermal absorption, although dermal skin
absorption may lead to systemic toxicity (see section 6.2).
5. Dose/Response Relationships
A no observable adverse effect level (NOAEL) in humans of at
least 0.13mg amitraz/kg bodyweight has been established by two
studies in volunteers.[12,18] In both, the NOAEL was derived from
the highest dose investigated and, between them, no change was
found in heart and respiratory rates, body temperature, blood
pressure, performance in psychometric tests, pupil responsiveness,
urine tests and electrocardiographs. The lowest dose causing
α2-adrenoceptor agonist effects was 0.25 mg/kg (unpublished data
quoted by Harvey et al.[19]). Two men given this dose developed
 2003 Adis Data Information BV. All rights reserved.
Proudfoot
signs of mild CNS depression with decreased heart rate and blood
pressure (unpublished report quoted by Larsen[12]). Oral adminis-
tration of approximately 2.5 mg/kg bodyweight impaired con-
sciousness, and induced hypothermia and bradycardia in a
4-month-old baby.[13]
In poisoned individuals, a plasma concentration of 100 µg/L
some 2 hours after ingestion was not associated with clinical
features,[17] while patients with concentrations of 450–500 µg/L
were drowsy or had only minor CNS depression.[1,17]
6. Clinical Features
Since it is almost certain that all human exposures to amitraz
have involved concomitant exposure to organic solvents that have
effects on the CNS and other organs, it is impossible to state
precisely the features of poisoning that are attributable to the
active pesticide rather than its vehicle. However, since it is highly
improbable that the general public will ever have access to non-
commercial amitraz, the issue is clinically academic if toxicologi-
cally unsatisfactory.
6.1 Ingestion
Features of toxicity commonly develop within 30–90 minutes
of ingestion.[5,7] Drowsiness and ataxia may progress to further
depression of consciousness and coma. Respiration may also be
depressed to the extent of requiring mechanical assistance.[3,6,7,15]
Respiratory acidosis, respiratory alkalosis and metabolic acidosis
may result.[8,11] Hypothermia, hypotension and sinus bradycardia
are common. As with clonidine, the effect of amitraz on the pupil
of the eye depends on the amount involved, smaller quantities
causing miosis and larger ones mydriasis. Hyperglycaemia with
blood glucose concentrations as high as 31 mmol/L (564 mg/dL)
have been reported.[8] In these cases, glycosuria is to be expected.
Less commonly, convulsions[3,7,8,14,15] have occurred. The pattern
of amitraz toxicity is confirmed by observations in children,[5,14,15]
the frequency of features in the three largest surveys being sum-
marised in table I. Although nausea and/or vomiting are common
(table I), they are thought to be caused by the solvent rather than
the amitraz content of commercial formulations.[4,7]
Additional features include minor elevations of transaminase
activities.[6,7,9,14,15] Minimal increases in alkaline phosphatase ac-
tivities also occur[7,15] but raised bilirubin concentrations have not
been reported. Polyuria has been described in some cases[3,7,10] and
may be secondary to glycosuria. Renal function is usually not
affected.[7,8,14] Single cases where there was hypernatraemia,[9]
hypokalaemia[4] and ventricular tachycardia[6] may have involved
factors other than amitraz and hydrocarbon solvents. Similarly, the
finding of prothrombin time prolongation in a young boy[9] is
Toxicol Rev 2003; 22 (2)
Poisoning with Amitraz 73

Table I. The clinical features of amitraz ingestion in children under the age been given to treat profound bradycardia, with good effect in some
of 14 years cases[8] but not others.[1] Multiple doses may be required[3,7] but the
Feature No. of children (%) drug is best avoided, if possible. Hypotension responds to appro-
Aydin et al.[14] Ertekin et al.[15] Kalyoncu et al.[8] priate expansion of the intravascular volume with or without the
(n = 24)a (n = 21) (n = 29) use of an inotrope. Metabolic acidosis should only be treated with
Coma/ 83 100 55 intravenous sodium bicarbonate if it persists after best efforts to
unconsciousness reverse respiratory failure, hypoxia and hypotension, and control
Convulsions 8 14 7 convulsions.
Hypotension 42 67 0 Once the patient’s immediate condition has been stabilised,
Bradycardia 54 62 10 gastric lavage may be considered if the procedure can be carried
Vomiting 50 62 out within 1 hour of ingestion, although the presence of a hydro-
Hypothermia 33 9 carbon in the formulation involved is a relative contraindication.
Respiratory 17 43 Alternatively, oral activated charcoal 50g may be considered;
depression however, there is no evidence that gut decontamination is of
Hyperglycaemia 71 48 72 clinical benefit in amitraz poisoning.
Glycosuria 42 38 21 It is unnecessary to attempt to reverse hyperglycaemia, al-
a Includes one case of dermal exposure. though hypoglycaemia should be corrected.

difficult to explain. More importantly, hypoglycaemia was found 7.2 Confirmation of the Diagnosis
in one child[8] and has implications for management. Non-specific
It is important to confirm as far as possible the nature of the
elevation and depression of the ST interval of the electrocardio-
pesticide ingested since the combination of impaired conscious-
gram occurred in one series[14] but not others.[8,15]
ness, miosis, bradycardia, with or without hyperglycaemia and
Despite 2,4-dimethylaniline being a major metabolite and a glycosuria, raises the possibility of organophosphorus insecticide
weak methaemoglobin inducer in dogs,[20] methaemoglobinaemia poisoning. Urgent measurement of serum or (preferably) red cell
does not appear to have complicated amitraz poisoning in humans. cholinesterase activity is indicated if diagnostic doubt persists.
Similarly, the finding of hypoglycaemia in one case makes it
6.2 Dermal Exposure
mandatory to measure the blood glucose concentration and correct
The features of poisoning after dermal exposure to amitraz are hypoglycaemia if indicated.
similar to those seen after ingestion but tend to develop later and
have been claimed to be less severe.[7,8] However, they may be life- 7.3 α2-Adrenoceptor Antagonists
threatening in some cases, although complete loss of conscious-
Yohimbine[21,22] and atipamezole,[23] specific α2-adrenoceptor
ness was much less common. Drowsiness, coma and respiratory
antagonists, have been used with good effect to prevent or reverse
distress developed in a 2-year-old child who had amitraz applied to
the toxicity of amitraz in animals but have not been assessed in the
the skin for the treatment of lice. There was no direct dermal
management of amitraz poisoning in humans. The use of
toxicity.[3] A young man who was transiently immersed up to the
atipamezole appears to be confined to veterinary medicine. Fortu-
shoulders in a dilute amitraz solution had headache, malaise and
nately, the duration of amitraz poisoning is comparatively short
vomiting over the next 3 days but a causal relationship was not
and the response to symptomatic and supportive management so
considered to be established.[2]
good that α2-adrenoceptor antagonists will not be required. Poten-
tially, yohimbine may have a role in the management of the most
7. Management
severe cases unresponsive to conventional measures.
The management of intoxication with amitraz is primarily
supportive and symptomatic. 8. Conclusions

The sudden appearance of reports of significant numbers of

7.1 Supportive Care
A clear airway and adequate ventilation must be ensured if
consciousness is impaired. Protracted or recurrent convulsions
should be controlled with intravenous diazepam. Atropine has
amitraz poisonings more than 20 years after the launch of the
pesticide on the market seems largely due to its availability in rural
regions of Turkey. Most intoxications have resulted from acciden-
tal ingestion and involved children. However, serious conse-

 2003 Adis Data Information BV. All rights reserved. Toxicol Rev 2003; 22 (2)
74
quences may follow dermal exposure. Hydrocarbon solvents in the
products commonly involved may contribute to the symptomatol-
ogy.
Acknowledgements
No sources of funding were used to assist in the preparation of this
manuscript. The author has no conflicts of interest that are directly relevant to
the content of this manuscript.
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Correspondence and offprints: Alex T. Proudfoot, National Poisons Informa-
tion Service (Birmingham Centre), City Hospital, Birmingham, B18 7QH,
UK.
Toxicol Rev 2003; 22 (2)