WORLD HEALTH ORGANIZATION FOOD AND AGRICULTURE
ORGANIZATION
ORGANISATION MONDIALE DE LA SANTE ORGANISATION POUR L'ALIMENTATION
ET L'AGRICULTURE
WHO/PCS/DS/94.79
Original: ENGLISH
Distr.: LIMITED
Date of issue: February 1994
WHO/FAO DATA SHEET ON PESTICIDES No. 79
AMITROLE
It must be noted that the issue of a Data Sheet for a
particular pesticide does not imply endorsement of the pesticide by
WHO or FAO for any particular use, or exclude its use for other
purposes not stated. While the information provided is believed to
be accurate according to data available at the time when the sheet
was compiled, neither WHO nor FAO are responsible for any errors or
omissions, or any consequences therefrom.
The issue of this document does Ce document ne constitue pas une
not constitute formal publication. Il ne doit faire
publication. It should not be l'objet d'aucun compte rendu ou
reviewed, abstracted or quoted résumé ni d'aucune citation sans
without the agreement of the l'autorisation de l'Organisation
Food and Agriculture des Nations Unies pour
Organization of the United l'Alimentation et l'Agriculture
Nations or of the World Health ou de l'Organisation Mondiale de
Organization. la Santé.
CLASSIFICATION:
Primary use: Herbicide
Secondary use: Plant growth regulator
Chemical group: Triazole
1.0 GENERAL INFORMATION
1.1 COMMON NAME: Amitrole (E-ISO, F-ISO).
1.1.1 Identity
IUPAC chemical name: 1-H-1,2,4-triazol-3-ylamine,
(formerly 1-H-3-amino-1,2,4-triazole)
CAS chemical name: 1-H-1,2,4-triazol-3-amine,
(formerly 3-amono-s-triazole).
CAS registry number: 61-82-5
RTECS registry number: XZ 3850000
Chemical formula: C2H4N4
Relative molecular mass: 84.08
Structural formula:
1.1.2 Synonyms: Aminotriazole; Triazolamine; ATA;
Amitril; Amitrol; AmizolR; CytrolR; DomatolR; ElmasilR;
ENT 25455; VoroxR; WeedarR; WeedazolR; 3A-T.
1.2 SYNOPSIS Amitrole is a non-selective foliage-
absorbed herbicide that inhibits chlorophyll formation and regrowth
from buds. The acute mammalian toxicity is low. Repeated exposure
induces goitre and repeated high doses resulted in thyroid tumours
in rats. Its use is restricted to non-food and non-feed stuff crops.
1.3 SELECTED PROPERTIES:
1.3.1 Physical characteristics: Pure amitrole is a
colourless crystalline powder with a bitter taste. It is a strong
chelating agent with a melting point of 153-159 °C and a specific
gravity of 1.138 at 20 °C. Corrosive to iron, aluminium, copper and
copper alloys.
1.3.2 Solubility: 300 g/L water at 20 °C; 260 g/kg
ethanol at 75 °C; moderately soluble in methylene chloride,
chloroform; insoluble in acetone, diethyl ether and hydrocarbons.
1.3.3 Stability: Amitrole is thermally stable. It is
also stable in neutral or alkaline media, but it forms salts. It
breaks down in ultraviolet light. Forms chelates with metals, and is
thus corrosive to aluminium, copper and iron.
1.3.4 Vapour pressure: Negligible (55 nPa, at 20 °C).
1.4 AGRICULTURE, HORTICULTURE AND FORESTRY
1.4.1 Common formulations: Available as water soluble
powder (50-95%) as well as liquids, water soluble concentrate and
aerosol sprays. Often used with an activator, ammonium thiocyanate
and with other herbicides like simazine.
1.4.2 Pests controlled: Used against perennial
broadleaf weeds, annual grasses such as bermuda grass, Canada
thistle, cattails, poison oak, poison ivy, quackgrass. Particularly
effective in the control of water hyacinth.
1.4.3 Use pattern: Foliar application to non-feed and
non-food crop locations, such as industrial land. Used around
established fruit trees after harvest, for spot application to
control Tussock grass. Applied while weeds in vigorous growth.
1.4.4 Unintended effects: Amitrole has high potential
mobility in soil. Degradation of amitrole in soil is usually
fairly rapid but variable with soil type and temperature. Therefore,
its retention in moist soils by absorption makes high leaching
potential very unlikely to be realised in practice. The few reports
of effects on non-target vegetation support this view.
1.5 PUBLIC HEALTH USE:
No recommended usage reported.
1.6 HOUSEHOLD USE:
1.6.1 Common formulations: Technical grade solutions (200
g/L) and as water soluble powder (10%), and in combination with
simazine and/or other herbicides.
1.6.2 Pests controlled: Amitrole has a wide spectrum
of activity against annual and perennial broad leaf and grass type
weeds.
1.6.3 Use pattern: Foliar application, but amitrole
is also translocated to the roots to kill deep rooted perennials.
May take up to three weeks for full effect. Do not plant vegetable
crops within eight months of autumn spraying of garden plots.
2.0 TOXICOLOGY AND RISKS
2.1 TOXICOLOGY - MAMMALS
2.1.1 Absorption route: Amitrole is absorbed from the
gastro-intestinal tract, by inhalation of spray-mists and to a
lesser extent through intact skin.
2.1.2 Mode of action: Amitrole has been shown to be
goitrogenic in several animal species. Biochemical mechanisms
include reduced thyroid uptake of iodine and inhibition of peroxidase
activity of the thyroid. The resulting reduction of thyroid hormones
induces a hypothalamus mediated TSH stimulation on the thyroid
itself. This prolonged stimulation is thought to be responsible for
the induction of thyroid cancers in animals treated with high doses
of amitrole.
2.1.3 Excretion products: Little metabolic
transformation of amitrole occurs in mammals and it is excreted in
the urine mainly unchanged within a few hours. Two urinary
metabolites have been identified in rats, i.e.
3-amino-5-mercapto-1,2,4-triazole and 3-amino-1,2,4-triazolyl-(5)-
mercapturic acid.
2.1.4 Toxicity, single dose:
Oral LD50
Rat 5 000 mg/kg b.w.
Rat 25 000 mg/kg b.w.
Mouse 11 000 - 14 700 mg/kg b.w.
Rabbit >2 150 mg/kg b.w.
Intraperitoneal LD50
Mouse >4 000 mg/kg b.w.
Intravenous LD50
Mouse 5 000 mg/kg b.w.
Rat >2 500 mg/kg b.w.
Dermal LD50 (24h)
Rabbit >10 000 mg/kg b.w.
Inhalation LC50 (4h)
Rat >439 mg/L
Signs of toxicity include dyspnoea, ataxia and diarrhoea with
vomiting. Coma and death appeared to be associated with respiratory
insufficiency. Gastrointestinal irritation and haemorrhage were the
only macroscopic findings. Single doses of amitrole (10 mg/kg s.c.
to rats) were shown to decrease iodine uptake and thyroid hormone
levels.
Dermal irritancy: Cutaneous application of 10 000 mg/kg b.w.
to rabbits or 2500 mg/kg b.w. to rats produced a temporary mild
erythema.
Ocular irritancy: A mild irritation of 28 - 48 hour duration
was observed following application of 3 mg to the conjunctival sac
of rabbits. No permanent damage was observed.
2.1.5 Toxicity, repeated doses:
Oral: Gavage administration of 100, 200 or 400 mg/kg b.w./day,
five days/week for four weeks, to rats resulted in a reduced growth
rate, reduced iodine content of the thyroid and an increased relative
thyroid weight.
Male and female beagle dogs showed no adverse effects in growth,
behaviour, haematology, histopathology (including thyroid), or in
liver and kidney function tests following exposure to gelatin capsule
doses of up to 12.5 mg/kg b.w./day, six days/week for 52 weeks.
Intraperitoneal: Increased thyroid weights (300-400%) were
noted in male and female rats receiving 21 intraperitoneal injections
of 1000 mg/kg b.w. over a period of 45 days. No effect on growth or
food consumption was observed. Liver catalase activity was reduced
more than 90% in rats receiving 1000 mg/kg b.w, 14 times over a
period of 30 days.
Amitrole (500 or 1000 mg/kg day), five days per week for five weeks
to chicks increased relative thyroid weight from day 10 onward.
Histopathology indicated hyperplasia and disappearance of the
colloid. The reversibility of the lesions was shown in birds treated
only for 17 days and allowed to recover for two weeks after the end
of treatment.
Inhalation: Exposure of rabbits, guinea pigs, rats or mice to
4 mg/L air, 2 hour/day for 10 weeks caused a reduction in body weight
in rabbits and guinea pigs, and a slight reduction in body weight in
rats and mice. Slight anaemia, lymphocytopenia and neutropenia were
observed in rabbits.
Rats were exposed to amitrole (0, 0.1, 0.32, 0.99 or 4.05 mg/L for
five hours/day, 5 times per week for 4 weeks). Blood levels of
thyroid hormones were found to be decreased and thyroid hyperplasia
was noted at all but the lowest dose level.
2.1.6 Dietary studies:
Short term: Numerous investigations have shown that amitrole
administered in drinking water or in the diet, may cause decreased
body weight gain, increased thyroid weight related with changes of
thyroid function in rats.
Amitrole was given to rats at a dose of 1000 mg/kg/diet for 83 days.
Thyroid weight and iodine content of thyroid were increased, starting
3 days after the beginning of treatment. Amitrole was given to rats
(0, 30, 100 or 300 mg/kg/diet) for 28 days followed by a recovery
period of 28 days. At dose levels of 100 mg/kg/diet or more,
amitrole rapidly suppressed T3 and T4 hormone levels and maintained
the depressed levels during treatment. Both T3 and T4 levels
returned to control values within three weeks following withdrawal of
amitrole from the diet. The NOEL was 30 mg/kg/diet.
Groups of rats were administered amitrole in the diet at dose levels
of 0, 2, 10 and 50 mg/kg/diet for 13 weeks. The only significant
findings were the histopathological changes found in the 10 and 50
mg/kg groups. The number of blood vessels per thyroid section was
found to be a good indication of histopathological changes in the
thyroid. The NOEL was 2 mg/kg/diet.
In a series of experiments in rats giving amitrole at various dose
levels (0 through 200 mg/kg/diet for 6 to 13 weeks) it was found that
measurement of iodine uptake is a sensitive method for assessing the
effects of amitrole on the thyroid. The NOEL was 2 mg/kg/diet.
Long term: Reversible thyroid hyperplasia has been reported
with long term feeding of mice with amitrole at levels of
1000 mg/kg/diet. In another study in mice (0, 1, 10, 100
mg/kg/diet), infective thyroid weights were elevated at the highest
dose level.
Amitrole was given to rats (0, 10, 50 or 100 mg/kg/diet for two
years) and found to cause thyroid hyperplasia after 68 weeks of
treatment. The NOEL was 10 mg/kg/diet. In another study in rats (0,
1, 10 and 100 mg/kg/diet) similar findings were reported including
dysplasia of the thyroid and reduced iodine uptake. The NOEL was 10
mg/kg/diet.
Authors who have detailed the time-course of the response of the
thyroid to amitrole treatment have shown that after a short lag phase
of a few days there is a rapid rise in TSH that is paralleled by
thyroid hypertrophy and hyperplasia. These effects peak and plateau
after 3-4 months and thereafter remain relatively stable despite
further exposure. A number of studies have shown that the
goitrogenic action of amitrole is reversible on withdrawal of the
herbicide exposure.
2.1.7 Supplementary studies of toxicity:
Carcinogenicity: In a mouse long-term study of over 100
chemicals, amitrole was used as a positive control compound at the
maximum tolerated dose level (1000 mg/kg b.w. by gavage from one to
four weeks of age, then 2192 mg/kg/diet for life). The majority of
male and female mice of two strains developed carcinoma of the
thyroid, and hepatomas. This dosage regimen reduced longevity.
Another study in mice confirmed a high incidence of hepatocellular
carcinomas and hepatomas following long term exposure to amitrole at
the highest dose.
In a study in rats (0, 10, 50 and 100 mg/kg/diet) showed an increased
incidence of thyroid tumours at the higher doses only.
In a study in rats amitrole was given in the drinking water (0.1%
corresponding to 1000 mg/kg/diet) for 18-20 months. All animals
developed follicular adenomas and some animals developed follicular
carcinomas as well. In another similar experiment (same dose level)
the latency for developing thyroid tumors was estimated to be one
year.
Teratogenicity: No malformations were observed in mice
foetuses removed on day 18. There was a marked decrease in body
weight gain in dams receiving over 1000 mg/L in drinking water from
days 6 to 18. Maternal body weight was reduced at and above 1000
mg/L and the foetuses of these mice were small and underdeveloped.
No teratogenic effects have been detected in rats given up to 1000
mg/kg b.w. day on days 6 to 15 gestation.
Reproduction: No effects on reproduction were observed in a
multi-genarian study where rats were fed amitrole at dietary levels
of 0, 25 or 100 mg/kg/diet for 61 and 173 days before mating to
produce the F1a and F1b generation respectively. Hyperplasia of the
thyroid was observed in all animals at the 100 mg dose but not at the
25 mg dose.
Mutagenicity: Amitrole was not mutagenic to the repair deficient
strains of Escherichia coli nor to several strains of Salmonella
typhimurium , with or without metabolic activation. Weak mutagenic
activity was observed with Streptomyces coelicolor . No evidence of
chromosomal damage was observed following in vitro incubation of
human leucocytes with 0.2 - 1% (w/v) amitrole. Concentrations over
0.2% were cytotoxic, inhibiting lymphoblast transformation.
Male and female Drosophila melanogaster reared on 10 mg amitrole/kg
media showed no evidence of amitrole induced sex-chromosome non-
disjunction or sex-linked dominant lethal mutations.
Other: The inhibition of many haem containing enzymes has been
demonstrated in vivo and in vitro . Amitrole inhibits thyroid,
liver, kidney, eye and blood catalases and the incorporation of both
59Fe and 14C-aminolevulinic acid into haem.
2.2 TOXICOLOGY - MAN
2.2.1 Absorption: Amitrole is absorbed from the
gastrointestinal tract. It may be absorbed by inhalation of spray
mists and minimally through intact skin.
2.2.2 Dangerous doses:
Single: The intentional ingestion of 20 mg/kg amitrole by a
female subject did not cause symptoms of poisoning.
Repeated: No published information available.
2.2.3 Observations in occupationally exposed workers:
A single case report describes the development of a chemical
pneumonitis after one exposure to an amitrole spray containing 19%
aminotriazole, 17% ammonium thiocyanate, less than 1% sodium
diethylsulfosuccinate and less than 1% ethylene oxide.
At an estimated dermal exposure of 340 mg/day/man over a 10 day
spraying operation no thyroid dysfunctions were detected.
Prolonged exposure for up to 16 years to unknown levels of amitrole
during its production and packaging did not cause thyroid
disfunction.
2.2.4 Observations on exposure of the general public:
No published information available.
2.2.5 Observations on volunteers: A single oral dose
of 100 mg of amitrole inhibited 131I intake of the thyroid for 24
hours in healthy and hyperthyrotid individuals. A dose of 10 mg
produced only slight effects.
Amitrole had no irritant effect in a 4 - 8 hour exposure dermal patch
test, and had only slight irritancy after 24 hours exposure.
2.2.6 Reported mishaps: In a suicide attempt, a
37-year old woman ingested a formulation of 30% amitrole and 56%
diuron. The amitrole dose was estimated to be 20 mg/kg b.w. and no
signs of intoxication were observed. Unchanged amitrole was excreted
in the urine within a few hours at a concentration of 1 g/L.
2.3 TOXICITY TO NON-MAMMALIAN SPECIES
2.3.1 Birds:
Oral LD50
Coturnix quail >316 mg/kg b.w.
Dietary LC50 (5 days)
Japanese quail >5000 mg/kg diet
Ring-necked pheasant >5000 mg/kg diet
Mallard duck >5000 mg/kg diet
2.3.2 Other species: Drosophila melanogaster
(larvae) LC5040 mg/kg diet. prolongation of development time
occurred in this species at doses above 10 mg/kg diet. No mutagenic
effect was seen.
3.0 FOR REGULATORY AUTHORITIES - RECOMMENDATIONS ON
REGULATION OF COMPOUND
3.1 RECOMMENDED RESTRICTIONS ON AVAILABILITY
Risks associated with dietary exposure led to the cancellation of all
food and feed uses of amitrole in 1971 in the United States of
America. For definition of categories see "Introduction to Data Sheets".
All liquid formulations over 25%, Category 4.
All other liquid formulations, all solid formulations, Category 5.
3.2 TRANSPORT AND STORAGE
Formulations in Category 4: Should be transported in clearly
labelled, rigid and leakproof containers, kept out of reach of
children, and away from food and drink. Storage should be under lock
and key and secure from access by children and other unauthorized
persons.
Formulations in Category 5: Should be transported and stored
in clearly labelled, leakproof containers, out of reach of children,
away from food and drink.
3.3 HANDLING
Formulations in Category 4: Protective clothing should be
used by all persons handling the compound. Adequate washing
facilities should be available at all times during the handling and
they should be close to the site of handling. Eating, drinking and
smoking should be prohibited during handling and before washing of
hands and face after handling.
Formulations in Category 5: No facilities other than those
needed for the handling of any chemical are required.
3.4 DISPOSAL AND/OR DECONTAMINATION OF CONTAINERS
All formulations: Containers may be decontaminated (for
method see Section 4.3). Decontamination procedures must be
especially thorough to avoid subsequent contamination of food and
feed crops and decontaminated containers should not be used for
transportation or storage of food or drink. Discarded containers
that are not decontaminated should be burned or crushed and buried
in a deep (more than 0.5 m) dry pit. Care must be taken to avoid
subsequent contamination of water sources.
3.5 SELECTION, TRAINING AND MEDICAL SUPERVISION OF WORKERS
Formulations in Categories 4 and 5: Special account should be
taken of the workers' ability to comprehend and follow instructions.
Training of workers in techniques to avoid contact is essential.
Pre-employment and periodic medical examinations are required,
including a check-up on thyroid function.
3.6 ADDITIONAL REGULATIONS RECOMMENDED IF DISTRIBUTED BY AIRCRAFT
Amitrole is not usually recommended for distribution by aircraft.
3.7 LABELLING
Formulations in Category 4 - Minimum cautionary statement:
Amitrole is a triazole herbicide. Avoid ingestion and inhalation of
amitrole. Avoid skin contact; wear protective clothing and
impermeable gloves when handling the material. Wash thoroughly with
soap and water after using the product. Keep the material out of
reach of children and well away from food stuffs, animal feed and
food containers. If poisoning occurs, call a physician. There are no
specific antidotes.
Formulations in Category 5 - Minimum cautionary statement:
This formulation contains amitrole, it may be poisonous if swallowed.
Keep the material out of reach of children and well away from food
stuffs, animal feed and food containers.
3.8 RESIDUES IN FOOD
As it is recommended only for non-edible crops, no MRLs are
recommended by FAO/WHO Joint FAO/WHO Meeting on Pesticide Residues
(JMPR). In 1993 the JMPR established a Temporary Acceptable Daily
Intake (TADI) of 0-0.0005 mg/kg b.w.
4.0 PREVENTION OF POISONING IN MAN AND EMERGENCY AID
4.1 PRECAUTIONS IN USE
4.1.1 General: Amitrole is a triazole herbicide of low
acute mammalian toxicity. It is absorbed from the
gastrointestinal tract and may also be absorbed through intact
skin or by inhalation of mist during spraying. Due to the
goitrogenic effect and carcinogenic action in laboratory tests,
use of amitrole in the United States of America has been
restricted to non-edible crops or non-crop land.
4.1.2 Manufacture and formulation - TLV: 0.2 mg/m3.
Closed systems and forced ventilation are required to reduce, as much
as possible, the exposure of workers to the chemical.
4.1.3 Mixers and applicators: When opening the
container and when mixing, protective impermeable boots, clean
overalls, gloves and respirator should be worn. Mixing, if not
mechanical, should always be carried out with a paddle of appropriate
length. When spraying tall crops a face mask should be worn, as well
as an impermeable hat, clothing, boots, and gloves. The applicator
should avoid working in spray mist and avoid contact with the mouth.
Particular care is needed when equipment is being washed after use.
All protective clothing should be washed immediately after use,
including the insides of gloves. Splashes must be washed immediately
from the skin, or eyes with large quantities of water. Before
eating, drinking, or smoking, hands and other exposed skin should be
washed.
4.1.4 Other associated workers: Persons exposed to
amitrole and associated with its application should wear protective
clothing and observe the precautions described above in 4.1.3. under
"Mixers and Applicators".
4.1.5 Other populations likely to be affected: With
correct use in agriculture, and in the home gardens, the general
population should not be exposed to hazardous amounts of amitrole.
4.2 ENTRY OF PERSONS INTO TREATED AREAS
Unprotected persons may enter treated area once application has
dried.
4.3 DECONTAMINATION OF SPILLAGE AND CONTAINERS
Residues in containers should be emptied in diluted form into a dry
deep pit (more than 0.5 m), taking care to avoid contamination of
groundwaters. Empty containers may be decontaminated by filling them
completely with water and by allowing them to stand for 24 hours
before emptying. The procedure should be repeated three times.
Impermeable gauntlets should be worn during the work and an adequate
soakage pit should be provided for the rinsings. Decontaminated
containers should not be used for transportation and storage of food
or drink. Spillage of amitrole and its formulations should be removed
by washing with a water and detergent solution and then rinsing with
large quantities of water.
4.4 EMERGENCY AID
4.4.1 Early symptoms of poisoning: Not known.
4.4.2 Treatment before person is seen by physician, if these
symptoms appear following exposure:
The person should stop work immediately, remove contaminated clothing
and wash contaminated skin with water, and soap if available, and
flush with large quantities of water. Vomiting may be induced if a
large dose has been ingested provided that the person is conscious.
5.0 FOR MEDICAL AND LABORATORY PERSONNEL
5.1 MEDICAL DIAGNOSIS AND TREATMENT IN CASES OF POISONING
5.1.1 General information: Amitrole is a triazole
herbicide of low acute mammalian toxicity which may be absorbed
from the gastrointestinal tract, through the intact skin, and by
inhalation of aerosols or mists during spray application.
Chronic high exposure may cause changes in the thyroid function.
5.1.2 Symptoms and signs: Unknown.
5.1.3 Laboratory: Urinary levels of amitrole could be
used as a measure of exposure.
5.1.4 Treatment: Symptomatic.
5.1.5 Prognosis: Unknown.
5.1.6 References to previously reported cases:
Geldmacher-V. Mallinckrodt M, Schmidt HP (1970), Arch Toxikol 27:
13-18.
PIMS (1978) Pesticide Incident Monitoring Service. Summary of
reported incidents involving Amitrole. No. 114. Office of Pesticide
Programs, USEPA.
5.2 SURVEILLANCE TESTS
Unknown.
5.3 LABORATORY METHODS
(References only are given.)
5.3.1 Detection and assay of compound:
Agrawal BBL, Margoliash E (1970), A spectrophotometric method for the
determination of aminotriazole and other aromatic amines. Anal
Biochem 34: 505-516.
Demint RJ, Frank PA, Comes RD (1970), Amitrole residues and rate of
dissipation in irrigation water. Weed Sci 18, 439-442.
Storherr RW, Burke J (1961), Determination of 3-amino-1,2,4-triazole
in crops. J Assoc Off Anal Chem 44: 196-199.
5.3.2 Other tests in case of poisoning: None.
REFERENCES
1. WHO (1994), Environmental Health Criteria 158; Amitrole; Geneva,
World Health Organization.
2. WHO (1994), Health and Safety Guide 85; Amitrole; Geneva, World
Health Organization.
3. FAO/WHO (1978), Pesticide Residues in Food: 1977 evaluations. FAO
Plant Production and Protection Paper 10 Sup, 1978.
4. The Pesticide Manual, A World Compendium (9th edition 1991),
Worthing, C.R. and Hance, eds., British Crop Protection Council, 20
Bridport Road, Thornton Heath, CR4 7QG, United Kingdom.
5. IARC (1986), IARC Monographs on the Evaluation of the Carcinogenic
Risk of Chemicals to Humans; Some Halogenated Hydrocarbons and
Pesticide Exposures, Volume 41, Lyon, IARC.
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