E X T O X N E T
Extension Toxicology Network
A Pesticide Information Project of Cooperative Extension Offices of
Cornell University, Michigan State University, Oregon State University, and
University of California at Davis. Major support and funding was provided
by the USDA/Extension Service/National Agricultural Pesticide Impact
Publication Date: 9/93
TRADE OR OTHER NAMES
Based on its potential hazard to fish and nontarget birds, some or
all uses of 4-Aminopyridine formulations are classified by the U.S.
Environmental Protection Agency (EPA) as Restricted Use Pesticides
(RUP). Restricted use pesticides may be purchased and used only by
certified applicators. 4-Aminopyridine is classified as a hazardous
waste when it is discarded. It is on the EPA's list of "Acutely
Hazardous" commercial pesticides. Grain bait formulations of 4-
Aminopyridine must bear the signal word "Caution" and powder concentrate
formulations must bear the signal word "Danger" (14). A registration
standard was issued for this material in September, 1980. Check with
specific state regulations for local restrictions which may apply (11,
4-aminopyridine is better known by the trade name "Avitrol." A
commonly used abbreviation is "4-AP." 4-AP is an extremely poisonous
bird poison, or avicide. It is probably the most prominent of the
avicides. It is registered as Avitrol by the EPA for use against red-
winged blackbirds, grackles, and blackbirds in agricultural fields,
pigeons and sparrows in public buildings, and various birds around
livestock feeding pens (2). Avitrol repels birds by poisoning a few
individual members of a flock of birds, causing them to become
hyperactive and to utter distress calls which signal other birds to
leave the site. Only a small number of birds need to be affected to
cause alarm in the rest of the flock. After one alarming exposure,
birds will usually not return to treated areas (5, 13). Avitrol is
available as grain baits or as a powder concentrate (14).
4-Aminopyridine is highly poisonous to mammals. While intended
strictly for use as a bird repellent, Avitrol has been known to cause
severe poisoning, and in some cases, death, in adult humans, because of
accidental ingestion of small amounts (6). It is rapidly absorbed from
the gastrointestinal tract (10). The seriousness and extent of
poisoning is dependent upon the concentration of active ingredient (4-
AP) in the formulation ingested. Poisonings have been characterized by
thirst, nausea, dizziness, weakness, and intense sweating, followed by
impairment of normal mental functioning (toxic psychosis), lack of
muscular coordination (ataxia), tremors, labored breathing, and
generalized seizures (12). Symptoms of intoxication from Avitrol in
rats, dogs, and horses include over-production of saliva, tendency to
become over-stimulated, trembling which can progress to convulsions.
Death can result from discontinued breathing (respiratory arrest) or
heart failure (cardiac arrest) (4, 2, 3).
Application of Avitrol to the skin, also referred to as
percutaneous exposure, may lead to systemic intoxication, or general
overall poisoning (4). A chemical worker who continued working for 1.5
hours in clothing contaminated with 2-Aminopyridine, a closely related
substance and convulsant, developed dizziness, headache, respiratory
failure and died two hours later. It is assumed that skin absorption
was a major contributing factor in this incident (8). The EPA assumes
that significant dermal exposure to 4-AP will not occur if label
guidelines are followed (12).
Avitrol may contribute to the excessive formation of a substance
called methemoglobin in human blood. This substance is similar to
hemoglobin, the oxygen-carrying part of the blood, except that it cannot
carry oxygen. The normal red blood cell has only 1% methemoglobin.
When there is excess methemoglobin in the blood, oxygen cannot be
transported and blood eventually becomes oxygen depleted, resulting in a
condition referred to as methemoglobinemia. Methemoglobinemia is also
called 'blue baby syndrome' because it is most problematic in infants,
and because its primary symptom is a purplish blue color of the skin,
technically referred to as 'cyanosis' (3, 8).
The amount of a chemical that is lethal to one-half (50%) of
experimental animals fed the material is referred to as its acute oral
lethal dose fifty, or LD50. The LD50 for 4-AP in rats is 20-29
milligrams per kilogram (mg/kg), and in dogs is 3.7 mg/kg (2, 12).
While LD50s for 4-Aminopyridine vary widely among different species, of
animals, it was highly toxic in all 41 animal species tested. The
toxicity of a particular formulation depends directly on the
concentration of the active ingredient (4-AP) in the formulation, as
well as the route of administration or exposure (12). For example, all
rabbits died after an injection of 5.5 mg/kg of 4-AP into their veins
(10). It is readily absorbed through the skin (8). When injected in
rats through the skin, its LD50 is 19 mg/kg. Its dermal LD50 in rabbits
is 326 mg/kg (4, 2, 3).
4-Aminopyridine is considered an eye irritant. In one study,
'iritis,' or inflammation of the iris, and 'conjunctivitis,'
inflammation of the conjunctiva were noted in the eyes of albino
rabbits, one hour after 10 mg of 4-Aminopyridine hydrochloride were
applied. These symptoms disappeared after seven days (12).
Breakdown of components essential to proper liver and brain
functioning was observed in a chronic toxicity experiment with this
avicide (10). However, since dietary intake of this avicide is assumed
to be negligible, and because significant repeated exposure to 4-AP is
not expected to occur, EPA did not require long-term toxicity studies
The EPA does not require long-term reproduction studies because
dietary intake of 4-Aminopyridine is expected to be negligible and since
prolonged human exposure is unlikely (12).
There is a lack of information, or 'data gap,' on the
teratogenicity of 4-Aminopyridine dusts to two types of test animals.
The EPA did not require the determination of the teratogenic potential
of technical 4-AP based on the assumption that inhalation and dermal
exposure will not occur if applicators are warned by the label to wear
protective clothing (12).
A data gap also exists for the mutagenicity, or mutagen-causing
potential, of 4-Aminopyridine dusts. Mutagenicity testing is required
by EPA for 4-AP unless applicators of dust formulations are required by
the label to wear protective clothing, including respirators (12).
Since dietary intake of 4-Aminopyridine is expected to be
negligible and prolonged human exposure is unlikely, the EPA does not
require long-term studies on the potential of 4-AP to cause tumors (12).
Therefore, Avitrol has no carcinogenicity status (8).
Laboratory research did not find any significant compound-related
diseased (pathologic) changes in any organ or tissue. No effects were
found in the blood and urine of rats and dogs. While the brains of
these animals appeared normal after high 4-AP dietary administration of
2.0-3.25 mg/kg/day, the weight of the brains was affected (12).
Fate in Humans and Animals
4-Aminopyridine is rapidly absorbed into the bloodstream from the
gastrointestinal tract (10). It is readily broken down, or metabolized,
in the liver into removable compounds which are passed from the body
(excreted) in urine (4). After intravenous and oral doses were given to
humans, 90.6% and 88.5% of 4-AP was excreted in the urine (10). It does
not appear to concentrate or build up in the skin (4, 10).
The central nervous system is strongly excited by 4-Aminopyridine.
Based on observations with 2-Aminopyridine, it is suggested that
individuals with a history of convulsive disorders may be at an
increased risk from exposure (8). The principal drug, or
pharmacological, action of 4-AP in the body is to encourage message-
carrying (transmitter) substances to be released throughout the nervous
system at various points referred to as neuroeffecter junctions and
synapses. These transmitter substances signal nerves, muscles, organs,
and other body components to function properly (6).
The EPA did not require data on the metabolism of 4-AP in animals
because residues of this material are not expected in animal food and
feed items (12).
Effects on Birds
An overdose of Avitrol can unnecessarily kill excessive numbers of
birds and/or protected bird species. A 50-foot protective area should
be left around the outer boundaries of the affected field to minimize
hazards to game birds (9).
The lethal concentration fifty, or LC50, is that concentration of a
chemical in air or water that kills half of the experimental subjects
exposed to it for a set time period. The following list gives the LC50s
for a few bird species:
Coturnix quail: 447 parts per million (ppm)
Mourning Dove: 316 ppm
Mallard Duck: 722 ppm
The results of an avian reproduction study suggest that it is
unlikely that ingestion of sublethal amounts of 4-AP will cause negative
effects on the reproductive systems of birds (12).
The potential for exposure of nontarget wildlife to 4-AP
formulations is great, particularly for grain-feeding birds. The fall
migration period is the most dangerous time for migratory birds, for
this is when finches and other small seed-feeding birds may ingest
lethal doses of pretreated baits that are applied to corn and sunflower
fields. It is important that Avitrol not be applied where nontarget
birds feed, as it is extremely poisonous to them. Precautions that are
given on product labels are intended to protect nontarget birds from
unintentional exposure to 4-Aminopyridine caused by inappropriate use of
the avicide (12).
Effects on Aquatic Organisms
Fish are adversely affected by 4-AP, and become increasingly
sensitive with increased exposure (3). It is characterized as
moderately toxic to warm water fish:
LC50 of channel catfish = 4 ppm (very soft water) to 2.43 ppm (very
LC50 of bluegill = 3.40 ppm (very soft water) to 3.20 ppm (very
No data are required by the EPA on the toxicity of 4-Aminopyridine
formulated products to cold water fish, because of the assumption that
4-AP residues should not occur in water as a result of application. The
EPA does not require data on the acute toxicity of this chemical to
aquatic invertebrates, based on its status as a minor use pesticide
Effects on Other Animals (Nontarget Species)
Endangered species may be adversely affected by 4-AP. Before
applying any product, it is recommended that U.S. Fish and Wildlife
Service personnel be consulted to ensure that no harm is done (12).
Reportedly, there is low or nonexistent potential for secondary
poisoning in animals such as cats, dogs or birds of prey that may feed
upon birds killed by Avitrol (7).
Breakdown of Chemical in Soil and Groundwater
4-Aminopyridine is readily held, or adsorbed, to soil particles and
is fairly persistent in soil (12, 3). It is then reportedly broken down
slowly by soil microorganisms. Since it strongly adsorbs to the soil,
it is more likely to remain near the soil surface where most microbial
degradation tends to occur (12).
Two studies on the tendency of 4-AP to move or leach with soil
water indicate that the avicide is relatively immobile in soils. This
is due to the fact that it adsorbs tightly to soil under most
conditions. 4-AP is not expected to be present in groundwater as a
result of its use on land. The EPA has not required studies on the fate
of 4-AP in soil because, based on use patterns of the avicide, soil
residues are expected to be low (12).
Under aerobic soil conditions, or those in which oxygen is present,
the time that it took for half of the applied 4-Aminopyridine to be
removed from the soil, ranged from three months in clay soil, to 32
months in sandy-loam soils. This time period is referred to as the
half-life of the material. The rate at which 4-AP is metabolized in
aerobic soil increases with greater amounts of organic matter (12).
Breakdown of Chemical in Water
4-AP is not expected to be present in surface water as a result of
land application of formulated products. All formulations of 4-AP are
required to display labels that indicate that water can be contaminated
by cleaning of equipment or disposal of waste associated with 4-AP (12).
Breakdown of Chemical in Vegetation
There is a limited amount of information available on the breakdown
and use (metabolism) of 4-Aminopyridine by plants. Available plant
metabolism data on sorghum indicate that some breakdown does occur, with
three breakdown products (metabolites). No metabolites were found in
corn. The avicide is translocated, or absorbed and moved, from one part
of a plant to another to varying degrees, depending on the manner in
which it is applied. Plant uptake of 4-AP is not expected to be
significant in corn and sunflowers. Residues of 4-AP do not appear to
occur in raw agricultural commodities such as corn, corn fodder or
forage, and sunflower seeds. (12).
PHYSICAL PROPERTIES AND GUIDELINES
Technical 4-Aminopyridine is a white crystalline solid that
contains about 98% active ingredient. It is included in a group of
pesticides that are not similar in chemical structure or toxicological
action to the other major chemical classes of pesticides (6). No
workplace standards have been established for 4-Aminopyridine, but
technical or concentrated forms of this compound should be handled with
great care, given its highly toxic nature (3). When using this product,
it is recommended that applicators wear protective clothing, including
long sleeves, gloves, and respirators. A thorough washing with soap
should be done after handling all concentrates (2).
This avicide should not be used where food, such as grain or meat,
might become contaminated through exposure. Pretreated baits and dust
products should be kept away from livestock, poultry, and pets when used
in feedlots, baits should be kept off the ground, out of reach of cattle
In its pure form, 4-AP has no odor and is stable under normal
temperatures and pressures, as well as in light. It is water-soluble,
meaning that it can dissolve fairly readily in water. Thermal
decomposition may release toxic oxides of carbon and nitrogen (8). As
long as it is kept dry, Avitrol has an indefinite shelf life (12, 2).
|NOEL: ||200 ppm (dogs); 3 ppm (rats) (12)
|ADI: ||0.0015 mg/kg/day (12)
|CAS #: ||504-24-5
|H2O solubility: ||moderately soluble; 8%, 12% (free base); 50% (HCl salt) (12)
|Solubility in other solvents: ||soluble in acids as salts; acetone; methanol; ether; benzene (12)
|Melting point: ||158 degrees C (2)
|Chemical Class/Use: ||Bird repellent (avicide)
7644 East 46th St.
Tulsa, Oklahoma 74145
Review by Basic Manufacturer
Comments solicited: October, 1991
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