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4-Aminopyridine

Publication Date: 9/93

TRADE OR OTHER NAMES

Avitrol, Amino-4-Pyridine.

REGULATORY STATUS

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, 12).

INTRODUCTION

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).

TOXICOLOGICAL EFFECTS

ACUTE TOXICITY

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).

CHRONIC TOXICITY

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 (12).

Reproductive Effects

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).

Teratogenic Effects

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).

Mutagenic Effects

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).

Carcinogenic Effects

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).

Organ Toxicity

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).

ECOLOGICAL EFFECTS

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 hard water)

LC50 of bluegill = 3.40 ppm (very soft water) to 3.20 ppm (very hard water)

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 (12).

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).

ENVIRONMENTAL FATE

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 (12).

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).

Exposure Guidelines:

NOEL: 200 ppm (dogs); 3 ppm (rats) (12)
ADI: 0.0015 mg/kg/day (12)

Physical Properties:

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)

BASIC MANUFACTURER

Avitrol Corporation
7644 East 46th St.
Tulsa, Oklahoma 74145

Review by Basic Manufacturer

Comments solicited: October, 1991
Comments received:

REFERENCES

  1. Avitrol Corporation. 1977. Literature on Avitrol. Tulsa, OK.
  2. Berg, G. L., ed. 1987. Farm chemicals handbook. Willoughby, OH: Meister Publishing Company.
  3. Clayton, G. D. and F. E. Clayton, eds. 1981. Patty's industrial hygiene and toxicology. Third edition. Vol. 2: Toxicology. NY: John Wiley and Sons.
  4. Gosselin, R. E., et al. 1984. Clinical toxicology of commercial products. Fifth edition. Baltimore, MD: Williams and Wilkins.
  5. McEwen, F. L. and G. R. Stephenson. 1979. The use and significance of pesticides in the environment. NY: John Wiley and Sons, Inc.
  6. Morgan, D. P. 1982 (Jan.). Recognition and management of pesticide poisonings. Third edition. U. S. Environmental Protection Agency Washington, DC: U.S. Government Printing Office.
  7. National Pest Control Association. 1972 (Mar.). Technical release: Avitrol. Number 5-72. Elizabeth, NJ.
  8. Occupational Health Services, Inc. 1986. Material safety data sheets. Secaucus, NJ: OHS, Inc.
  9. Thomson, W. T. 1980. Fumigants, growth regulators, repellents, and rodenticides. Agricultural Chemicals, Book III. Fresno, CA: Thomson Publications.
  10. TOXNET. 1975-1986. National library of medicine's toxicology data network. Hazardous Substances Databank. Public Health Service. National Institute of Health. U. S. Department of Health and Human Services. Bethesda, MD: NLM.
  11. U. S. Environmental Protection Agency. 1987 (Oct. 23). Subject: Active ingredients subject to restricted use classification. Office of Pesticide Programs, Registration Division. Washington, DC.
  12. _____. 1980 (Sept.). Pesticide registration standard: 4- Aminopyridine: Avitrol. Office of Pesticides and Toxic Substances. Washington, DC.
  13. Ware, G. W. 1978. Theory and application. San Francisco, CA: W.H. Freeman and Company.
  14. Meister, R.T. (ed.). 1992. Farm Chemicals Handbook '92. Meister Publishing Company, Willoughby, Ohio.