Regulatory Status and Risk Assessment of Pheromones in the United States

         There are similarities between the regulatory oversight of pheromones in the United States and Canada. In the United States, arthropod (i.e., insect, arachnid, and crustacea) pheromones are exempt from regulation under the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) when used to attract pests for survey and detection purposes, provided these products are labeled accordingly. The rationale for this exemption is that these products are not pesticides, since there is no pesticidal effect. Arthropod pheromones also are exempt from FIFRA regulation when used in traps for attracting, trapping, or killing arthropods, where the pheromone is the sole active ingredient.

         Any pesticide (except for certain genetically modified microbial pesticides) can be tested on 10 acres of land or less, without a requirement for obtaining an Experimental Use Permit (EUP). Such small scale field trials cannot, however, be done on food crops or animal feed that are to be used in commerce. Further details on the conditions under which such small scale field trials can be conducted with pesticides can be found at 40 CFR 172.3.

         There was reasonable argument brought to the Agency that 10 acres of land was not sufficient for evaluating the efficacy and utility of arthropod pheromones. Testing on a larger acreage was needed to determine whether pheromones would likely achieve any kind of control over target pests. Therefore, in 1994, the EPA exempted arthropod pheromones from the requirement of an EUP when used in non-food or crop destruct applications on up to 250 acres of land and at a maximum rate of 150 grams of pheromone active ingredient per acre per year.

         Further regulatory relief was given to arthropod pheromones when the EPA allowed their use on food crops provided the pheromone product consisted of retrievably-sized polymeric dispensers. Again, an EUP would not be needed for use of these types of products on up to 250 acres of cropped land and at an application rate of no more than 150 grams active ingredient per acre per year. Pesticides cannot legally be used on food crops without establishment of a tolerance, which sets forth the maximum residues of active and inert ingredients allowable in, or on, food crops. Therefore, the EPA published an exemption from the requirement of a tolerance for arthropod pheromone active ingredient residues in food crops, and also for the most common dispenser polymeric ingredients, when the pheromone products are tested under the above field conditions.

         A subgroup of arthropod pheromones, namely lepidopteran pheromones, can be tested on food crops at up to 250 acres of land irrespective of the mode of application, provided the active ingredient is used at less than 150 grams per acre per year. This group of pheromones commonly used to control moths and butterflies, are defined chemically as unbranched aliphatic hydrocarbon chains of 9-18 carbons, containing up to 3 double bonds, and ending in an alcohol, acetate, or aldehyde functional group. This regulatory relief allows for the use of products which contain lepidopteran pheromone active ingredients encapsulated in microbeads. Tolerance exemptions also have been established for the active lepidopteran pheromone ingredients when used on food crops under the above conditions.

         Except for use in traps, or for survey and detection purposes, all pheromones either require an EUP or must be registered prior to testing on greater than 250 acres of land, or if more than 150 grams of active ingredient per acre is needed to be used each year. As mentioned earlier, employment of pheromones for arthropod survey and detection purposes does not constitute a pesticidal use. Use of pheromones in traps is presumed not to increase human and environmental exposure significantly above the natural background pheromone levels. Further, pheromones control the target pests by a non-toxic mode of action (e.g., repellency or via mating disruption), are invariably target species-specific, and achieve pest control at very low use rates. Thus far also, in laboratory animal testing, arthropod pheromones have been shown to be of no significant toxicity, and minimally, if at all, irritating.

         Lepidopteran pheromones are the most numerous of registered active pheromone ingredients. There have been no reported adverse effects during research and development, manufacture and synthesis, or from use of lepidopteran pheromones in trapping and monitoring programs. Likewise, there have been no reported adverse health or environmental effects from their use in registered products. There exists an extensive acute toxicity data base which shows no toxicity to laboratory animals after oral, dermal and pulmonary exposures. The lepidopteran pheromones are not mutagenic. On the other hand, only a limited number of studies have been done to assess toxicity from subchronic or longer exposures to lepidopteran pheromones. However, information on the lack of toxicity from longer term exposure to related fatty acids, aliphatic alcohols, and aldehydes would support a conclusion of no significant toxicity of lepidopteran pheromones, and certainly from exposure to the pheromones at concentrations used in pesticide products. Where determined with lepidopteran pheromones, dietary residues would be expected to be in the part per billion range to non-existent. The known oxidative metabolic pathways of naturally-occurring fatty acids and alcohols also can be used to predict the likelihood of digestion by humans, and biodegradation by microorganisms in the environment. Again, where determined, fate of lepidopteran pheromones in the environment is short-lived, i.e., from one to two days in soil and seven days in water.

         Studies thus far done show no toxicity of lepidopteran pheromones to birds. However, toxicity has been observed in studies done with daphnia and fish. These effects however, likely are caused by suffocation from exposure to high concentrations of the water-insoluble pheromones which creates a surface film under conduct of the studies.

         Sufficient information on the chemical identity and manufacturing process of a pheromone must be submitted to the U. S. EPA, for a determination of whether the active ingredient meets the definitional criteria of a typical lepidopteran pheromone as an unbranched aliphatic compound containing up to three double bonds, and ending in an alcohol, aldehyde, or acetate functional group. Examples of some "unusual" lepidopteran pheromones which would not meet the above definition include the processionary moth pheromone which contains a triple bond, and the Bucculatrix thurberiella pheromone which contains a terminal nitrate group. Some lepidopteran pheromones are ketones, or may contain up to four double bonds and 23 carbons, or contain propanoate or butyrate functional groups. A recent publication [W. Francke and S. Schulz "Pheromones", in Comprehensive Natural Products Chemistry (K. Mori, ed.) Volume 8; 1999, Elsevier] serves as an excellent reference for the appreciation of the chemical structural complexity of insect pheromones. In general, the mammalian toxicology and non-target organism studies typically required for registration of these "unusual" pheromones would be the same as those required for non-lepidopteran pheromones and biochemical pesticides in general [see articles below by Russell Jones and Roger Gardner for details of these requirements].

         A toxicology data base does not exist to support a general conclusion of human and non-target organism safety from exposure to "unusual" lepidopteran and non-lepidopteran pheromones. However, BPPD encourages registrants to provide data and information from publicly available sources to support waivers of any required toxicology studies. However, as a point of caution in waiving toxicology data requirements for pheromones based on structural similarity alone, a compound has been isolated from the water hemlock which has many properties similar to the lepidopteran pheromones. The compound (E,E,E)-(-)-8,10,12-heptadecatriene-4,6-diyne-1,14-diol is a seventeen carbon chain, ending in an alcohol, and has three double bonds. Unlike the lepidopteran pheromones, the water hemlock material contains two triple bonds. The common name of this compound is cicutoxin (CAS 505-75-9), which can cause nausea, vomiting, and abdominal pain after acute exposure, which is rapidly followed by seizures, central nervous system depression, and even death. Survivors may experience impaired intellectual function and acute anxiety reactions. This material is not to be confused with conine, the toxic alkaloid component of poison hemlock, and associated with the death of Socrates.