NON-TARGET ORGANISM & ECOLOGICAL EFFECTS DATA REQUIREMENTS FOR BIOCHEMICAL PESTICIDES

Chair, Biochemical Classification Committee Biopesticides & Pollution Prevention Division Office of Pesticide Programs U. S. Environmental Protection Agency

         Introduction: The passage of the Food Quality Protection Act (FQPA¹) of 1996 amended both the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA) to, among other mandates, consider the protection of wildlife and the environment from the adverse effects of any pesticide, to be equally important with the protection of human health. Therefore, prior to granting a registration, the potential for any pesticide to cause adverse effects to non-target organisms and the environment must be thoroughly investigated. When compared to conventional chemicals, however, the data requirements for biochemical pesticide active ingredients are much reduced due to their unique nature, which includes: a non-toxic mode of action, generally low use rates, and no to low persistence in the environment. Additionally, many naturally-occurring biochemical active ingredients are virtually indistinguishable from the same substances already present in the environment (e. g. naturally-occurring plant and insect hormones, secondary plant metabolites, etc.).

         A tiered approach to hazard identification and risk assessment is used for biochemical active ingredients wherein hazards identified in Tier I screening (if any) will trigger more rigorous Tier II and/or Tier III studies. On advantage to the tiered approach is that it minimizes the number of data requirements and is far less costly to the registrant than registration of conventional chemical pesticides². To date, no biochemical active ingredient or product has ever triggered a requirement for Tier II or Tier III non-target organism and ecological fate/effects studies.

         Prior to determining which basic data requirements need to be fulfilled for registration or for an Experimental-Use Permit (EUP), each candidate biochemical pesticide is subjected to a case-by-case characterization of its actual and potential risks to non-target organisms and the environment. A preliminary screen of the data usually occurs during the biochemical classification process (see The Biochemical Classification Committee & The Classification of Biochemical Pesticides in these Proceedings) and is more fully explored during pre-registration meetings with registrants. Following the pre-registration meeting and a formal submission of studies requested by BPB, risk assessors conduct an in-depth science review of all exposure and toxicity data. The following discussion will present the process whereby the Biochemical Pesticides Branch (BPB) of BPPD characterizes the risks and makes determinations regarding the types of studies and data that are needed to fully assess the risk associated with the use of a biochemical pesticide and how these risks are mitigated by risk management activities.

         Characterization of the Risk: Similar to human health risk characterization, risks to non-target organisms are characterized via a preliminary assessment of toxicity and of all conceivable exposure pathways to non-targets by application of the biochemical pesticide. The risk characterization is summarized in the following equation:

         Toxicity (or Lethality) x Exposure = Risk

         Although biochemical pesticides, by definition, act via a non-toxic mode of action, they can still be lethal to the target pest. Examples of lethal, but non-toxic modes of action are suffocation, dessication, and growth regulation of insects. Suffocating agents (typically oils) act by physically preventing respiration of the target pest, resulting in death by asphyxiation. Desiccating agents (some oils, certain organic acids, and some soaps) kill the target pest by solubilizing waxy cuticles and causing cell and subsequent organism death by rapid water loss. Insect growth regulators (IGRs) disrupt normal insect developmental processes which ultimately result in death, but not by any direct toxic action. Due to the broad-spectrum, non-species specific activity of many biochemical pesticides, all unintentional exposure pathways and potential lethality to non-targets must be assessed. The following discussion will focus on the detailed information that are required by reviewers to conduct an risk assessment.

         Components of the Risk Assessment: The preliminary assessment of toxicity is facilitated by a complete understanding of the product chemistry of the biochemical active ingredient. These data/information include (but are not limited to):

(i)	mode of action;
(ii)	potential for mutagenicity/carcinogenicity (or is it structurally related to known mutagens/carcinogens);
(iii)	persistence/degradation rate;
(iv)	environmental fate (what are the degradation products and where do they go); and
(v)	product formulation (is it a liquid, granular, or dust)

         The aforementioned factors highlight the importance of a good product chemistry submission (see Product Chemistry Data Requirements for Biochemical Pesticides in these Proceedings). A complete understanding of the chemistry of the biochemical active ingredient is essential to assessing the risks to non-targets and the environment. Other information needed for the risk assessor to identify exposure pathways includes (but is not limited to):

(i)	application method (foliar, soil, or fog applications; seed treatments);
(ii)	application rate and timing (amount per unit area; applications per growing season; early, mid-, and/or late season applications);
(iii)	use sites (terrestrial or aquatic; agricultural, natural area, or urban/homeowner); and
(iv)	target pest(s)

         Other data/information may be required on a case-by-case basis, depending on the nature of the active ingredient and the use sites proposed for the product. The risk assessor also must have an in-depth understanding of the chemistry and use patterns of the formulated product, particularly of the other (formerly known as "inert") ingredients (buffers, diluents, stabilizers, surfactants, etc.) that are applied with the end-use product. These intentionally added ingredients may have unanticipated adverse effects to non-targets and the environment; human health concerns may also arise if the product is intended for food use.

         The Risk Assessment: Once the components of the risk assessment have been assembled, the risk assessor uses this information to assess the full range of potential and actual exposure pathways of a biochemical pesticide to non-target organisms and the environment. Toxicity (or lethality) data for the toxicity component of the risk equation (see above) are typically obtained from the tiered guideline studies conducted and submitted by the registrant to support a registration. A list of non-target organism study requirements, arranged as Tiers I, II, and III, is presented in a table in 40 CFR §158.690 (d)³. It is extremely important to refer to the footnotes at the bottom of this table, for they will provide explicit information regarding the types of products and/or use sites for which specific tests will be required. Additionally, preferred test organisms will be listed. The tiered study guidelines are summarized below:

Tier I:	Tier II:	Tier III:
Avian Acute Oral Toxicity	Volatility	Terrestrial Wildlife Testing
Avian Dietary Toxicity	Leaching	Aquatic Animal Testing
Freshwater Fish LC50	Adsorption/Desorption	Non-Target Plant Studies
Freshwater Invertebrate LC50	Octanol/Water Part. Coeff.	Non-Target Insect Studies
Non-Target Plant Studies	UV Absorption
Non-Target Insect Studies	Aerobic Soil Metabolism
	Aerobic Aquatic Metabolism
	Soil Photolysis
	Aquatic Photolysis

         Tier I guideline studies are basically acute toxicity studies designed to determine acute, short-term effects of pesticide exposure to non-target organisms. The need for Tier II and Tier III studies are triggered only when one or more Tier I studies demonstrate significant adverse effects to non-targets. Tier II studies are environmental fate studies that provide additional information on the degradation and persistence of biochemical pesticides and the potential for subchronic/chronic exposure. Tier III studies are longer term and more rigorous non-target studies on terrestrial and aquatic organisms and will be needed especially if the active ingredient is shown to persist in the environment. As stated previously, no biochemical active ingredient or product has yet triggered a requirement for Tier II or Tier III non-target organism and ecological fate/effects studies.

         Once the exposure pathways to non-target organisms have been determined and the potential for toxicity (or lethality) to non-target organisms is understood, a risk assessment is conducted that incorporates all exposure, toxicity, target pest, and use pattern information. Upon completion of the risk assessment, the biochemical pesticide is subjected to a risk management analysis. This is generally conducted (in BPPD) by the Regulatory Action Leader (or RAL) for the product, in close consultation with the science reviewer(s). The RAL is the principal point of contact with the registrant of a particular product and is responsible for administratively guiding the product through the regulatory maze.

         Waiver Requests: Submission of guideline studies is the most unambiguous approach to satisfy the data requirements for registration. The guideline studies are designed to provide the BPB risk assessor with the necessary information to assess the risks posed by a biochemical pesticide when it is used according to its proposed label directions. However, there may be circumstances where the registrant believes that conducting a study to support a particular data requirement is unnecessary, or may be too costly to conduct. The registrant may then request a waiver from the requirement for conducting one or more guideline studies.

         Study waiver requests must be submitted individually for each guideline study for which the registrant desires a waiver (i.e. each waiver request must be addressed on a guideline-by-guideline basis). Each waiver request must be accompanied by a scientific rationale (including technical information/data) that credibly supports the waiver request and will assure the BPB risk assessor that a guideline study will not be needed to complete the risk assessment. Data from non-guideline studies are acceptable on a case-by-case basis only if they provide information/data that is equivalent to information/data that would have been generated by guideline studies and they are conducted according to generally accepted scientific principles. Non-guideline studies obtained from the open technical literature (e. g. scientific journal articles) must have a reasonably complete description of the materials and methods to assure the BPB risk assessor that the submitted data will be useful in completing the risk assessment. Journal abstracts and reports from technical meeting proceedings generally do not contain sufficient information and, therefore, are typically classified as unacceptable for use in risk assessments. Similarly, testimonials found in advertising literature and anecdotal information unsupported by credible data are also unacceptable.

         Another approach to supporting waiver requests is to demonstrate that there will be no exposure of non-target organisms (either directly or indirectly) to the biochemical pesticide following application to the proposed use site(s) and target pest(s) listed on the product label. For example, if the registrant request waivers from the study data requirements for fish toxicity and aquatic invertebrate toxicity, it must be demonstrated that the product is intended solely for terrestrial uses and that it is highly unlikely that fish or aquatic invertebrates would be exposed directly or indirectly (via runoff or spray drift) to the biochemical pesticide product. The product label would also be required to contain specific language warning the product user to avoid applying the product on or near aquatic sites and environmental hazards statements indicating that the product is toxic to fish and aquatic invertebrates. Should the registrant not want to place this environmental hazards statement on the label, they would be required to present data demonstrating that the product was not toxic to fish and aquatic invertebrates when applied at the maximum proposed rate. Alternatively, the registrant could present data demonstrating that the active ingredient rapidly degraded to non-toxic compounds following application, thereby minimizing exposure.

         As stated above, each waiver request must be accompanied by a scientific rationale that credibly supports the specific waiver request. It is highly unlikely, that the rationale developed for one waiver request will support a waiver from a different guideline (the example used above being a possible exception). For example, a rationale used to support a waiver from the fish toxicity study requirements cannot be used to support a waiver from avian toxicity studies. Each waiver must address the potential risk to non-targets based exposure (e.g. the application method/rate and site, and the likely non-target organisms that may be present) and the toxicity and/or lethality of the biochemical active ingredient. The other ("inert") ingredients must also be considered when developing a scientific rationale to support a waiver request.

         It is noted here that the cost of conducting a study is never considered as a justification for granting a waiver.

         Risk Management: After the risk assessment is completed, the biochemical pesticide is subjected to a risk management analysis by the RAL for the product, in close consultation with the science reviewer(s). If minor risks regarding toxicity/lethality of the biochemical pesticide are identified in the risk assessment, the risks may be mitigated by addition of precautionary statements and environmental hazards statements (see discussion above under Waiver Requests) on the product label. Conversely, if it is determined that risks cannot be mitigated with restrictive label language, and that severe adverse effects may result if the product is used as intended, BPPD may recommend that the product be transferred to the Registration Division where it would be treated as a conventional chemical pesticide and would receive a higher level of scrutiny and the reduced data requirements would not apply. Usually, if adverse non-target organism and environmental effects are indicated in the risk assessment it is also likely that there may be analogous adverse effects to human health.

         Guidance for Non-Target Organism, Fate, and Expression Data Requirements: Guidance for all non-target organism, fate, and expression data requirements may be found in Subpart D, Data Requirement Tables: 40 CFR §158.202⁴ and in the table under 40 CFR §158.690 (d)³. Specific information on individual non-target organism, fate, and expression testing guidelines is located in the OPPTS Harmonized Guidelines Series 850 and Series 835 and may be accessed in downloadable format at the U.S. EPA website

References

1.	The Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and Federal Food, Drug, and Cosmetic Act (FFDCA) As Amended by the Food Quality Protection Act (FQPA) of August 3, 1996. United States Environmental Protection Agency, Office of Pesticide Programs, 730L97001, March 1997.
2.	Rose, R. I. 1995. Ecological Effects. USDA IR-4/EPA Minor Use Biopesticide Workshop. Washington, DC, November 7-8, 1995. pp. 50-54.
3.	Subpart D - Purposes of the Registration Data Requirements. 40 CFR §158.202 (a, d, and h). Code of Federal Regulations, Title 40, Parts 150 to 189, revised as of July 1, 2001, Protection of the Environment.
4.	40 CFR §158.690 (d) Nontarget Organism, Fate, and Expression Data Requirements Table. Code of Federal Regulations, Title 40, Parts 150 to 189, revised as of July 1, 2001, Protection of the Environment.