THE BIOCHEMICAL CLASSIFICATION COMMITTEE AND THE CLASSIFICATION OF BIOCHEMICAL ACTIVE INGREDIENTS
Chair, Biochemical Classification Committee
Biopesticides & Pollution Prevention Division - Office of Pesticide Programs, EPA
Introduction: The Biopesticides & and Pollution Prevention Division was created for the purpose of bringing safer pesticide products into the market place and to encourage the adoption of these safer, reduced risk products and related integrated pest management (IPM) practices. The BPPD was formed as a pilot project in 1994 and became a permanent Division of USEPA's Office of Pesticide Programs (OPP) in 1995. The safer, reduced risk products that are scientifically reviewed and registered in BPPD are known as biological pesticides, or biopesticides. Biopesticides are distinguished from conventional chemical pesticides by their unique modes of action, low use volumes, target species specificity, or natural occurrence. There are three categories of biopesticides: biochemicals, microbials, and plant-incorporated protectants (PIPs). This paper will focus on biochemical pesticides and will update information presented in the USDA IR-4 Minor Use Biopesticide Workshop in 19951. Microbial pesticides and PIPs will be addressed by other authors in these Proceedings.
With the creation of BPPD, it became necessary to develop a process that would distinguish the differences between biochemical pesticide active ingredients and conventional chemical pesticide active ingredients. This necessity was driven by a need to determine the appropriate Division within OPP that would conduct the science review and registration activities for a particular active ingredient or product. The Biochemical Classification Committee was formed shortly after the creation of BPPD to oversee this process. The regulatory authority to accomplish this goal is found in 40 CFR §158.65(a)2 where it states: "When necessary, the Agency will evaluate products on an individual basis to determine whether they are biochemical or conventional pesticides." The first step in the evaluation process was to establish criteria for classifying a pesticidal active ingredient as biochemical.
Biochemical Classification Criteria: The two most important criteria that must be met for a substance to be classified as a biochemical pesticide are:
| i. | it is a generally naturally-occurring substance; and |
| ii. | it has a non-toxic mode of action. |
In regard to the first criterion, it is important to note that not all biochemicals are naturally-occurring. A synthetic active ingredient can be classified as a biochemical if it is structurally similar, and functionally identical to a naturally-occurring substance. An example of a synthetic substance that meets the criteria for classification as a biochemical is indolebutyric acid (IBA), a structural and functional analog of the naturally occurring plant hormone, indoleacetic acid (IAA). In regard to the second criterion, the "natural occurrence" of a substance does not immediately lead to the presumption that it has a non-toxic mode of action. An example of a substance in this category would be pyrethrum, a natural insecticide obtained from certain chrysanthemum flowers that is known to be a very potent neurotoxin. This toxic mode of action would preclude pyrethrum from being classified as a biochemical. Another factor that is considered during the biochemical classification process is that a non-toxic mode of action against the target pest does not presume a lack of toxicity to humans and non-target organisms. All substances must be assessed for their potential to cause human dermal or eye irritation, sensitization, or the likelihood of toxicity via the inhalation route of exposure. The potential for subchronic effects must also be considered. If there is a potential for human toxicity, there may be analogous effects on non-target organisms.
Non-Toxic Modes of Action: There are several non-toxic modes of action whereby biochemicals accomplish their pesticidal activity. These are roughly grouped according to the following categories:
| i. | Plant and insect growth regulators (PGRs and IGRs); |
| ii. | Lures & attractants/repellents (including irritants); |
| iii. | Suffocating agents; |
| iv. | Dessicants; |
| v. | Coatings; |
| vi. | Pheromones; and |
| vii. | Systemic Acquired Response (SAR)-inducers |
Biochemical PGRs and IGRs may naturally-occurring growth regulating substances and their functionally-identical, synthetic, structural analogs, and will include those substances that mimic or block the activity of naturally-occurring growth substances. Lures, attractants, and repellents encompass all those substances generally considered to be non-pheromone semiochemicals. Dessicants accomplish their activity by solubilizing or physically perturbing waxy cuticles of plants or insects such that the organisms succumb to rapid evaporative water loss. Coatings are substances commonly found in the environment (e.g. clay particles), and have a passive mode of action (i.e. there is no biochemical interaction against the target pest). When applied to plant foliage, coatings function as physical barriers to infections by plant pathogens, cause unpalatable abrasiveness to phytophagous insects, or act as physical irritants. Pheromones, like PGRs and IGRs, can be naturally-occurring or functionally-identical, synthetic, structural analogs, and can be used as either mating disruptants or as attractants to lure target pests (usually insects) into traps. Another interesting mode of action is that of the systemic acquired response (SAR) in plants. Substances that induce the SAR response have no direct activity against the target pest, but function to enhance the inherent capacity of plants to resist infection by plant pathogens, or produce secondary plant metabolites that cause the plant to be unpalatable, or possibly toxic to a pest.
Other Criteria: There are other criteria the Committee may consider when making a classification decision, but these criteria may not necessarily be used to determine whether a candidate substance will be classified as a biochemical or conventional chemical. These criteria are used by the Committee as a preliminary risk assessment to determine the data requirements that need to be fulfilled to support a full registration of the new active ingredient. These other criteria are listed below:
| i. | Potential effects on non-target organisms; |
| ii. | Persistence in the environment; |
| iii. | Application rates and timing; and |
| iv. | Product performance (efficacy); |
Ideally, biochemical pesticides will have little or no effects on non-target organisms, degrade rapidly in the environment, have low application rates and are applied when non-targets are least likely to be present, and have a reasonable degree of efficacy against target pests. Exceeding the limits of the first three criteria will not necessarily be a barrier to a successful biochemical classification. The BPPD has registered many products that have broad spectrum effects on targets and non-targets, that persist in the environment, and/or are applied at relatively high rates. These issues are typically managed by the use of restrictive language (i.e. explicit use directions and precautionary statements) on the product label. For example, if a product has been determined to be a hazard to honey bees or other pollinators, the registrant will be instructed to have a label statement that restricts application of the biochemical pesticide at times when these beneficial non-target insects are present at the use site.
Product performance, more commonly known as efficacy, can be a considerable barrier to a successful biochemical determination. According to the Code of Federal Regulations [40 CFR158.202(i)3], efficacy studies must be performed on all products prior to registration. However, efficacy studies are only required to be submitted for Agency review when the product is intended for use against public health pests (e.g. cockroaches, mosquitoes, fire ants, rodents, etc.). Efficacy studies for other products are required on a case-by-case basis. For biochemical classification purposes, the Committee usually requires the submission of efficacy data in situations where the substance is new or unique, and for which there is little information available regarding its use and/or mode of activity as a pesticide. Efficacy data may also be required for common, well characterized substances that have never before been used for pesticidal purposes. It is extremely important that efficacy data are included in any application for a biochemical classification. The Committee must have confidence that a proposed product will perform in a manner that supports its label claims. Any efficacy data submitted to the Committee for review need not be generated using a USEPA guideline study (although guideline studies may be required for registration). The Committee will accept any scientifically-credible study conducted according to generally accepted procedures that provides sufficient information to assess the performance of a product against the intended target pest.
Biochemical-like Substances: There are a limited number of active ingredients classified as biochemical active ingredients that have a toxic mode of action. These substances are not easily categorized and the Committee has had some difficulty is classifying them. For lack of better definitions, they have been termed "biochemical-like" substances or "gray-area" chemicals. Although they have a toxic mode of action, their toxicity is extremely low. As a group, they are typically simple molecules, ubiquitous in the environment, and for which there is a large publically-available data base regarding their chemistry, environmental fate and effects, and toxicity to humans and non-target organisms. When accepted for review and registration within BPPD, a "biochemical-like" compound is not classified as a biochemical, but as "not a biochemical, but eligible for a reduced data set." We can arrive at this determination because we will have much confidence in the available data/information that there will be no likelihood of adverse effects to humans or the environment when the compound is used for the proposed pesticidal purposes.
The Classification Process: The classification process usually begins with a receipt of information and data from a potential new registrant. A preliminary review of the submitted information is generally conducted by the Committee Chair and this information is summarized prior to review by the full Biochemical Classification Committee. Upon completion of Committee review a determination is made and forwarded to the BPPD managers for concurrence. Once concurrence has been obtained Division management, a letter is sent to the applicant containing an explanation of the Committee determination. If the Committee determines that the candidate substance meets the criteria for classification as a biochemical, the applicant will be notified by letter with a recommendation that they schedule a pre-registration meeting with the scientists and risk managers in the Biochemical Pesticides Branch of BPPD. It is at the pre-registration meeting, that the registrant will meet with BPPD staff to more fully discuss the data requirements necessary to support a registration of the product. Pre-registration meetings are not required, but it is strongly suggested that all registrants schedule at least one meeting prior to initiating any registration activities.
Unsuccessful applications for biochemical classification usually fall into one of three categories:
| i. | there was insufficient information to render a decision; |
| ii. | the candidate substance is a pesticidal active ingredient, but does not meet the minimum criteria for classification as a biochemical; or |
| iii. | the candidate substance is not a pesticide. |
Applicants who have submitted insufficient information for biochemical classification will be notified that additional information is needed before a determination can be made. If a candidate substance is determined to be conventional chemical pesticide, the applicant will be notified to contact the appropriate USEPA staff in either the Registration Division (RD) or the Antimicrobials Division (AD). Finally, if the Committee determines that the candidate substance is not a pesticide, the applicant will be informed that no registration activities will be required, but that the product may not be marketed using any implicit or explicit pesticidal claims on the product label nor any advertising information. Unregistered products that are sold for use as pesticides will be subject to enforcement actions. Applicants may always appeal an unsuccessful biochemical classification determination and there is no deadline for the resubmission of information or data to support the appeal.
Information Needed for a Successful Classification: It is extremely important that the active ingredient or ingredients present in any biochemical pesticide be clearly defined. Extracts obtained from plant homogenates, microbial cultures, and other mixed biological matrices (e.g. composts, crop residues such as straw, grass clippings, etc.) may have demonstrated biological activity against pests, but the chemistry of such extracts is to ill-defined to permit an adequate risk assessment. The chemistry of any new biochemical active ingredient must be completely understood in order to facilitate hazard identification and identify any potential risks to human health, non-target organisms, and the environment. Applicants for biochemical classifications, at the minimum, must provide the following product chemistry information for a new candidate active ingredient:
| i. | chemical identity of the active ingredient [Chemical Abstract Service (CAS) name and synonyms and/or International Union of Physical and Applied Chemists (IUPAC) name]; |
| ii. | CAS Number (if available); |
| iii. | a structure; and |
| iv. | Any other available physical/chemical information/data |
Additionally, the applicant must submit explicit information demonstrating that the substance is naturally-occurring or (if not naturally-occurring) that it is structurally-similar and functionally identical to a naturally-occurring substance. Detailed information regarding the active ingredient's mode of action is required. A classification application that states only that the active ingredient is, for example, a fungicide or an insecticide, are inadequate and generally unacceptable for biochemical classification determinations. The applicant must explicitly detail how the active ingredient accomplishes its fungicidal or insecticidal activity (e.g. it prevents fungal spore adhesion, or it solublizes insect cuticles, etc.). This type of information permits the Committee to independently assess whether the candidate active ingredient actually has a non-toxic mode of action. Other required information includes the species of target pest(s) and product application data (method, rate, timing). These items were discussed above in the Other Criteria section.
Human Health Data/Information: Any human health data that is available regarding the candidate active ingredient should be submitted with an application for biochemical classification. USEPA guideline studies need not be submitted. These data/information can be obtained from the open technical literature (e.g. scientific journal articles), on-line data bases (e.g. TOXLINE), material safety data sheets (MSDS), or from publically-available information in data bases maintained by other Federal agencies. It is important to note that approval of a substance for non-pesticidal use by another Federal agency does not constitute automatic approval of this substance for use as a pesticide by USEPA. A good example of the aforementioned situation is an applicant's use of the FDA GRAS4 (Generally Recognized As Safe) status of a substance to support human health and safety claims. The GRAS designation is used by FDA to support uses of substances as food additives, but does not address the use of these substances as pesticides. The routes of exposure to humans and non-target organisms can be quite different when a substance is used as a pesticide. Therefore, FDA GRAS status alone will not adequately support a successful biochemical classification determination, although it is good supplementary information. It is incumbent upon the applicant to summarize any data/information sent to the Committee for review.
Biochemical Classification Committee Membership: The Biochemical Classification Committee is made up primarily of USEPA staff in the Biochemical Pesticides Branch (BPB) of BPPD and is comprised of a biologist, a chemist, a toxicologist, an environmental scientist, a microbiologist, and a toxicologist. The Committee also has a representative from the Registration Division (RD) to provide concurrence when a conventional chemical determination is made and to approve transfer of that active ingredient to RD for science review and registration. On an ad hoc basis, we also include a member from the Antimicrobials Division (AD) if we have reason to believe that a candidate active ingredient is an antimicrobial pesticide. Current members of the Committee from BPB are: Russell S. Jones, Ph.D. (Chair, biologist); Freshteh Toghrol, Ph.D. (senior scientist, chemist); Roy Sjoblad, Ph.D. (microbiologist); Andrew Bryceland (environmental scientist); and Roger Gardner (toxicologist); and from RD, Carl Grable. The AD member of the Committee is as assigned by that Division.
Final Notes: Information sent to the Committee to support an application for biochemical classification does not substitute for a registration application. The Committee data review is a process internal to BPPD that is conducted solely for the purpose of determining whether the candidate substance is to be registered in BPPD (as a biochemical), in RD (as a conventional chemical), or in AD (as an antimicrobial). The intended use of the product must be clearly delineated, as the intended use may determine which OPP Division may ultimately register the product. For example, a substance that meets the minimum criteria for classification as a biochemical may still be registered in AD if it is intended for use in an antimicrobial product (e.g. sanitizers, disinfectants, etc.). While there is no requirement for the submitted information to pass a PR86-5 screen, it is important that all information sent for review is briefly summarized and is pertinent to a biochemical classification. Applicants are cautioned not to send to much information. Submission of voluminous and redundant data/information will tend to slow the review process. Items such as marketing/advertising literature, anecdotal information, and user testimonials are not useful in rendering a biochemical classification determination. When the applicant is confident that there is sufficient data/information available to support a biochemical classification determination, the data package may be sent directly to the Committee Chair at the following address:
| Biochemical Classification Committee Biopesticides & Pollution Prevention Committee U. S. Environmental Protection Agency Office of Pesticide Programs Ariel Rios Bldg. (7511C) 1200 Pennsylvania Avenue, NW Washington, DC 20460 |
Preliminary inquiries as well as complete applications may be submitted by email (jones.russell@epa.gov ), but applicants are cautioned not to send any information considered by them to be confidential business information (CBI) by electronic media. Overall data requirements for Biochemical Pesticides are listed in Tables in 40 CFR §158.690 (a) through (d). Additional information regarding Biopesticides (biochemicals, microbials, and plant-incorporated protectants, or PIPs) as well as a list of biopesticde active ingredients contained in EPA- registered products can be obtained at the following website: www.epa.gov/oppbppd1/biopesticides.