The global market for biopesticides has been projected at over $3.7 billion by the year 2017. A significant proportion of the global growth of the biopesticides market continues to occur in the United States. As of 2014, EPA had registered over 430 biopesticide active ingredients, and 1320 biopesticide products. In the United States, all pesticide products, including biopesticides, must be registered by the U.S. Environmental Protection Agency (EPA) before they can be sold or distributed in commerce. The EPA administers a comprehensive and complex regulatory scheme that requires the proponent of registration of a biopesticide to demonstrate that the biopesticide product, when used as intended, does not present “unreasonable adverse effects to the environment” and that there is a “reasonable certainty of no harm” resulting from dietary exposure to residues of the pesticide that occur on foods. Experience teaches us that the U.S. regulatory system has unique requirements from other regulatory systems.
The EPA regulates the sale and distribution of pesticides in the United States under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). The definition of “pesticide” in FIFRA
1. Koivunen, M., O. Duke, S., Coats, J., and Beck, J., Chapter 1, Pest Management with Natural Products, ACS Symposium Series, 2013 American Chemical Society.
3. 7 U.S.C. §§ 136 – 136y.
includes “(1) any substance or mixture of substances intended for preventing, destroying, repelling, or mitigating any pest, (2) any substance or mixture of substances intended for use as a plant regulator, defoliant, or desiccant, and (3) any nitrogen stabilizer”. It is important to note the definition of “plant regulator” in FIFRA: “any substance or mixture of substances intended, through physiological action, for accelerating or retarding the rate of growth or rate of maturation, or for otherwise altering the behavior of plants or the produce thereof”. This very broad statutory language includes substances not otherwise considered to be pesticides -- biostimulants, for example -- and significantly expands the universe of substances that require EPA registration.
EPA classifies “biopesticides” as a specific category of pesticides. This category includes biochemical pesticides, microbial pesticides, and plant-incorporated-protectants (which are often referred to as “PIPs”). EPA defines a “biochemical” pesticide as a substance that: (1) is naturally occurring or is structurally similar and functionally identical to a naturally occurring substance (for example, a synthetic analogue of a naturally occurring substance); (2) has a history of exposure to humans and the environment with minimal toxicity; and (3) provides its pesticidal function by a non-toxic mode of action to the intended target. Examples of biochemical pesticides include attractants, anti-feedants, dessicants, pheromones, plant regulators, and other biologically based substances that operate based on a non-toxic mode of action.
“Microbial” pesticides are defined as (1) eukaryotic microorganisms, including, but not limited to, protozoa, algae, and fungi; (2) prokaryotic microorganisms, including, but not limited to, Eubacteria and Archaebacteria; or (3) parasitically replicating microscopic elements, including,
4. 7 U.S.C. § 136(u). The statute excludes from the definition of pesticide new animal drugs regulated by the FDA and certain liquid chemical sterilants.
5. 7 U.S.C. § 136(v) (emphasis added).
6. U.S. EPA, Pesticides: Regulating Biopesticides, http://www.epa.gov/oppbppd1/biopesticides.
7. 40 Code of Federal Regulations (C.F.R.) § 158.2000(a)(1). As regards the “non-toxic” mode of action, this does not mean a “non-lethal” mode of action. As an example, a substance that provides a barrier to a necessary food substrate will result in the death of the target pest; it does not do so, however, by toxic means.
but not limited to, viruses. Microbial pesticides typically have greater target specificity than biochemical pesticides (other than pheromones). Typical modes of action of microbial pesticides include direct toxicity, ecological competition, growth inhibition, and use of the pest as a growth substrate.
“Plant-incorporated-protectants” (PIPs) are pesticidal substances that are intended to be produced and used in a living plant, or in the produce thereof, along with the genetic material necessary for the production of the substance. The PIP also includes any inert ingredient contained in the plant, or its produce. To register a pesticide product for sale or distribution in the United States, EPA must determine that the uses proposed for the pesticide product will not cause “unreasonable adverse effects on the environment.” The definition of unreasonable adverse effects on the environment incorporates the food safety standard in the Federal Food, Drug, and Cosmetic Act (FFDCA) - which requires, inter alia, that EPA establish concentration limits for pesticide residues occurring on edible food at the level that EPA has determined there is a “reasonable certainty of no harm” resulting from dietary exposure to such residues.,
8. 40 C.F.R. § 158.2100(b).
9. 40 C.F.R. § 174.3. PIPs are genetically engineered transgenic or cisgenic pesticidal constructs. EPA has separate regulatory requirements for PIPs, which are more extensive than the requirements for biochemical and microbial pesticides. Consideration of the PIP-specific regulatory process is outside the scope of this paper. For a comprehensive treatment of PIPs regulation – past, present, and future – at EPA, see Matthews, K.A., Regulation of Biopesticides by the Environmental Protection Agency, in Biopesticides: State of the Art and Future Opportunities; Coats, et al., ACS Symposium Series, 2014 American Chemical Society.
10. FIFRA, Section 3(a), 7 U.S.C. § 136a(a). “Unreasonable adverse effects on the environment” is defined as “(1) any unreasonable risk to man or the environment, taking into account the economic, social, and environmental costs and benefits of the use of any pesticide, or (2) a human dietary risk from residues that result from a use of a pesticide in or on any food inconsistent with the standard under section 346a of Title 21.” Section 2(bb), 7 U.S.C. § 136(bb).
11. 21 U.S.C. §§ 301-399(d).
12. 21 U.S.C. § 346a(b)(2). EPA refers to such concentration limits for pesticide residues as “tolerances.” Regulatory agencies in other countries often refer to pesticide residue concentration limits as “maximum residue levels” (MRLs).
13. EPA’s regulation of pesticides also must address requirements of the Endangered Species Act (16 U.S.C. §§ 1531-1544); the Migratory Bird Treaty Act (MBTA) (16 U.S.C. §§ 703-712); and the Clean Water Act (33 U.S.C. §§ 1251-1387). Aside from the Endangered Species Act, the requirements of which EPA has committed to address during the pesticide registration review process, these statutes are rarely implicated in the context of biopesticide registrations.
U.S. EPA’s Biopesticides Registration Process
At EPA, the Office of Chemical Safety and Pollution Prevention (OCSPP) is responsible for regulating the sale, distribution, and use of chemicals. OCSPP’s Office of Pesticide Programs (OPP) is responsible for regulating pesticides under FIFRA. There are three Divisions within OPP that are responsible for registering pesticide products: the Antimicrobial Division, which registers antimicrobial pesticides; the Registration Division, which registers conventional chemical pesticides; and the Biopesticides and Pollution Prevention Division (BPPD), which registers reduced risk, biologically based biopesticides.
BPPD was established in 1995 to co-locate all regulatory functions related to biopesticides (science assessments, registration, and registration review) in one organisation within OPP. Separate data requirements were also promulgated specifically for biopesticides. As a class, biopesticides are deemed to pose fewer potential risks than conventional chemical pesticides. Therefore, the data requirements applicable to biopesticides are significantly less than those applicable to conventional chemical pesticides or antimicrobial pesticides. The data requirements were developed with the understanding that biopesticides are safer pesticide products that, typically, do not present equivalent potential risks to humans or non-target organisms as are presented by conventional chemical pesticides. Moreover, the timeframes in which EPA must make regulatory decisions on biopesticides applications are much shorter than for conventional chemicals, and the registration application fees are much lower.
A. Initiation of Application Review
Notwithstanding the truncated data requirements, shortened review and decision timeframes, and reduced fees applicable to biopesticides, EPA conducts a rigorous review of biopesticide registration applications.
14. Other regulatory bodies refer to these products as “biocides.” “Antimicrobials” and “biocides” are synonymous.
15. In 2004, FIFRA was amended by the Pesticide Registration Improvement Act (PRIA), which established a fee-for-service system for pesticide registrations. Section 33 of FIFRA sets forth a complete schedule of fees and application review times applicable to FIFRA regulatory decisions. 7 U.S.C § 136w-8. PRIA also established specific time periods for EPA to act on FIFRA regulatory applications.
Although not mandatory, the biopesticide registration process should begin with a “pre-submission” meeting. The biopesticides registration application pre-submission meeting allows a prospective applicant the opportunity to provide BPPD staff with information regarding the application prior to its submission, and to receive feedback from BPPD on the not-yet-submitted application. The pre-submission meeting is very important to an efficient review process. If the prospective applicant substantively engages in the pre-submission meeting, there is a substantial likelihood that EPA will provide specific guidance that allows for an improved application. The ultimate goal is to have registrations applications be more substantively complete, thus decreasing the number of applications where the decision deadline must be extended because they are significantly deficient.
If the prospective pesticide registration applicant intends to seek registration of a pesticide as a biochemical pesticide, the applicant must first submit certain information to BPPD’s Biochemical Classification Committee (BCC). The BCC determines whether a particular substance qualifies as a biochemical pesticide. Currently, Dr. Russell Jones, Senior Scientist for BPPD’s Biochemical Pesticides Branch, is the Chair of the BCC. Dr. Jones can guide the prospective applicant through the process for making a submission to the BCC.
The biopesticides registration process begins with formal submission of a pesticide registration application. Acceptance of a pesticide registration application by OPP requires payment of the applicable fee. Once the application has been accepted by OPP, it undergoes an initial content screen that can last up to 21 days. The purpose of the initial content screen is to determine if the application package appears to contain all of the required forms, data and draft labeling, and if all
16. See U.S. EPA, Implementing the Pesticide Registration Improvement Act – Fiscal Year 2012 Ninth Annual Report (March 1, 2013), http://www.epa.gov/pesticides/fees/2012annual_report/improve-registration-fy2012.pdf.
19. EPA provides guidance on preparing a biopesticide registration application at http://www.epa.gov/oppbppd1/biopesticides.
submitted materials are properly formatted. If the application passes the initial content screen, it is forwarded to the relevant registering division (i.e., AD, BPPD, or RD), and the regulatory time period mandated by PRIA begins.
Upon receiving an application that has passed the initial content screen, BPPD conducts a “preliminary technical screening.” The purpose of the preliminary technical screen is to determine if the application, data, and information submitted as part of the application are accurate and complete, are consistent with the proposed label, and contain sufficient data and information to support any necessary FFDCA tolerance or tolerance exemption.
If a biopesticide registration application fails either the 21-day initial content screen or the preliminary technical screen, EPA is to notify the applicant of such failure and the applicant will have 10 business days after the notification to correct the deficiency. FIFRA mandates that if the applicant does not correct the deficiency within 10 business days of notification of the application failing either the initial content screen or the preliminary technical screen, the application is to be rejected. Upon passing the 21-day initial content screen and the preliminary technical screen, the application undergoes substantive science review. During the formal science review process, BPPD assesses data and information addressing specific data requirements pertaining to the chemistry and composition of the product, the potential for human health effects, and the potential for environmental effects based on the product’s proposed use patterns.
B. Substantive Review of Pesticide Registration Applications
20. 7 U.S.C. § 136w-8(f)(4)(B)(iii).
21. 7 U.S.C. § 136w-8(f)(4)(B)(i)(II).
22. 7 U.S.C. § 136w-8(f)(4)(B)(iv).
23. 7 U.S.C. § 136w-8(f)(4)(B)(ii).
EPA’s pesticides data requirements are located at 40 Code of Federal Regulations (C.F.R.) Part 158. The biochemical pesticide data requirements are at Subpart U (§§ 158.2000 to 158.2084) of Part 158. These data requirements include: verification of product identity, composition and physicochemical characteristics; human health toxicity; nontarget organism toxicity; and environmental fate.
EPA’s pesticides data requirements are tiered, i.e., Tier 1 baseline data are required and, depending upon results of the Tier 1 studies, additional data may or may not be required. The biochemical pesticides Tier 1 human toxicity data requirements include information related to acute and subchronic health effects. The higher level tier II and Tier III data requirements may be triggered by adverse results in Tier I testing. Tier 1 environmental effects data requirements include avian, aquatic, nontarget plant, and insect testing. Again, Tier II and Tier III environmental effects data requirements may be triggered by adverse results in Tier I testing. In addition to the human toxicity and environmental effects data, submission of efficacy data is required if the product label makes claims as to public health pests. These include arthropod and arachnid pests that vector diseases (e.g., ticks, fleas, mosquitoes, etc.). Also, to meet the food safety requirements of the FFDCA, for food uses, either residue data are required or data must be submitted demonstrating that the active ingredient qualifies for an exemption from the requirement of a tolerance. An exemption from the requirement of a tolerance is granted where EPA determines that the data submitted support a finding that no exposure limitation is required to meet the FFDCA’s “reasonable certainty of no harm” standard.
25. 40 C.F.R. Part 158 may be accessed from the U.S. Government Publishing Office at http://www.ecfr.gov/cgi-bin/retrieveECFR?gp=1&SID=f1c4d366a30ff6852b
26. Product identity, composition, and physicochemical characteristics are important information for EPA to evaluate a biopesticide registration application and grant a registration. One category of substances where this may prove important is plant extracts. Registration of plant extracts can be challenging in the United States. FIFRA registration requires identification of the specific active ingredient conferring the pesticidal effect and the composition of the product formulation. Given that the composition of botanical extracts often is complex, registration of such extracts can prove difficult.
EPA has developed test guidelines to assist biopesticide registration applicants in preparing complete data packages. The Biochemical Pesticides Test Guidelines, OCSPP Series 830-880, are on EPA’s website at http://www.epa.gov/oppbppd1/biopesticides/regtools/index.htm.
The Microbial Pesticides data requirements are set forth at 40 C.F.R. Part 158, Subpart V (§§ 158.2100 to 158.2174). Microbial pesticides can include either living or killed microbial formulations and may present greater potential risk concerns than biochemical pesticides (in contrast to biochemical pesticides, microbial pesticides may act by toxic mechanisms). Thus, the data required to register a microbial pesticide generally are greater and more complex than are the data required to register a biochemical pesticide. In addition to the basic data required generally, e.g., product identity, physicochemical characteristics, human health toxicity, and non-target effects, the microbial pesticide data requirements include deposition of a sample into a nationally recognized culture collection; testing to determine pathogenicity; and cell culture study for viruses. In general, residue data are not required, as microbial pesticides that meet the FIFRA registration standard almost invariably qualify for an exemption from the requirement of a tolerance. Another way of looking at this is that microbial pesticides that meet the FIFRA no unreasonable adverse effects standard invariably do not pose dietary risks. As with biochemical pesticides, EPA must determine that the data submitted support a finding that no exposure limitation is required to meet the FFDCA’s “reasonable certainty of no harm” standard. Also as with biochemical pesticides, submission of efficacy data is required if the product label makes claims as to public health pests (e.g., ticks, fleas, mosquitoes, etc.). The Microbial Pesticides Test Guidelines, OCSPP Series 885, may be found on EPA’s website at http://www.epa.gov/oppbppd1/biopesticides/regtools/index.htm.
As noted above, PRIA established specific time frames for EPA to assess pesticide registration applications and to render registration decisions. If, however, BPPD reviewers determine that the data and information submitted with a pesticide registration application are inadequate to satisfactorily address the applicable data requirements, EPA will issue a “75-day deficiency letter” to the applicant. The 75-day deficiency letter identifies the unsatisfied data requirement, specifies the deficiency, and informs the applicant as to what data and information are needed to cure the deficiency. The applicant is given 75 days to cure the deficiency, or to request extension of the PRIA decision timeframe. Extensions of the decision timeframe always allow for what BPPD considers to be sufficient time for the applicant to cure the deficiency and for BPPD to complete its assessment of the supplemented application package. Applicants, however, are not required to agree to an extension of the decision timeframe. If an applicant declines to negotiate a new decision deadline, EPA can either deny the registration application outright, or EPA can issue a determination that it has not been provided sufficient information to support granting the registration. If EPA determines that it has insufficient information to render a positive registration decision, EPA may inform the applicant that it “cannot grant” the registration on the basis of the data and information on file. If EPA issues a “cannot grant” determination, the application is taken out of the PRIA queue. Removal from the PRIA queue effectively means that there is little likelihood of a decision on the application. The applicant may, however, at any time, commit to submitting the necessary data and information and negotiate a new date for EPA to make a registration decision.
Prospects for an expanding market for biopesticides in the United States are strong. Moreover, in the United States, the regulatory requirements for biopesticides registration have been reduced and the time frames for obtaining a registration have been shortened. Thus, the United States is considered to have a favorable environment for registering biopesticides. To take full advantage of the favorable regulatory environment in the United States, companies seeking to register biopesticide products in the United States must be fully cognizant of the regulatory requirements for biopesticides registration, which, notwithstanding that they may be lower than the requirements for conventional chemical pesticides, still must be fully satisfied to obtain a U.S. biopesticide registration.
27. registration applicants to ensure, to the greatest extent possible, that the pesticide registration application is complete and ready for review, prior to submission.
28. See, e.g., http://www.battelle.org/docs/energy-environment/battelle