U.S. EPA Regulatory Process Overview for Microbial and Biochemical Pesticides
Sharlene R. Matten, Ph.D., Biologist, U.S. EPA/OPP/BPPD
This paper provides an overview of the regulatory process for U.S. registration of microbial and biochemical pesticides.
A. Terms and Regulations
What are Biopesticides?
Biopesticides are certain types of pesticides derived from animals, plants, bacteria, and certain minerals. For example, canola oil and baking soda have pesticidal applications and are considered biopesticides. At the end of 2001, there were approximately 195 registered biopesticide active ingredients and 780 products. Biopesticides fall into three major classes:
| (1) | Microbial pesticides consist of a microorganism (e.g., a bacterium, fungus, virus or protozoan) as the active ingredient. Microbial pesticides can control many different kinds of pests, although each separate active ingredient is relatively specific for its target pest[s]. For example, there are fungi that control certain weeds, and other fungi that kill specific insects. The most widely used microbial pesticides are subspecies and strains of Bacillus thuringiensis, or Bt. Each strain of this bacterium produces a different mix of proteins, and specifically kills one or a few related species of insect larvae. While some Bt proteins control moth larvae found on plants, other Bt proteins are specific for larvae of flies and mosquitoes. The target insect species are determined by whether the particular Bt produces a protein that can bind to a larval gut receptor, thereby causing the insect gut to rupture and the insect to starve to death. |
| (2) | Plant-Incorporated-Protectants (PIPs) are pesticidal substances that plants produce from genetic material that has been added to the plant using modern biotechnology methods. For example, scientists can take a gene that tells the soil bacterium to make a pesticidal protein, and introduce a gene into the plant's genetic material. The plant is then able to manufactures a protein that has pesticidal properties. The pesticidal protein and its genetic material are regulated by EPA, but not the plant itself. |
| (3) | Biochemical pesticides are naturally-occurring substances that control pests by non-toxic mode of action. Conventional pesticides, by contrast, are generally synthetic materials that directly kill or inactivate the pest. Biochemical pesticides include substances, such as insect sex pheromones, that interfere with mating, as well as various scented plant extracts that attract insect pests to traps. Because it is sometimes difficult to determine whether a substance meets the criteria for classification as a biochemical pesticide, BPPD has established an internal committee called the Biochemical Classifications Committee to make such decisions. |
| (4) | FIFRA, FFDCA, FQPA, and Other Regulatory and Legislative Information The U.S. Environmental Protection Agency (EPA) regulates pesticides under two major statutory authorities, the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food Drug and Cosmetic Act (FFDCA). These statutes were both amended by the Food Quality Protection Act (FQPA). 4.1 FIFRA requires EPA registration for all pesticides sold in U.S. Under FIFRA, the EPA has the authority to regulate the development, sale, distribution, use, storage, and disposal of pesticides. FIFRA generally prohibits the sale or distribution or a pesticide unless it is registered. A product may be registered either unconditionally (see FIFRA section 3(c)5) or conditionally (see FIFRA section 3(c)(7). To be granted a registration, FIFRA requires that a pesticide will not cause "unreasonable adverse effects" to human health or the environment. The Agency's policy regarding approval or denial of applications for conditional registration of pesticide products under section 3(c)7(C) of FIFRA is set forth in 51 Federal Register 7629-34 (March 5, 1986). FIFRA section 3(c)7(C) authorizes EPA to issue a conditional registration for a pesticide product containing an active ingredient not contained in any previously registered product (a new chemical) in the absence of certain required data, if the Agency determines that all three of the following conditions are met before issuance of the conditional registration:
As amended by the Federal Food Quality Protection Act of 1996 (FQPA), FIFRA defines the term "unreasonable adverse effects on the environment" to mean: "(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 408 of the Federal Food, Drug, and Cosmetic Act" (7 U.S.C. 136 (bb)). 4.2 FFDCA, revised substantially in August 1996, regulates many aspect of food, drug and cosmetic safety including provisions for the establishment of pesticide tolerances for crops. A tolerance is the maximum permissible level for pesticide residues allowed in or on commodities for human food and animal feed. The EPA determines that there is a level of exposure below which "there is a reasonable certainty that no harm will result from complete exposure of the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information" (21 U.S.C. 346a(b)(2) and c(2)(A)). EPA and the Food and Drug Administration (FDA) are responsible for administering the Act. 4.3 FQPA of 1996 amended the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food Drug, and Cosmetic Act (FFDCA). These amendments fundamentally changed the way EPA regulates pesticides. The requirements included a new safety standard of "a reasonable certainty of no harm" that must be applied to all pesticides used on foods. This standard provides for special provisions for infants and children. 4.4 The Endangered Species Act (ESA) of 1973 prohibits any action that may adversely affect an endangered or threatened species or its habitat. In compliance with this law, EPA must ensure that the pesticidal products it registers will not harm endangered species. Although the Office of Pesticide Programs (OPP) has included endangered species considerations in its risk assessments for many years, the Endangered Species Protection Program (ESPP), as an entity, started in 1988. The ESPP is performed in cooperation between the U.S. Fish and Wildlife Service (FWS), EPA Regions, States, and pesticide users. ESPP is located in the Field and External Affairs Division (FEAD) of OPP. |
| (5) | Regulations Regulatory information may include items such as Federal Register documents, the FIFRA docket, Pesticide Regulation Notices, FQPA regulations, and information about locating state regulatory agencies. The Code of Federal Regulations (CFR) is a codification of the rules published in the Federal Register by the Executive departments and agencies of the Federal Government. The CFR is divided into 50 titles which represent broad areas subject to Federal regulation, with environmental regulations contained mainly in Title 40. Each volume of the CFR is revised once each calendar year and updated on a quarterly basis, Title 40 is issued every July 1. |
B. Regulatory Process
In the United States, all products that have or claim pesticidal properties are regulated by the Environmental Protection Agency (EPA). There are eight steps or phases to the regulatory process for any pesticide action. These include: 1) Pre-registration, 2) Submission, 3) Screening, 4) Regulatory Coordination, 5) Data Review, 6) Regulatory Review, 7) Management Review and Regulatory Decision and 8) Administrative Close-out. Each of these phases are briefly summarized below. Several of these phases may be revisited several times in the review process prior to a final regulatory decision.
(1) Pre-Registration
The pre-reregistration phase occurs well in advance submitting the actual pesticide registration application and supporting materials to EPA for review. The application and set of information submitting in support of the registration is collectively referred to as a submission or submission packet. Pre-registration meetings are needed to establish the data requirements for a specific product or the type of information required to support a data waiver. The pre-registration meetings or consultations do not have a formal data package requirement, but background materials discussing the active ingredient and the end-product uses are extremely useful and typically provided by the prospective registrant. In order to facilitate a productive meeting, an agenda should be developed at least two weeks prior to the meeting and should be agreed upon by both the prospective registrant and the Agency. The prospective registrant should contact the appropriate branch chief or team leader in the Biopesticides and Pollution Prevention Division (BPPD) to arrange for a pre-registration meeting (see BPPD Contacts List). The Branch Chief and/or the Team Leader will designate an EPA OPP BPPD staff person to serve as the Regulatory Action Leader (RAL). Thereafter, the RAL will serve as the prospective registrant's principle contact with the Agency. All regulatory actions in BPPD are coordinated by the RAL.
(2) Submission
The submission phase involves the submission of required, recommended, or other wise necessary information and how tat information must be formatted for the submission package to be considered. Proper formatting of the submission package is critical to moving the application into the queue to be reviewed and acted upon.
2.1 Forms
For guidance in selecting the appropriate forms consult the Pesticide Registration Kit. The registrant (or prospective) should contact the RAL, team leader, or branch chief in the Biopesticides and Pollution Prevention Division (see BPPD Contacts List) for additional information prior to a submission.
Specific forms listed below are provided as an aid for registering a pesticide product:
| (a) | EPA Form No. 8570-1, Application for Pesticide Registration/Amendment |
| (b) | EPA Form No. 8570-4, Confidential Statement of Formula |
| (c) | EPA Form No. 8570-5, Notice of Supplemental Registration of Distribution of a Registered Pesticide Product |
| (d) | EPA Form No. 8570-17, Application for an Experimental Use Permit |
| (e) | EPA Form N. 8570-25, Application for Notification of State Registration of a Pesticide to Meet a Special Local Need |
| (f) | EPA Form No. 8570-27, Formulator's Exemption Statement |
| (g) | EPA Form No. 8570-28, Certification of Compliance with Data Gap Procedures |
| (h) | EPA Form No. 8570-32, Certification of Attempt to Enter into an Agreement with other Registrants for Development of Data |
| (i) | EPA Form No. 8570-34, Certification with Respect to Citations of Data (as referenced in PR Notice 98-5) |
| (j) | EPA Form No. 8570-35, Data Matrix (as referenced in PR Notice 98-5) |
| (k) | EPA Form No. 8570-36, Summary of the Physical/Chemical Properties (as referenced in PR Notice 98-1) |
| (l) | EPA Form No. 8570-37, Self-Certification Statement for the Physical/Chemical Properties (as referenced in PR Notice 98-1) |
2.2 General Pesticide Information
Additional resources commonly needed by prospective registrants are listed below. Weblinks are provided for each of the resources lists.
2.3 PR Notices
Pesticide Registration Notices are issued by the OPP to inform pesticide registrants and other interested persons of updates and clarifications to important pesticide registration policies, procedures and regulatory decisions. Some useful PR Notices are listed below.
| (a) | 83-3 Label Improvement Program--Storage and Disposal Statements |
| (b) | 84-1 Clarification of Label Improvement Program |
| (c) | 86-5 Standard Format for Data Submitted under FIFRA |
| (d) | 87-1 Label Improvement Program for Pesticides Applied through Irrigation Systems (Chemigation) |
| (e) | 87-6 Inert Ingredients in Pesticide Products Policy Statement |
| (f) | 90-1 Inert Ingredients in Pesticide Products; Revised Policy Statement |
| (g) | 93-7 Labeling Revisions Required by the Worker Protection Standard (WPS) |
| (h) | 93-11 Supplemental Guidance for PR Notice 93-7 --- Labeling Revisions Required by the Worker Protection Standard (WPS) |
| (i) | 98-1 Self Certification of Product Chemistry Data |
| (j) | 98-5 New forms for the Certification with Respect to Citation of Data |
| (k) | 98-10 Notifications, Non-notifications, and Minor Formulation Amendments |
| (l) | 2000-5 Guidance for Mandatory and Advisory Labeling Statements |
| (m) | 2001-1 First Aid Statements on Pesticide Product Labels |
| (n) | 2001-5 Guidance for Voluntary Resistance Management Labeling |
2.4 Data Requirements
The minimum data requirements for microbial and biochemical pesticides in the U.S. are addressed in two documents: U.S. EPA 40CFR 158.690 Biochemical Pesticides Data Requirements, and U.S. EPA 40CFR 158.740 Microbial Pesticides Data Requirements.
These data generally fall into one of five categories of data:
| (a) | 83-3 Label Improvement Program--Storage and Disposal Statements |
| (b) | Residue Data |
| (c) | Toxicology Data |
| (d) | Non-target Organism and Environmental Expression Data |
| (d) | Product Performance/Efficacy |
Microbial Pesticide Data Tables and Test Guidelines are available on the EPA OPP Biopesticides website. These tables and guidance documents include the following:
| Microbial Pesticide Data Tables and Test Guidelines | |
| Biochemical Pesticide Data Tables and Test Guidelines | |
| A complete set of OPPTS Harmonized Test Guidelines | |
| For further information on Biopesticides go to the EPA website |
2.5 Format
A key step in getting a registration action into the queue to be reviewed is for the prospective registrant to have the submission package in the proper format. The Agency has deliniated its standard format guidance in PR Notice 86-5. This PR Notice contains requirements for organizing and formatting submissions of supporting data. However, this PR Notice does not address the substance of test reports themselves. PR Notice 86-5 applies to all data that are submitted to EPA to satisfy data requirements for granting or maintaining pesticide registrations, experimental use permits (EUPs), tolerances, and related approvals under certain provisions of FIFRA and FFDCA. These data are defined in FIFRA section 10(d)(1). This Notice does not apply to commercial, financial, or production information, which are, and must continue to be, submitted under a separate cover and a different submission format. If the guidance is not followed as outlined in PR Notice 86-5, the "submittal package" will not be put into the queue for BPPD review.
The "submittal package" must contain as its first item a transmittal document that identifies the submitter, the type of regulatory action to be considered (e.g., amendment, Experimental Use Permit, new active ingredient registration, Section 18 emergency exemption, Section 24 special local needs registration, tolerance, data call-in), the transmittal date, and the list of studies (with appropriate data citation). The list of studies should be subdivided by discipline and, if known, the EPA-assigned number for the regulatory action. PR Notice 86-5 specifies how each study should be formatted including, but not limited to, pagination, certification of good laboratory practices, Confidential Business Information (with statement of Data Confidentiality Claims under FIFRA Section 10(d)).
2.6 Tolerance Petition
EPA administers the issuance of a tolerance, the maximum allowable level of a pesticide residue in a food or feed, under FFDCA. Also, FFDCA provisions that also allow for the application and granting of exemption from tolerance requirements when a tolerance is not necessary to protect public health. Without an appropriate tolerance or tolerance exemption, a food containing pesticide residues is considered "adulterated," and may not legally be moved in interstate commerce. To date, most biological pesticides have been granted an exemption from the requirement for a tolerance after review of pertinent data.
If there is a first food or feed, then the registrant (petitioner) must provide the Agency with a Tolerance Petition either for a tolerance or tolerance exemption to be granted.. An appropriate FQPA template for the Tolerance Petition must be used by the petitioner: see OPPTS Public Document Drafting Templates - Company Notice of Filings for Pesticide Petitions.
A tolerance fee must be submitted to the Agency unless a fee waiver is granted or if it is not required. Once the tolerance fee is paid then BPPD RAL puts the Tolerance Petition into scientific review. The Agency must also publish, a "Notice of Filing" of the Tolerance Petition in the Federal Register and provide the public an opportunity to comment (usually for at least 30 days after publication). A public docket is created to receive public comments. Once the scientific review is completed, the RAL will draft a Final Tolerance Rule, Temporary Tolerance Rule, or Time-Limited Tolerance Rule that will either establish a tolerance or an exemption from the requirement for a tolerance. The Tolerance Rule is reviewed by BPPD, Office of General Counsel, and OPP upper management prior to its publication in the Federal Register.
3 Screening
EPA screens or surveys the submission package to determine if it is complete and ready to enter the queue for review and evaluation. There are two types of screens utilized: Front-End screen and New Chemical screen. The Front-End screen is done by the OPP's Information Resources and Services Division (IRSD) and includes those requirements stated in PR Notice 86-5. The "Front-End" screen includes a general review of the forms, company information, package completeness, EPA-assigned regulatory number, and review of formatting as directed by PR Notice 86-5. A submittal package must pass the "Front-End"screen before it is placed into the BPPD queue for review. If the submittal package does not pass the Front-End screen, a transmittal letter will be sent by IRSD to the registrant explaining why the submittal package failed to meet PR Notice 86-5 requirements. Usually, the RAL will also write a letter to the registrant.
The New Chemical screen for an unregistered pesticide active ingredient not contained in any previously registered pesticide prduct will determine whether the package has any major deficiencies that prohibit a full scientific review of the data, e.g., missing data or appropriate data waivers lacking, unsuitable guideline studies, inclusion of a tolerance petition plus appropriate fees for a food or feed use. Typically the New Chemical screen will be done within two weeks after the BPPD RAL has received a submittal package that has passed the "Front-End" Review (passed PR Notice 86-5). The New Chemical screen is done by the RAL and BPPD scientific reviewers. There are other informal screens that may occur throughout the regulatory decision-making process.
If the new chemical passes the New Chemical screen, the RAL will prepare a "Notice of Receipt" and publish that notice in the Federal Register. A public docket is established with the publication of the "Notice of Receipt" and public comments are received (usually for at least 30 days after publication). If a new chemical fails the New Chemical screen, a deficiency letter outlining the areas that need to be addressed is prepared by the RAL and sent to the registrant. The registrant must address the deficiencies before the data can be fully reviewed. For an Experimental Use Permit, the RAL will publish a "Receipt of Application" in the Federal Register (FR), a public docket will be created and public comments will be considered for a period of at least 30 days following publication of the notice in the FR.
4 Regulatory Coordination
The RAL is the most important contact person with in the Agency for the prospective registrant. This is the person with whom a registrant will have the most contact. The regulatory process for all regulatory actions in BPPD is coordinated by the RAL. The RAL is chosen by the Branch Chief and/or the Team Leader. The RAL is also responsible for managing all of the correspondence, meetings, and telephone calls between the registrant and the Agency. The RAL prepares all of the regulatory documents including those published in the Federal Register. The RAL is responsible for tracking all related actions for a particular pesticide product and updates the pesticide tracking database, as appropriate.
5 Data Review
The data review is conducted by BPPD science reviewers in conjunction with contract reviewers. The function of the data review is to provide the RAL and the other regulatory managers with a scientific review of the data and an assessment (and likelihood) of the risks associated with the proposed uses of the pesticide active ingredient and pesticide end-products. Data requirements for microbial and biochemical pesticides are summarized in the Section b.(2) Submission above and are tailored to the specific microbial or biochemical pesticide, as appropriate. Typically, the data are segregated by discipline. For microbial pesticides, there is one science reviewer for the product characterization data and human toxicology data and one science reviewer for the ecological non-target data. The outcome of the data review is a document or set of documents (data evaluation record (DER) for each individual study, risk assessment document, cover memo with a summary of the assessment and recommendations to the regulatory managers). For a new chemical, BPPD prepares an integrated risk assessment and risk management document called a Biopesticides Registration Action Document (BRAD).
The data review step takes the longest time in the regulatory process. This process may take a few months or it may take years depending on the nature of the risk, the workload of the reviewers, and priority of the regulatory action under review. It may be iterative as the data reviewers identify potential issues.
There are generally two steps in the data review: primary and secondary review. The primary review is conducted by the BPPD science reviewer or outside contract reviewer. The primary reviewer is responsible for the detailed review of the data. The secondary review is completed a second BPPD scientist. The secondary reviewer is responsible for reviewing the primary review and looking for any technical errors and/or science policy inconsistencies.
6 Regulatory Review
Once the data reviews are completed, they are given to the RAL. The RAL has the job of completing and coordinating the necessary regulatory review steps before a regulatory decision can be made. Some of the regulatory review process is conducted before, during, and after the data reviews. If the action is for a new active ingredient, the RAL will coordinate the steps needed to determine whether there will be a conditional registration under FIFRA section 3(c)7(C) [see Section A.] or an unconditional registration under FIFRA section 3(c)5.
The total time involved in the final regulatory review steps conducted by the RAL can vary from approximately two to six months. These steps include, but are not limited to: a) label review, b) Confidential Statement of Formula review, c) public docket maintenance, d) creation and review of all regulatory documents within and outside the Agency and any briefing documents, e) public and Congressional correspondence, and f) coordination of data reviewer, management, and Office of General Counsel review of documents.
For a New Chemical active ingredient, the RAL is also responsible for creating a Biopesticides Registration Action Document (BRAD) that integrates the risk assessment and risk management analyses, a Fact Sheet, Registration Decision memorandum, Registration Notice, Tolerance Rule, and Federal Register notice announcing the approval of the new pesticide active ingredient (and end-products). If there were any public comments, the RAL must include a review and a response to those comments in the Agency's regulatory documents. Depending on the nature of the risk, the Agency may choose to hold external peer review meetings, such as the FIFRA Scientific Advisory Panel. These types of meetings are rarely held for issues related to microbial and biochemical pesticides.
7 Management Review and Regulatory Decision
Management review refers to those steps in the regulatory decision-making process that occur after the RAL has prepared the necessary regulatory documents for management concurrence and signature. The data reviewers will have already reviewed and concurred with these documents. The parties involved in management review are: BPPD management (branch chief, team leader, and division director), OPP management (Office Director or Deputy Office Director), and the Assistant Administrator's (AA's) office for the Office of Prevention, Pollution, and Toxic Substances). Depending on the nature of the issues involved, the management review stage can take a few weeks to a few months. Management review may also involve additional negotiation steps with the registrant as to the specific terms and conditions of registration. The management review will culminate in the actual regulatory decision with the appropriate approval signatures on all documents. Some regulatory actions are signed by the Division Director, BPPD and some regulatory actions are signed by the Office Director or Deputy Office Director. The RAL will verify which signatory authority is required.
Following the regulatory decision, the RAL will provide an "accepted" stamp on the approved label. The RAL should call the registrant and notify them that the regulatory decision has been made. Typically, the RAL will fax a copy of the regulatory decision to the registrant. The signed regulatory decision letter and other documents (e.g., science reviews, label, BRAD, Fact Sheet) will be sent to the registrant. Often, the registrant will request to pick up a copy of the regulatory decision and all accompanying documents.
For an Experimental Use Permit (EUP), in addition to the above, the RAL is expected to inform and send copies of the EUP approval letter to the appropriate EPA Regions.
8 Administrative Close-out
Following the regulatory decision, the RAL will publish the Final Tolerance Rule, the Approval of an EUP, the Notice of Registration (or Conditional) of a New Active Ingredient or other documents, as appropriate, in the Federal Register. The RAL is expected to close-out all of the related items in the tracking database and the official regulatory files. Certain materials, such as the BRAD and Fact Sheet prepared by EPA, are forwarded to the BPPD web master for posting. Materials are posted as quickly as possible by the BPPD web master.