To open up the US crop protection market for an active substance you have already registered elsewhere, you will need to compare your existing data against the regulatory requirements of the US Environmental Protection Agency (EPA). In this blog, we outline the US regulatory landscape and suggest ways of optimizing registration success within it.
1: Check the US EPA pesticide category to identify the registration process
EPA regulates registration of all pesticides. Whether registering a new crop protection or pesticide active substance, a new product containing an active substance, or a new use for an existing product, you will need to follow the registration process required by EPA. This will be specific to pesticide category, with different categories defined by EPA:
- Conventional pesticides
- Antimicrobial pesticides
- Inert ingredients
Each of these has different criteria set by EPA for pre-application meetings, data requirements, workplans, etc., and EPA’s Office of Pesticide Programs (OPP) has a separate division for each of the first three categories. For successful approval of an active substance, it is important to have a thorough understanding and knowledge of EPA’s regulatory processes and requirements.
2: Understand the US regulatory landscape for active substances for crop protection
The legal, scientific and administrative processes by which EPA regulates crop protection products and their active substances are determined by a number of pesticide laws:
- Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), which covers pesticide registration and label approval, as well as distribution, sale and use of pesticides in the USA
- Federal Food, Drug, and Cosmetic Act (FFDCA), which sets pesticide tolerances in or on food or animal feed
- Food Quality Protection Act (FQPA), which assesses reasonable certainty of no harm and re-registration reviews every 15 years
- Pesticide Registration Improvement Act (PRIA), which establishes the framework for EPA when registering pesticides, including the fee structures, and is reauthorized every five years
- Endangered Species Act (ESA), which requires that EPA ensures no action it authorizes, funds or carries out will jeopardize the existence of a listed endangered species and its critical habitat.
EPA uses an iterative process to characterize the nature and magnitude of the risks to human health and ecological species. Therefore, it requires expert review and interpretation of the regulatory requirements to ensure the datasets meet the needs of and support appropriate regulatory decisions by EPA.
After registration, EPA conducts a review every 15 years to determine whether the active substance meets the latest FIFRA standards. Changes in regulatory requirements since the previous review may mean there are data gaps and, therefore, new assessments have to be performed and new data have to be generated for registration review.
3: Be aware of differences between EPA and other regulatory regimes in terms of data requirements
Much of the core data is the same but there are likely to be differences which necessitate new studies to provide a complete dataset to EPA. Examples of differences include:
- Crop groupings and representative crops
- Environmental and field assessments
- Ecotoxicology and non-target species studies
- Water and food risk assessment approaches and models used.
It is advisable to anticipate these differences and, if necessary, to consult EPA. For example, the different US crop groupings (Federal Regulations Part 40 Section 180.41) may mean that your tolerance data are for a crop that is not representative of a particular group. It becomes important to seek support from experienced regulatory consultants to understand the gaps and to develop strategies to ensure the submission meets all the data requirements needed by EPA.
4: Determine data requirements for EPA registration of your active substance
A number of factors determine the type of data required for a pesticide to be registered with EPA, starting with the proposed uses that will be claimed on the product label. The full requirements are given in 40 Code of Federal Regulations (CFR) Part 158.
A full data set can be compiled by generating new data or, more likely, by combining new data and leveraging existing data (read across, QSARs where applicable) and submitting waiver requests. It may be possible to leverage knowledge of the chemistry of the active substance and of previous regulatory assessments or decisions for substances in the same classes of chemistry. There may already be substantial data which can be bridged that way, or from a product with similar chemistry, and used in another industry. Furthermore, EPA may grant data waivers where it agrees with a submitted rationale that indicates the characteristics or planned use of the active substance make a specific data requirement irrelevant.
EPA publishes information and guidance on its approach to bridging and data waivers.
5: Understand EPA’s interpretation of data for active substance registration and registration review
Although EPA publishes comprehensive information for applicants, this doesn’t convey intangibles relating to the way it interprets data and makes decisions. EPA seeks proof of no unreasonable adverse impact on humans or the environment, as done in other countries, but EPA differs in its approach. Whereas the EU, for example, bases assessment of active substances on the intrinsic hazards they pose, EPA relies on a risk management process with no hazard-based classification or cut-off criteria.
Use of risk assessment is fundamental to EPA’s whole approach to protecting human health and ecological species. Risk is a function of both hazard and exposure – a distinction sometimes summarized by saying “a lion is intrinsically a hazard, but a lion safely constrained in a zoo is not a risk, since there is no exposure” (EC 2016). EPA risk assessment evaluates potential harm to humans, wildlife, fish and plants, and potential contamination of surface or ground water.
The human health risk assessment process includes four steps:
Step1: hazard identification
Step 2: dose–response assessment
Step 3: exposure assessment
Step 4: risk characterization
Multiple lines of evidence are brought together to determine the hazard, and to estimate the current and potential exposure scenarios and consequences – i.e. risks – of the exposure to the active substance or plant protection product.
EPA starts the risk assessment process with a detailed plan defining the purpose, scope and technical approaches to be used. EPA has a systematic review process with increased transparency and decisions published on public dockets, allowing the public to comment on its decisions.
With such specific requirements and processes in place, it is worth partnering with an experienced regulatory consultant who understands the implications of the way EPA has interpreted data in past decision making and who can develop innovative regulatory strategies. EPA itself encourages collaboration with an experienced regulatory consultant (EPA 2021). Furthermore, as non-US applicants must appoint a US-resident agent (EPA 2021), it makes sense to identify a partner that can fulfill both roles.
6: Leverage the opportunity for a pre-application meeting with EPA
Prior to a regulatory submission, you should consider having a pre-application meeting with EPA (sometimes referred to as a pre-submission meeting). This is a rich opportunity for in-depth discussion with EPA, confirming data and labeling requirements (see OPP Label Review Manual, 2021).
In particular, the pre-application meeting is essential for discussing the nature of the active substance and the implications for compiling a complete dataset. Use it to obtain EPA advice specific to your active substance:
- Discuss potential uses, efficacy, product chemistry, exposure profile and scenarios with proposed uses
- Agree how the potential use scenarios translate into different toxicological and exposure or residue data requirements, and identify data gaps
- Discuss tolerances and labeling requirements (see later)
- Agree on data waivers or bridging, and discuss data access from EPA records (and agree compensation for the originators of the data).
7: Gather the information EPA needs before and for the pre-application meeting
EPA has published guidance for pre-application meetings from the OPP. You will need to provide detailed information to obtain EPA’s agreement to a meeting, and then compile extensive data for the meeting. This should include searching public databases for material relevant to the substance. EPA publishes a list of US Government pesticide information resources, for example:
- EPA OPP Pesticide Chemical Search, which contains a broad array of published scientific and regulatory information on plant protection active substances
- Regulations.gov, which contains rulemaking and other pesticide dockets published by EPA
- National Pesticide Information Retrieval System, which contains searchable registered and cancelled product information, company and active substance information
- CompTox Chemicals Dashboard, which is EPA’s database on over 900,000 substances.
It is essential to be thorough when supplying information, so that EPA can ensure it brings the right experts to the pre-application meeting and avoids any chance of having to repeat the process and lose time. Similarly, it is important to line up your questions ahead of the meeting to maximize its impact on the subsequent process of making the registration application.
8: Consider whether you should apply for reduced risk status for your active substance
EPA has a conventional reduced risk pesticide (CRRP) program. This aims to expedite the review and regulatory decisions on conventional pesticides that can be demonstrated to pose less risk to human health and the environment compared to others in the market. EPA’s aim with the CRRP program is to expedite the process of getting low-risk pesticides to growers.
There are many advantages to having CRR status, both at federal and state level (see Box 1). Moreover, having it may help expedite the registrations in other, developing geographies.
To obtain reduced risk status, it will be important to understand your active substance and to compare its profile with other products in the market (both active substances and end-use products) against the criteria developed by EPA. Successful applications require a good understanding of how EPA reviews the applications and of the relevant data points to bring forth against cut-off criteria that are applied on a case-by-case basis and are not clearly defined or knowable in advance.
Box 1: Advantages of reduced risk status for an active substance
|– Expedited decision timeframe under PRIA and the North American Free Trade Agreement Technical Working Group on Pesticides joint review process|
– Opportunity for expedited establishment of maximum residue limits by the Codex Alimentarius Commission
– Marketing advantage: reduced risk claims aren’t included on labels but CRR status is used to marketing advantage
– End-user preference for crops treated with reduced risk pesticide products
– Expedited decision timeframe by California Department of Pesticide Registration
9: Plan the next steps if EPA’s regulatory determination is a conditional registration
EPA may grant conditional registration for a new active ingredient, allowing it to be marketed and used while you obtain further data. Conditional registration can be granted if the application is for use on a major crop, or for a minor crop without a suitable pesticide, and provided use of the pesticide would not significantly increase the risk of unreasonable adverse effects on people or the environment.
A conditional registration is time limited, based on the time needed for generating the data. EPA’s published list of conditional registrations from 2000 to 2021 shows that time limits are commonly 1–2 years. The data requests are often very specific, e.g. inhalation toxicity in a specific species, and range from a single test to multiple studies.
EPA’s approach to tracking conditional registrations is under review and it may be worth consulting a regulatory expert to predict what your obligations will be.
10: Apply for registration with individual states
Following EPA approval, active substances must be registered in each state and territory where your active substance will be marketed or used. Legislation differs from state to state and in the five US territories, because regional differences in climate and farming methods affect exposure, residue levels and environmental fate. All state and territorial pesticide agencies are listed by the National Pesticide Information Center, with links to each agency.
On submission to EPA, we suggest you apply to California Department of Pesticide Regulation (DPR) because it has the most exacting registration process and has different and often more strict data requirements compared with other states or the federal government. There is also emphasis on transparency and labeling with respect to the chemicals that are known to cause cancer, birth defects, or other reproductive effects under Safe Drinking Water and Toxic Enforcement Act, also known as Proposition 65, carried out by the Office of Environmental Health Hazard Assessment (OEHHA).
To optimize the chance of successfully registering your new active substance with EPA, you will need a deep understanding of EPA’s processes and how it uses data to reach decisions. You will also need to keep abreast of developments that may occur under a new administration, as well as ongoing evolution of requirements (e.g. crop grouping is currently in revision).
If you are looking for regulatory science expertise to smooth the journey to the US market for your active substance or to re-registration of an existing substance, consider us your source. Our dedicated North American team will bring decades of experience of providing high-quality scientific and regulatory consulting services to your decisions on data requirements and regulatory strategies. Let our experts support you as your active substance navigates the regulatory pathway to successful EPA registration.
EC (European Commission). Frequently asked questions: endocrine disruptors. 15 June 2016. https://ec.europa.eu/commission/presscorner/detail/en/MEMO_16_2151
EPA (Environmental Protection Agency). How to Register a Pesticide Product – A Guide for Applicants New to the Process. Office of Pesticide Programs, Office of Chemical Safety and Pollution Prevention, United States Environmental Protection Agency, January 15, 2021. https://www.epa.gov/pesticide-registration/how-register-pesticide-guide-applicants-new-process
EPA (Environmental Protection Agency). Pesticide Registration Manual. https://www.epa.gov/pesticide-registration/pesticide-registration-manual
OPP (Office of Pesticide Programs). Label Review Manual. Updated January 2021. https://www.epa.gov/sites/default/files/2021-02/documents/full-lrm_2-22-21.pdf