EPA Issues Final Rule Intended to Accelerate Use of Plant-Incorporated Biotechnologies
On May 31, 2023, the U.S. Environmental Protection Agency (EPA) issued a final rule that exempts a class of plant-incorporated protectants (PIP) created using genetic engineering from registration requirements under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and from the food or feed residue tolerance requirements under the Federal Food, Drug, and Cosmetic Act (FFDCA). 88 Fed. Reg. 34756. EPA states that the final rule includes exemptions as described in its October 2020 proposal for PIPs, now termed “PIPs created through genetic engineering from a sexually compatible plant” and “loss-of-function PIPs.” It also includes the process through which EPA determines their eligibility for exemption and the associated recordkeeping requirements. According to EPA, the exemptions reflect the biotechnological advances made since 2001, when EPA first exempted PIPs derived through conventional breeding and excluded from the exemptions those PIPs created through biotechnology. EPA notes that it anticipates that the exemptions will benefit the public by ensuring that human health and the environment are adequately protected while also reducing the regulatory burden for the regulated community. These exemptions may also result in increased research and development (R&D) activities, commercialization of new pest control options for farmers, particularly in minor crops, and increase the diversity of options for pest and disease management, which could provide environmental benefits. The final rule will be effective on July 31, 2023.
Summary of the Proposed Rule
On October 9, 2020, EPA proposed an exemption under FIFRA and the FFDCA for certain PIPs that are created in plants using biotechnology. 85 Fed. Reg. 64308. EPA proposed to:
- Exempt “plant-incorporated protectants based on sexually compatible plants created through biotechnology” (40 C.F.R. Section 174.26) from the requirement of a tolerance under FFDCA and from certain registration requirements under FIFRA, except for the following requirements:
- A proposed requirement of recordkeeping (40 C.F.R. Section 174.73);
- A proposed eligibility determination process (40 C.F.R. Part 174, Subpart E); and
- The existing adverse effects reporting requirement for exempt PIPs (40 C.F.R. Section 174.71);
- Clarify the general qualifications for exemption for PIPs at 40 C.F.R. Section 174.21;
- Clarify how the proposed exemption relates to the existing exemption for PIPs derived from sexually compatible plants at 40 C.F.R. Section 174.25; and
- Allow the existing inert ingredient exemption at 40 C.F.R. Section 174.705 to include biotechnology.
According to EPA, the proposed rule explained the proposed exemption for “PIPs based on sexually compatible plants created through biotechnology,” detailed the rationale underlying that proposal, described associated definitions that were proposed for codification or amendment, and also described the two primary considerations that EPA believed together would constitute the basis for meeting the FIFRA Section 25(b)(2) standard for exemption (the pesticidal substance is found in plants that are sexually compatible with the recipient plant; and limitations on the expression profile). The proposed rule also described the details of the proposed eligibility determination process and included a proposed recordkeeping requirement for exempted PIPs listed under 40 C.F.R. Section 174.21(d).
EPA states that in addition, it proposed edits to 40 C.F.R. Section 174.21 to clarify the applicability of this framework to other PIP exemptions and proposed to clarify the relationship between the proposal on “PIPs based on sexually compatible plants created through biotechnology” and the exemptions currently at 40 C.F.R. Section 174.25, “Plant-incorporated protectant from sexually compatible plant,” and 40 C.F.R. Section 174.508, “Pesticidal substance from sexually compatible plant; exemption from the requirement of a tolerance.” EPA also proposed to allow the existing inert ingredient exemption at 40 C.F.R. Section 174.705 to include inert ingredients created using biotechnology so long as they still meet the existing criteria.
Summary of the Final Rule
Exemption for “PIPs Created Through Genetic Engineering from a Sexually Compatible Plant”
The final rule includes an exemption for a category of “PIPs created through genetic engineering from a sexually compatible plant.” This category is exempt from all FIFRA requirements, except for the adverse effects reporting requirements at 40 C.F.R. Section 174.71, the recordkeeping requirements at 40 C.F.R. Section 174.73 (as specified in 40 C.F.R. Section 174.21(d)), and the eligibility determination process outlined in Subpart E. In the proposed rule, EPA termed PIPs described under 40 C.F.R. Section 174.26 as “PIPs based on sexually compatible plants created through biotechnology.” In the final rule, EPA has updated the name of the PIPs described under 40 C.F.R. Section 174.26 to “PIPs created through genetic engineering from a sexually compatible plant” based on public comment.
Exemption of “Loss-of-Function PIPs”
The final rule exempts “loss-of-function PIPs” from all FIFRA requirements, except for the adverse effects reporting requirements at 40 C.F.R. Section 174.71, the recordkeeping requirements at Section 174.73 (as specified in 40 C.F.R. Section 174.21(d)), and the eligibility determination process outlined in Subpart E. According to EPA, the exempt PIPs represent a subcategory of PIPs described in the proposed rule. In the final rule, EPA creates a separate exemption for “loss-of-function PIPs,” which allows it to create criteria specific to these types of PIPs and an accompanying definition for increased clarity. EPA states that it made this change in response to comments that indicated the need for greater clarity and the broadening of the exemption text related to “loss-of-function PIPs” regarding the identicality of the substance. EPA notes that the modified genetic material of a “loss-of-function PIP” constitutes both the pesticidal substance and the active ingredient. The language describing the exemption appears in 40 C.F.R. Section 174.27.
Eligibility Determination Process
The final rule includes a Subpart E that describes the eligibility determination process and documentation required for an exemption of certain PIPs. Specifically, according to EPA, for a PIP listed under 40 C.F.R. Section 174.21(d) to be eligible for exemption, an exemption eligibility determination must be completed prior to engaging in FIFRA-regulated activities. EPA states that it “agrees with commenters arguing that requiring an eligibility determination will provide additional clarity to developers of PIP products under certain circumstances and increase transparency and public trust in products containing these PIPs.” EPA notes that the primary difference between the proposed and final rule is the restriction of the self-determination option to only certain PIPs exempted by this rulemaking. In the proposed rule, all exempted PIPs had the option of self-determination. In the final rule, only developers of “loss-of-function PIPs” (40 C.F.R. Section 174.27) currently have the option to self-determine whether the exemption criteria are met, however. To that end, EPA made modifications to proposed 40 C.F.R. Sections 174.90, 174.91, and 174.93. In addition, EPA made minor revisions to the titles of these three subsections from the proposed rule for clarity.
EPA states that “[g]iven the straightforward criteria describing ‘loss-of-function PIPs’ (i.e., a focus on function rather than source plant or underlying sequence), EPA believes it is appropriate for ‘loss-of-function PIPs’ to be eligible for the self-determination option as it is unlikely for a developer to accidentally misdetermine exemption eligibility of these PIPs.” Additionally, according to EPA, the mode of action of “loss-of-function PIPs” (i.e., reduction or elimination of an endogenous gene) is fundamentally different from “PIPs created through genetic engineering from a sexually compatible plant” (e.g., intentional production of a pesticidal protein), and as such, further lends itself to the availability of a self-determination option. EPA notes that although “PIPs created through genetic engineering from a sexually compatible plant” are not currently eligible for the self-determination option, “EPA intends to reconsider this in future rulemakings.”
EPA states that a separate determination of eligibility of exemption for purposes of the FFDCA exemption for a PIP proposed for use in food or feed is required only if that determination has not already been submitted under FIFRA. This is because the exemption eligibility determination process described in 40 C.F.R. Section 174.21 already requires the applicant to certify that the PIP meets the general qualifications for exemption, which includes exemption under the FFDCA for PIPs used in food or feed. According to EPA, a scenario in which a developer will need an exemption eligibility determination specifically for the purposes of FFDCA, but not FIFRA, would be when residues of a PIP are in or on food imported into the United States, but the PIP is not intended to be sold or distributed for pesticidal use (e.g., PIP-containing seed or plant sold for planting) in the United States (and thus is not subject to FIFRA regulation).
Recordkeeping Requirements for PIPs Exempt by This Rulemaking
At 40 C.F.R. Section 174.73, Subpart D, EPA is codifying a requirement under FIFRA Section 3(a) that any person who is required to submit documentation for the eligibility determination of a PIP under 40 C.F.R. Section 174.21(d) must maintain documentation of either the request for EPA confirmation or the letter of self-determination (or both, if applicable), as well as all supporting documentation for the specific exemption, as specified in Subpart E. EPA notes that these documents must be maintained for five years starting with the effective date of the exemption. According to EPA, this text is minorly revised from the proposed text for clarity.
Clarification of General Qualifications for Exemption
EPA notes that the rule includes final edits to the “General Qualifications for Exemptions” provisions at 40 C.F.R. Section 174.21 to clarify the applicability of this framework to other PIP exemptions. For paragraph (a), the revision simply clarifies that this paragraph is specific to the active ingredient of the PIP, rather than the PIP as a whole. According to EPA, this is because the definition of a PIP under 40 C.F.R. Section 174.3 also includes “any inert ingredient,” and inert ingredients are not exempt under Subpart B but rather Subpart X. In the proposed rule, EPA used the phrase “pesticidal substance” in its proposed revisions to 40 C.F.R. Section 174.21(a), while in the final rule, EPA uses the phrase “active ingredient.” EPA states that the active ingredient definition at 40 C.F.R. Section 174.3 includes both the genetic material and any pesticidal substance produced (e.g., a protein). Exemption criteria related to both the genetic material and the pesticidal substance are specified in exemptions under Subpart B. As such, the titles for the exemptions in Subpart B are similarly codified to specify “active ingredient.”
The final rule revises paragraph (b) to refer to Subpart W rather than the specific sections and to specify that the tolerance exemptions apply to the residues of the active ingredient, rather than the PIP as a whole for the same rationale as outlined for the edit to 40 C.F.R. Section 174.21(a). EPA notes that although paragraph (b) specifies active ingredient, there are separate tolerance exemptions specific to both the residues of the pesticidal substance (e.g., 40 C.F.R. Section 174.541) and the genetic material (i.e., 40 C.F.R. Section 174.507) under Subpart W.
The final rule revises paragraph (c) to refer to Subpart X, rather than the specific section of 40 C.F.R. Section 174.705.
The final rule also includes a new paragraph (d) in 40 C.F.R. Section 174.21 to accommodate the exemption eligibility determination process and the recordkeeping requirements. EPA states that this paragraph specifies that for PIPs listed in the subsequent subparagraphs, the exemption is contingent upon compliance with recordkeeping requirements and the eligibility determination process. According to EPA, the addition of paragraph (d) does not impact the exemption under 40 C.F.R. Section 174.25 for PIPs from sexually compatible plants through conventional breeding, as this exemption is not identified in paragraph (d). EPA notes that it made two revisions to 40 C.F.R. Section 174.21(d) since it issued the proposed rule. First, EPA added a clarification that 40 C.F.R. Section 174.73 is implemented “per sections 8 and 9 of FIFRA (U.S.C. §§ 136f and 136g).” EPA notes that those sections of FIFRA specify EPA’s inspection authority and impose recordkeeping requirements and that they still apply to the PIPs exempted under this rule. Secondly, “[Reserved]” was moved to 40 C.F.R. Section 174.21(d)(3) and replaced in its proposed position at 40 C.F.R. Section 174.21(d)(2) with “Loss-of-function plant-incorporated protectants” to accommodate the newly created exemption for these types of PIPs at 40 C.F.R. Section 174.27.
Clarification of the Exemption for Sexually Compatible PIPs
The final rule clarifies the relationship between the newly exempted “PIPs created through genetic engineering from a sexually compatible plant” and “loss-of-function PIPs” with the previous FIFRA and FFDCA exemptions related to conventionally bred plants (i.e., 40 C.F.R. Sections 174.25 and 174.508). EPA inserted “created through conventional breeding” at the end of each section title and inserted an additional criterion into 40 C.F.R. Sections 174.25 and 174.508, stating that the genetic material is transferred only through conventional breeding. According to EPA, the exemptions at 40 C.F.R. Sections 174.25 and 174.508 “have always meant ‘only through conventional breeding,’ but this clarification is necessary given the amended definition for ‘sexually compatible.’”
Inert Ingredient Exemption Includes Genetic Engineering
EPA notes that while it revised 40 C.F.R. Sections 174.25 and 174.508 to include a criterion specifying that the genetic material is transferred from the source plant to the recipient plant only through conventional breeding, it did not propose or adopt a parallel revision at 40 C.F.R. Section 174.705.
EPA states that the amended definition for “sexually compatible” states that “plants must be capable of forming a viable zygote through the union of two gametes through conventional breeding” (emphasis added), which differs from the definition promulgated in 2001 that specified that “a viable zygote is formed only through the union of two gametes through conventional breeding” (emphasis added). The amendment of the “sexually compatible” definition therefore removes the criterion that the gamete formation may only occur through conventional breeding, which would otherwise preclude the use of genetic engineering to create PIPs that are exempt even if those PIPs are moved between sexually compatible plants. EPA states that because it is not adding an additional conventional breeding criterion to 40 C.F.R. Section 174.705, as it is for 40 C.F.R. Sections 174.25 and 174.508, the inert ingredient exemption at 40 C.F.R. Section 174.705 is no longer bound by conventional breeding and therefore allows for the exemption of inert ingredients that are initiated through biotechnology, so long as they still meet the existing criteria of that section.
This final rule reflects the next step EPA’s Office of Pesticide Programs (OPP) is taking on the path of regulation of biotechnology pesticide products. It sets forth how OPP will address products created by “Clustered Regularly Interspaced Short Palindromic Repeats” (CRISPR). In more general terms, CRISPR refers to manipulating plant genes with a method that was not available at the time the first biotechnology regulations were developed by EPA in the mid-1990s. This is why EPA needs to “update” its regulations, which is the purpose of the final rule.
Proponents of biotechnology methods argue that CRISPR allows the genes of plants to be manipulated more precisely and can be used “simply” to drop out a gene or add one from the same — sexually compatible — genome of the target plant. It follows that this is much like “traditional plant breeding,” only done more precisely and more rapidly. Critics will likely question whether any product using this method, and not using traditional methods, might have some kind of unexpected result or unintended consequence. Also expected are adverse comments regarding these products, even though EPA (among many others) lays out a rationale that this is an extension of its current regulations exempting products of traditional plant breeding from regulation under FIFRA and FFDCA (and not exempting such products from other regulatory authorities).
There also were concerns raised in comments submitted in response to the October 9, 2020, proposed rule. Some in industry remain concerned that the final rule creates differential treatment for products due solely to the methods of development (i.e., biotechnology vs. conventional), thus subjecting products created using biotechnology to additional regulatory and recordkeeping requirements, even in cases when those products could have been created using older R&D approaches.
EPA’s basic requirements for biotechnology products that regulate interspecies gene manipulation would not change. Also worth noting is that the rule also would allow a developer to submit the product for EPA review to affirm that it qualifies for the exemption (i.e., an M009 Pesticide Registration Improvement Act (PRIA) action, which can lead to EPA delays in processing). The EPA docket includes a slide deck with a helpful summary of the final rule and its rationale.