37830 Federal Register / Vol. 66, No. 139 / Thursday, July 19, 2001 / Rules and Regulations
Indian Tribal Governments (63 FR expected to affect energy supply, ENVIRONMENTAL PROTECTION 27655, May 19, 1998), do not apply to distribution, or use. AGENCY this rule. Executive Order 13175, entitled Consultation and Coordination XII. Submission to Congress and the 40 CFR Part 174 with Indian Tribal Governments (65 FR Comptroller General [OPP–300368B; FRL–6057–6] 67249, November 6, 2000), which took The Congressional Review Act, 5 effect on January 6, 2001, revokes U.S.C. 801 et seq., as added by the Small RIN 2070–AC02 Executive Order 13084 as of that date. Business Regulatory Enforcement EPA developed this rulemaking, Exemption From the Requirement of a Fairness Act of 1996, generally provides however, during the period when Tolerance Under the Federal Food, that before a rule may take effect, the Executive Order 13084 was in effect; Drug, and Cosmetic Act for Residues thus, EPA addressed tribal agency promulgating the rule must Derived Through Conventional considerations under Executive Order submit a rule report, which includes a Breeding From Sexually Compatible 13084. For the same reasons stated for copy of the rule, to each House of the Plants of Plant-Incorporated Executive Order 13084, the Congress and to the Comptroller General Protectants (Formerly Plant- requirements of Executive Order 13175 of the United States. EPA will submit a Pesticides) do not apply to this rule either. For the report containing this rule and other same reasons, this rule does not have required information to the U.S. Senate, AGENCY: Environmental Protection any substantial direct effect on States, the U.S. House of Representatives, and Agency (EPA). on the relationship between the national the Comptroller General of the United ACTION: Final rule. government and the States, or on the States prior to publication of this final distribution of power and rule in the Federal Register. This final SUMMARY: The substances plants responsibilities among the various rule is not a ‘‘major rule’’ as defined by produce for protection against pests, and the genetic material necessary to levels of government, as specified in 5 U.S.C. 804(2). Executive Order 13132, entitled produce these substances, are pesticides Federalism (64 FR 43255, August 10, List of Subjects in 40 CFR Part 174 under the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), if humans 1999). This rule directly regulates Environmental protection, growers, food processors, food handlers intend to use these substances for Administrative practice and procedure, ‘‘preventing, destroying, repelling or and food retailers, not States. This Agricultural commodities, Pesticides action does not alter the relationships or mitigating any pest.’’ These substances, and pests, Plants, Reporting and distribution of power and produced and used in living plants, recordkeeping requirements. responsibilities established by Congress along with the genetic material necessary to produce them, are also in the preemption provisions of FFDCA Dated: July 12, 2001. section 408(n)(4). ‘‘pesticide chemical residues’’ under the Christine T. Whitman, Federal Food, Drug, and Cosmetic Act Pursuant to section 605(b) of the (FFDCA). EPA calls these substances, Regulatory Flexibility Act (RFA) (5 Administrator. along with the genetic material U.S.C. 601 et seq.), the Agency hereby Therefore, 40 CFR chapter I is necessary to produce them, plant- certifies that this final rule will not have amended as follows: incorporated protectants. In this final a significant economic impact on a rule, EPA exempts from the FFDCA substantial number of small entities. PART 174—[AMENDED] section 408 requirement of a tolerance, The Agency’s determination is based on residues of the pesticidal substance the fact that an exemption from the 1. The authority citation for part 174 portion and residues of any inert requirement of a tolerance under continues to read as follows: ingredient of any plant-incorporated FFDCA section 408, such as that protectant derived through conventional contained in this rule, will not Authority: 7 U.S.C. 136–136y and 21 breeding from a plant sexually adversely affect any small businesses. U.S.C. 346a and 371. compatible with the recipient food Additional information about the plant. EPA has determined that there is Agency’s determination may be found 2. Section 174.475 is added to subpart a reasonable certainty that no harm will in the small entity impact analysis W to read as follows: result from aggregate exposure to these prepared as part of the economic § 174.475 Nucleic acids that are part of a residues. analysis for the FIFRA rulemaking, plant-incorporated protectant; exemption DATES: This rule is effective September which is available in the public version from the requirement of a tolerance. of the official record (Ref. 25). The 17, 2001. Objections and requests for Agency has also previously assessed Residues of nucleic acids that are part hearings must be received by EPA on or whether establishing tolerances, of a plant-incorporated protectant are before September 17, 2001. exemptions from tolerances, raising exempt from the requirement of a ADDRESSES: Objections and hearing tolerance levels or expanding tolerance. requests may be submitted by regular mail, electronically, or in person. Please exemptions might adversely impact [FR Doc. 01–17982 Filed 7–16–01; 11:45 am] small entities and concluded, as a follow the detailed instructions for each general matter, that there is no adverse BILLING CODE 6560–50–S method as provided in Unit II. of the economic impact associated with these SUPPLEMENTARY INFORMATION. actions. See 46 FR 24950, May 4, 1981. FOR FURTHER INFORMATION CONTACT: By This rule is not subject to Executive mail: Philip Hutton, Biopesticides and Order 13211, entitled Actions Pollution Prevention Division, Office of Concerning Regulations That Pesticide Programs (7511C), Significantly Affect Energy Supply, Environmental Protection Agency, 1200 Distribution, or Use (66 FR 28355, May Pennsylvania Ave., NW., Washington 22, 2001), because this action is not DC 20460; telephone number: (703)
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308–8260; e-mail address: I. General Information biotechnology that may develop and [email protected]. A. Does this Document Apply to Me? market plant-incorporated protectants. Potentially affected categories and SUPPLEMENTARY INFORMATION: You may be potentially affected by entities may include, but are not limited this action if you are a person or to: company involved with agricultural
Categories NAICS codes Examples of potentially affected entities
Pesticide manufacturers 32532 Establishments primarily engaged in the formulation and preparation of agricultural and household pest control chemicals
Seed companies 111 Establishments primarily engaged in growing crops, plants, vines, or trees and their seeds
Colleges, universities, and professional schools 611310 Establishments of higher learning which are engaged in de- velopment and marketing of plant-incorporated protectants
Establishments involved in research and development in the 54171 Establishments primarily engaged in conducting research in life sciences the physical, engineering, or life sciences, such as agri- culture and biotechnology
This listing is not intended to be 2. In person. The Agency has submitted for inclusion in the public exhaustive, but rather provides a guide established an official record for this version of the official record. for readers regarding entities likely to be action under the docket control number Information not marked confidential affected by this action. Other types of OPP–300368B. The official record will be included in the public version entities not listed above could also be consists of the documents specifically of the official record without prior affected. The North American Industrial referenced in this action, any public notice. If you have any questions about Classification System (NAIC) codes have comments received during an applicable CBI or the procedures for claiming CBI, been provided to assist you and others comment period, and other information please consult the person listed under in determining whether or not this related to this action, including any FOR FURTHER INFORMATION CONTACT. action might apply to certain entities. information claimed as Confidential II. Objections and Hearing Requests To determine whether you or your Business Information (CBI). This official business may be affected by this action, record includes the documents that are Under section 408(g) of the FFDCA, as you should carefully examine the physically located in the docket, as well amended by the Food Quality Protection applicable provisions of part 174 in title as the documents that are referenced in Act (FQPA), any person may file an 40 of the Code of Federal Regulations those documents. The public version of objection to any aspect of this regulation (CFR). If you should have any questions the official record, which includes and may also request a hearing on those regarding the applicability of this action printed, paper versions of any electronic objections. The EPA procedural to a particular entity, consult the comments submitted during an regulations which govern the technical person listed in the FOR applicable comment period, is available submission of objections and requests FURTHER INFORMATION CONTACT. for inspection in the Public Information for hearings appear in 40 CFR part 178. and Record Integrity Branch (PIRIB), Although the procedures in those B. How Can I Get Additional Rm. 119, Crystal Mall #2, 1921 Jefferson regulations require some modification to Information , Including Copies of This Davis Highway, Arlington, VA, from reflect the amendments made to the Document and Other Related 8:30 a.m. to 4 p.m., Monday through FFDCA by the FQPA of 1996, EPA will Documents? Friday, excluding legal holidays. The continue to use those procedures, with 1. Electronically.You may obtain PIRIB telephone number is (703) 305– appropriate adjustments, until the electronic copies of this document, and 5805. necessary modifications can be made. The new section 408(g) provides certain other related documents that C. How Should I Handle CBI that I Want essentially the same process for persons might be available electronically, from to Submit to the Agency? the EPA Internet Home Page at http:// to ‘‘object’’ to a regulation for an www.epa.gov/. To access this Do not submit any information exemption from the requirement of a document, on the Home Page select electronically that you consider to be tolerance issued by EPA under new ‘‘Laws and Regulations,’’ ‘‘Regulations CBI. You may claim information that section 408(d), as was provided in the and Proposed Rules,’’ and then look up you submit to EPA in response to this old FFDCA sections 408 and 409. the entry for this document under the document as CBI by marking any part or However, the period for filing objections ‘‘Federal Register—Environmental all of that information as CBI. is now 60 days, rather than 30 days. Documents.’’ You can also go directly to Information so marked will not be A. What Do I Need to Do to File an theFederal Register listings at http:// disclosed except in accordance with Objection or Request a Hearing? www.epa.gov/fedrgstr/. To access procedures set forth in 40 CFR part 2. information about the EPA’s program for In addition to one complete version of You must file your objection or biopesticides go directly to the Home the comment that includes any request a hearing on this regulation in Page for the Office of Pesticide Programs information claimed as CBI, a copy of accordance with the instructions at http://www.epa.gov/pesticides/ the comment that does not contain the provided in this unit and in 40 CFR part biopesticides. information claimed as CBI must be 178. To ensure proper receipt by EPA,
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you must identify docket control Protection Agency, 1200 Pennsylvania from the requirement of a tolerance for number OPP–300368B in the subject Ave., NW., Washington, DC 20460. such residues. Food includes articles line on the first page of your If you would like to request a waiver used for food or drink by humans or submission. All requests must be in of the tolerance objection fees, you must other animals. A food containing writing, and must be mailed or mail your request for such a waiver to: pesticide residues may not be moved in delivered to the Hearing Clerk on or James Hollins, Information Resources interstate commerce without an before September 17, 2001. and Services Division (7502C), Office of appropriate tolerance or an exemption 1. Filing the request. Your objection Pesticide Programs, Environmental from the requirement of a tolerance. must specify the specific provisions in Protection Agency, 1200 Pennsylvania Section 408 of the FFDCA applies to the regulation that you object to, and the Ave., NW., Washington, DC 20460. all ‘‘pesticide chemical residues ’’ grounds for the objections (40 CFR 3. Copies for the docket. In addition which are defined as residues of either 178.25). If a hearing is requested, the to filing an objection or hearing request a ‘‘pesticide chemical’’ or ‘‘any other objections must include a statement of with the Hearing Clerk as described in added substance that is present on or in the factual issues(s) on which a hearing Unit II., you should also send a copy of a commodity or food primarily as a is requested, the requestor’s contentions your request to the PIRIB for its result of the metabolism or other on such issues, and a summary of any inclusion in the official record that is degradation of a pesticide chemical’’ (21 evidence relied upon by the objector (40 described in Unit I.B.2. Mail your U.S.C. 321(q)(2)). The FFDCA defines CFR 178.27). Information submitted in copies, identified by docket control ‘‘pesticide chemical’’ as: ‘‘any substance connection with an objection or hearing number OPP–300368B, to: Public that is a pesticide within the meaning of request may be claimed confidential by Information and Records Integrity the Federal Insecticide, Fungicide, and marking any part or all of that Branch, Information Resources and Rodenticide Act, including all active information as CBI. Information so Services Division (7502C), Office of and inert ingredients of such pesticide.’’ marked will not be disclosed except in Pesticide Programs, Environmental (21 U.S.C. 321(q)(1)). FIFRA section 2(u) accordance with procedures set forth in Protection Agency, 1200 Pennsylvania defines ‘‘pesticide’’ as: ‘‘(1) any 40 CFR part 2. A copy of the Ave., NW., Washington, DC 20460. In substance or mixture of substances information that does not contain CBI person or by courier, bring a copy to the intended for preventing, destroying, location of the PIRIB described in Unit must be submitted for inclusion in the repelling, or mitigating any pest, (2) any I.B.2. You may also send an electronic public record. Information not marked substance or mixture of substances copy of your request via e-mail to: opp- confidential will be included in the intended for use as a plant regulator, [email protected]. Please use an ASCII public version of the official record defoliant, or desiccant, and (3) any file format and avoid the use of special without prior notice. nitrogen stabilizer’’ (7 U.S.C. 136(u)). characters and any form of encryption. Under FIFRA section 2(t), the term Mail your written request to: Office of Copies of electronic objections and ‘‘pest’’ includes ‘‘(1) any insect, rodent, the Hearing Clerk (1900), Environmental hearing requests will also be accepted nematode, fungus, weed, or (2) any Protection Agency, 1200 Pennsylvania on disks in WordPerfect 6.1/8.0 file other form of terrestrial or aquatic plant Ave., NW., Washington, DC 20460. You format or ASCII file format. Do not or animal life or virus, bacteria, or other may also deliver your request to the include any CBI in your electronic copy. microorganism’’ with certain exceptions Office of the Hearing Clerk in Rm. C400, You may also submit an electronic copy (7 U.S.C. 136(t)). Waterside Mall, 401 M St., SW., of your request at many Federal Under FFDCA section 408(c), EPA can Washington, DC 20460. The Office of Depository Libraries. establish an exemption from the the Hearing Clerk is open from 8 a.m. requirement of a tolerance for a to 4 p.m., Monday through Friday, B. When Will the Agency Grant a ‘‘pesticide chemical residue’’ only if excluding legal holidays. The telephone Request for a Hearing? EPA determines that granting such an number for the Office of the Hearing A request for a hearing will be granted exemption is ‘‘safe’’ (21 U.S.C. Clerk is (202) 260–4865. if the Administrator determines that the 346a(c)(2)(A)(i)). The FFDCA defines 2. Tolerance fee payment. If you file material submitted shows the following: ‘‘safe’’ to mean that ‘‘there is a an objection or request a hearing, you There is a genuine and substantial issue reasonable certainty that no harm will must also pay the fee prescribed by 40 of fact; there is a reasonable possibility result from aggregate exposure to the CFR 180.33(i) or request a waiver of that that available evidence identified by the pesticide chemical residue, including fee pursuant to 40 CFR 180.33(m). You requestor would, if established resolve all anticipated dietary exposures and all must mail the fee to: EPA Headquarters one or more of such issues in favor of other exposures for which there is Accounting Operations Branch, Office the requestor, taking into account reliable information’’ (21 U.S.C. of Pesticide Programs, P.O. Box uncontested claims or facts to the 346a(c)(2)(A)(ii)). This includes 360277M, Pittsburgh, PA 15251. Please contrary; and resolution of the factual exposure through drinking water, and identify the fee submission by labeling issues(s) in the manner sought by the residential and other indoor uses, but it ‘‘Tolerance Petition Fees.’’ requestor would be adequate to justify does not include occupational exposure. EPA is authorized to waive any fee the action requested (40 CFR 178.32). In establishing an exemption from the requirement ‘‘when in the judgement of requirement of a tolerance, FFDCA the Administrator such a waiver or III. Under What Authority Is EPA section 408(c) does not authorize EPA to refund is equitable and not contrary to Issuing this Final Rule? consider potential benefits associated the purpose of this subsection.’’ For This exemption from the requirement with use of the pesticide chemical in additional information regarding the of a tolerance is being issued under the determining whether the pesticide waiver of these fees, you may contact authority of section 408(c) of the FFDCA chemical may be exempted. James Tompkins by phone at (703) 305– (21 U.S.C. 346a(c)). Under FFDCA FFDCA section 408 requires EPA to 5697, by e-mail at section 408, EPA regulates pesticide give special consideration to exposure [email protected], or by mailing a chemical residues by establishing of infants and children to the pesticide request for information to Mr. Tompkins tolerances limiting the amounts of chemical residue in establishing an at Registration Division (7505C), Office residues that may be present in or on exemption and to ‘‘ensure that there is of Pesticide Programs, Environmental food, or by establishing exemptions a reasonable certainty that no harm will
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result to infants and children from that have toxic properties, or the recipient plant, and residues of any aggregate exposure to the pesticide production of specific toxic substances inert ingredient introduced through chemical residue’’ (21 U.S.C. in response to pest attack. In breeding conventional breeding from plants 346a(b)(2)(C)(ii)(I)) and (c)(2)(B)). plant varieties, humans have frequently sexually compatible with the recipient FFDCA section 408(b)(2)(D) specifies intentionally used these mechanisms to plant. For plant-incorporated other general factors EPA must consider create varieties with varying abilities to protectants, the recipient plant is the in establishing an exemption (21 U.S.C. prevent, destroy, repel or mitigate pests. living plant that receives the genetic 346a(b)(2)(D)). FFDCA section 408(c)(3) Based on human experience in material necessary to produce the prohibits an exemption unless there is breeding, growing, preparing, and pesticidal substance and in which the either a practical method for detecting consuming food from such plant plant-incorporated protectant is and measuring levels of pesticide varieties and the large and varied intended to be produced and used. chemical residue in or on food or there information developed through 2. How does this exemption relate to is no need for such a method, requiring systematic scientific study available in the exemption from the FFDCA EPA to state the reason for this the literature, EPA recognized that requirement of a tolerance for residues determination (21 U.S.C. 346a(c)(3)). residues of many plant-incorporated of nucleic acids? This exemption can be protectants, in or on food or feed, would paired with EPA’s tolerance exemption IV. Context qualify for exemption from regulation for residues of nucleic acids that are A. What Role Does this Exemption Play under FFDCA section 408. (Hereafter, part of a plant-incorporated protectant, in EPA’s Approach to Plant- EPA will use the term ‘‘in food’’ to published elsewhere in a companion Incorporated Protectants? represent the concept of ‘‘in or on food document in this issue of the Federal or feed’’ in this preamble). Register. That exemption applies to The substances plants produce for For EPA to exempt any residue of a residues of the genetic material portion protection against pests are pesticides pesticide, including any residue of a of all plant-incorporated protectants, under the FIFRA definition of pesticide, plant-incorporated protectant, EPA must and, thus, also applies to residues of the if humans intend to use these find that there is a reasonable certainty genetic material necessary for the substances for ‘‘preventing, destroying, that no harm will result from aggregate production of the pesticidal substance repelling or mitigating any pest.’’ These exposure to the residue, including all portion of plant-incorporated substances, produced and used in living anticipated dietary exposures and all protectants derived through plants, along with the genetic material other exposures for which there is conventional breeding from sexually necessary to produce them, are reliable information. EPA takes this compatible plants, and the residues of designated ‘‘plant-incorporated action today with regard to residues of the genetic material necessary for the protectants’’ by EPA. plant-incorporated protectants derived production of any inert ingredient To understand the role this exemption through conventional breeding from introduced through conventional plays in EPA’s approach to plant- sexually compatible plants because it breeding from plants sexually incorporated protectants, the following has determined that there is a compatible with the recipient plant. two considerations must be understood. reasonable certainty that no harm will Because of these actions, all residues of First, what constitutes the residues of result from aggregate exposure to the plant-incorporated protectants derived plant-incorporated protectants derived residues, including all anticipated through conventional breeding from through conventional breeding from dietary exposures and all other sexually compatible plants are exempt plants sexually compatible with the exposures for which there is reliable from FFDCA section 408 requirements. recipient plant and why EPA is information. exempting them from the requirement of Under FFDCA section 408, the term B. Does this Final Rule Have Any a tolerance. Second, how this exemption residue is defined broadly to include Relevance to Other Types of Pesticides? from the FFDCA requirement of a residues of the active and inert Nonviable plant tissues, organs or tolerance for residues of plant- ingredients of the pesticide itself and parts that are used as pesticides, will incorporated protectants derived residues that are present in the food as not be covered by this exemption. through conventional breeding from a result of the metabolism or other Residues of such pesticides are subject sexually compatible plants relates to the degradation of the pesticide (21 U.S.C. to the regulations found in 40 CFR parts exemption from the FFDCA requirement 321(q)). For plant-incorporated 177 through 180 rather than 40 CFR part of a tolerance published elsewhere in protectants derived through 174. An example of this type of this issue of the Federal Register for conventional breeding from sexually pesticide would be the powder, residues of nucleic acids that are part of compatible plants, EPA anticipates the produced by drying and grinding a plant-incorporated protectant. residues will consist of the pesticidal cayenne pepper, dusted on plants to 1. What constitutes the residues of substance and the genetic material protect them from pests. plant-incorporated protectants derived necessary for production of the Residues of substances that are through conventional breeding from pesticidal substance, and any substance isolated from a plant’s tissues and then sexually compatible plants and why is that might function as an inert applied to plants and/or to food for pest EPA exempting them? In developing its ingredient as defined for plant- control will not be covered by this approach to plant-incorporated incorporated protectants (e.g., any exemption. Residues of these types of protectants, EPA took into account the selectable marker), and the genetic pesticides in formulations such as those properties of pesticidal and other material necessary for production of the for foliar application are subject to substances produced and used in plants. inert ingredient. regulations found in 40 CFR parts 177 In particular, EPA recognized that This action exempts from the through 180 rather than 40 CFR part plants have evolved, and thus naturally requirement of a tolerance under 174. An example of this type of possess, various mechanisms to resist FFDCA section 408, residues of the pesticide would be pyrethrum isolated pests. The mechanisms of resistance can pesticidal substance portion of plant- from chrysanthemum plants, formulated be varied, including, for example, incorporated protectants derived with other ingredients for foliar structural characteristics of the plant, through conventional breeding from application, and sprayed onto other the production of general metabolites plants sexually compatible with the plants for pest control.
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Residues of substances that are FFDCA. Included in that package was a In the 1994 Federal Register synthesized will not be covered by this proposal to exempt from the FFDCA document, EPA presented two options exemption. Residues of such pesticides requirement of a tolerance, residues of for describing a standard based on the are subject to regulations found in 40 the pesticidal substance portion of relatedness of plants. Option 1, the CFR parts 177 through 180 rather than plant-pesticides derived from closely Agency’s preferred option proposed at 40 CFR part 174. An example of this related plants. 40 CFR 180.1137(a), used sexual type of pesticide is the herbicide, On July 22, 1996, EPA published a compatibility as a measure of atrazine. supplemental document in the Federal relatedness between plants. Under this Register (61 FR 27891) (FRL–5387–4) on option, residues of a pesticidal C. What Is the History of this Final Rule? one aspect of its November 23, 1994, substance produced in a living plant as This final rule is an additional step in Federal Register documents; i.e., how part of a plant-pesticide would be fully implementing the ‘‘Coordinated the concept of inert ingredient related to exempt from the requirement of a Framework for Regulation of plant-pesticides. tolerance if the genetic material that Biotechnology’’ of the United States of In August of 1996, Congress enacted encodes for the pesticidal substance or America which was published in the the FQPA which amended the FFDCA leads to the production of the pesticidal Federal Register by the Office of and FIFRA. On May 16, 1997, EPA substance is derived from a plant that is Science and Technology Policy (OSTP) published in the Federal Register a sexually compatible with the recipient on June 26, 1986 (51 FR 23302). supplemental document (62 FR 27132) plant and has never been derived from EPA sponsored, or co-sponsored with (FRL–5717–2) to provide the public a source that is not sexually compatible other Federal agencies, three with an opportunity to comment on with the recipient plant. conferences dealing with plant related EPA’s analysis of how certain FQPA Option 2 would utilize the rank of issues: On October 19–21, 1987, a amendments to the FFDCA and FIFRA genus as the taxonomic standard for meeting on‘‘Genetically Engineered apply to the proposed tolerance describing closely related plants, as well Plants: Regulatory Considerations’’ at exemption for pesticide chemical as sexual compatibility. This option Cornell University, Ithaca, New York; residues derived from closely related would exempt residues of a pesticidal on September 8–9, 1988, a ‘‘Transgenic plants. substance derived from a plant Plant Conference’’ in Annapolis, On April 23, 1999, EPA published a classified in the same genus as the Maryland; on November 6–7, 1990, a supplemental document (64 FR 19958) recipient plant, as well as residues of a conference on ‘‘Pesticidal Transgenic (FRL–6077–6) in the Federal Register pesticidal substance derived from a Plants: Product Development, Risk soliciting comment on whether to plant sexually compatible with the Assessment, and Data Needs’’ in change the name of this type of recipient plant. Under both Options 1 Annapolis, Maryland. Information from pesticide. and 2, residues of the pesticidal these conferences has been incorporated The documents and the reports of the substance derived from plants sexually as appropriate in development of this meetings described above are available compatible with the recipient plant final rule. in the record for the rulemaking for would be exempt, even if the source and In developing its approach to plant- plant-incorporated protectants as recipient plants are classified in incorporated protectants, EPA requested described in Unit X. different genera. the advice of two scientific advisory EPA proposed that ‘‘sexually groups at three meetings. On December V. What are the Key Features of the compatible,’’ when referring to plants, 18, 1992, pursuant to section 25 of Proposed Exemption? would mean ‘‘capable of forming a FIFRA, a subpanel of the FIFRA The development of this exemption viable zygote through the fusion of two Scientific Advisory Panel (SAP) was consists of a proposed rule which gametes, including the use of bridging convened to review a draft policy on appeared in the November 23, 1994, and/or wide crosses between plants.’’ plant-pesticides (now called plant- Federal Register (59 FR 60535), and two EPA proposed that ‘‘bridging crosses incorporated protectants) and to supplemental documents; one between plants’’ would mean the respond to a series of questions posed document that appeared on July 22, ‘‘utilization of an intermediate plant in by the Agency, primarily on EPA’s 1996, in the Federal Register (61 FR a cross between the intermediate plant approach under FIFRA. On July 13, 37891), and a second that appeared in and the first plant, in order to cross the 1993, EPA requested the advice of a the May 16, 1997, Federal Register (62 plant resulting from that zygote with a subcommittee of the EPA Biotechnology FR 27132). third plant that would not otherwise be Science Advisory Committee (BSAC) on able to produce viable zygotes from the A. November 23, 1994, Federal Register a series of scientific questions dealing fusion of its gametes with those of the Proposed Rule with EPA’s approach to plant-pesticides first plant. The result of the bridging under FFDCA. On January 21, 1994, a In the 1994 Federal Register cross is the mixing of the first and third joint meeting of the subpanel of the SAP document (59 FR 60535, November 23, plant through the formation of an and the BSAC subcommittee was held 1994), EPA proposed to exempt residues intermediate zygote.’’ EPA proposed and EPA asked advice on approaches to of a category of plant-pesticides it that ‘‘wide crosses between plants’’ plant-pesticides under both FIFRA and believed would qualify for an would mean ‘‘to facilitate the formation FFDCA. Advice from these scientific exemption. The proposed exemption of viable zygotes through the use of advisory groups was considered in was based upon the premise that new surgical alteration of the plant pistil, finalizing this rule. dietary exposures would not likely arise bud pollination, mentor pollen, EPA published in the November 23, for these residues if the genetic material immunosuppression, in vitro 1994, Federal Register a package of five leading to the production of the fertilization, pre-pollination and post- separate documents (59 FR 60496, pesticide chemical residues is derived pollination hormone treatments, 60519, 60535, 60542, 60545) (FRL– from a plant that is closely related to the manipulation of chromosome numbers, 4755–2, FRL–4755–3, FRL–4755–4, recipient plant; i.e., if the plant that is embryo culture, or ovary and ovule FRL–4755–5, FRL–4755–8) which the donor of the genetic material is cultures or any other technique that the described EPA’s policy and proposals closely related to the plant receiving the Administrator determines meets this for plant-pesticides under FIFRA and genetic material. definition.’’
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Neither of the options was intended to published in the Federal Register, a was given the opportunity to comment exempt residues of a pesticidal supplemental document (62 FR 27132) on EPA’s more detailed rationale substance that is significantly different to provide the public with an supporting the statement. Fifth, EPA functionally from the pesticidal opportunity to comment on EPA’s also described in greater detail how the substance as it occurs in the source analysis of how certain FQPA rationale presented in the 1994 Federal plant. amendments to the FFDCA and FIFRA Register document (59 FR at 60538) The Agency also requested comment affect this proposed exemption. concerning the safety for human on the utility of an exemption criterion EPA stated in the May 16, 1997, consumption of food from plants that based on the process (e.g., rDNA) used supplemental document its belief that meet the sexually compatible standard to introduce the plant-incorporated most of the substantive factors the applies to infants and children. The protectant into a plant (59 FR at 60514, FFDCA now requires EPA to consider public was given the opportunity to 60540, 60541). This approach was when evaluating pesticide residues were comment on the more detailed rationale discussed by the SAP Subpanel and considered when the Agency proposed specifically addressing infants and BSAC Subcommittee at the joint the exemption in 1994. EPA, thus, in the children as part of the larger human meeting of these scientific advisory supplemental document, specifically population. groups held on January 21, 1994. In this sought comment only on its evaluation approach, residues of plant- VI. What are the Key Features of this of the requirements imposed by FQPA Final Rule? incorporated protectants developed that the Agency had not addressed in through techniques other than those of the proposed rule. EPA sought comment In this final rule, EPA exempts modern biotechnology would be on the following five considerations. residues of the pesticidal substance and exempted, e.g., residues of those plant- First, whether there are substances, inert ingredient portion of plant- incorporated protectants developed outside of the food supply, sharing a incorporated protectants derived through conventional plant breeding common mechanism of toxicity with through conventional breeding from would be exempted. Residues of those residues of pesticidal substances plants sexually compatible with the plant-incorporated protectants that were derived from sexually compatible recipient plant. The following language not exempted could subsequently be plants. Commenters were asked to is added to 40 CFR 174.479: considered for exemption on the basis of submit information on the cumulative Residues of a pesticidal substance that is risk potential. part of a plant-incorporated protectant from The joint Subcommittee/Subpanel effects of such substances and the pesticidal substances that were the a sexually compatible plant are exempt from report justified such an approach on the the requirement of a tolerance if all the following three considerations. First, the subject of the proposed exemption (59 following conditions are met: National Institutes of Health Guidelines FR 60535). Second, whether there are (a) The genetic material that encodes for for Research Involving Recombinant substances, outside of the food supply, the pesticidal substance or leads to the DNA Molecules established a precedent related via a common mechanism of production of the pesticidal substance is that has worked well. Second, although toxicity to such residues to which from a plant that is sexually compatible with humans might be exposed through non- the recipient food plant. new techniques, such as rDNA are more (b) The genetic material has never been precise than conventional plant occupational routes of exposure. Commenters were asked to describe derived from a source that is not sexually breeding, it is possible to make with compatible with the recipient food plant. rDNA novel genetic modifications never routes through which such exposure (c) The residues of the pesticidal substance before possible. The novel combinations might occur, including exposure to are not present in food from the plant at possible with modern genetic major identifiable subgroups of human levels that are injurious or deleterious to techniques create uncertainties about populations (e.g., infants and children). human health. how the gene will function and how its Commenters were requested, if such Pertinent associated definitions in 40 products may affect the plant’s routes were identified, to provide CFR 174.3 are discussed in greater detail phenotype and its impact upon the information on the nature and levels of in a companion document published environment and human health. Third, expected exposures. Comments were elsewhere in this issue of the Federal establishing rDNA methodologies as a also sought on these two issues with Register on FIFRA regulations for plant- criterion for oversight may give the regard to Option 2, the alternative incorporated protectants. public more confidence that risk option for describing closely related In this final rule, plant means an potential is being evaluated. As a result, plants (described in Unit V.A.). Third, organism classified using the 5-kingdom approved products may move to the commenters who possess information classification system of Whittaker (Ref. marketplace more easily (Ref. 6). on substances occurring in food from 1) in the kingdom, Plantae. Therefore, plants that may have estrogenic effects the term ‘‘plant’’ includes, but is not B. What Issues Were Discussed in the and may be used as plant-incorporated limited to, bryophytes such as mosses, Supplemental Documents? protectants were requested to send such pteridophytes such as ferns, Subsequent to publication of the information to EPA. Fourth, EPA gymnosperms such as conifers, and November 23, 1994 Federal Register described in greater detail the rationale angiosperms such as most major crop document (59 FR 60535), EPA supporting the statement made in the plants. published two supplemental documents 1994 Federal Register document (59 FR Also included in the regulatory text at directly relevant to this exemption: one at 60513) that ‘‘plant-pesticides are § 174.485, subpart X, is an exemption on July 22, 1996 (61 FR 37891), and likely to present a limited exposure of for residues of inert ingredients in another on May 16, 1997 (62 FR 27132). pesticidal substances to humans. In plants derived through conventional 1. July 22, 1996. The July 22, 1996, most cases, the predominant, if not the breeding from sexually compatible supplemental document (61 FR 37891) only, route of exposure will be dietary. plants. discussed how the concept of inert Significant respiratory and dermal ingredient related to plant-pesticides. exposures will be unlikely.’’ No VII. How Do the Proposed Rule and 2. May 16, 1997. In August of 1996, comments were received on this Final Rule Differ? the FFDCA and FIFRA were amended statement during the first comment This exemption from the requirement by the FQPA. On May 16, 1997, EPA period for the proposed rule. The public of a tolerance is adopted with several
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changes from the proposed rule received on the November 23, 1994 taxonomy (genus) in conjunction with published in 1994 (59 FR 60535, proposed rule and the May 16, 1997 sexual compatibility to define closely November 23, 1994). EPA has changed supplemental document. EPA reviewed related plants. The Agency also the name of this type of pesticide from and considered all comments received requested comment on the utility of an ‘‘plant-pesticide’’ to ‘‘plant-incorporated on the proposed rule and supplemental exemption criterion based on the protectant’’ as described in the document and prepared detailed process (e.g., rDNA) used to introduce companion document on FIFRA responses to these comments. These the plant-incorporated protectant into a regulations for plant-incorporated responses can be found at appropriate plant (59 at FR 60514, 60540, 60541). protectants published elsewhere in this points in this preamble and in the During the comment period for the issue of the Federal Register. EPA Agency’s summary of public comments 1994 proposed rule, EPA received 19 exempts at this time only a subgroup of and EPA’s response on issues associated comments addressing the options for the category it proposed to exempt in with plant-incorporated protectants describing pesticidal substances derived 1994: Residues of pesticidal substances (Ref. 2). from closely related plants. Nine of and inert ingredients derived through these comments supported Option 1 and A. From Whom Did EPA Receive conventional breeding from plants generally agreed that the sexual Comments? sexually compatible with the recipient compatibility standard is reasonable and plant. In a companion document In response to the package of adequately addresses food safety issues. published elsewhere in this issue of the documents published in the Federal Three comments favored Option 2, with Federal Register, EPA solicits Register in 1994, EPA received letters one of these comments arguing that additional comment on alternative from industry, academia, professional species belonging to the same genus are options for the plant-incorporated and trade associations, government closely related and thus have a high protectants derived through modern agencies, state regulatory authorities, degree of biochemical similarity even biotechnology, e.g., recombinant DNA public interest groups and private though they may not be sexually techniques, from plants sexually citizens. Some of the commenters sent compatible. The commenter also cited compatible with the recipient plant. separate letters for each of the five the history of safe use of foods from In response to concerns expressed in dockets associated with the 1994 plant varieties developed through plant comments and to make EPA’s approach Federal Register documents. Other breeding. EPA also received comments more consistent with the policy of the commenters sent a single letter expressing serious reservations about Food and Drug Administration (FDA), addressing all five dockets. EPA using, for this exemption, a taxonomic EPA has added a condition to the received comments on the July 22, 1996, standard for describing closely related exemption that addresses levels of supplemental document, and on the plants (i.e., Option 2), because substances that are injurious or May 16, 1997, supplemental document, taxonomic categories, and the deleterious to human health in food which provided the public an relationship of a given plant species to from plants in sexually compatible opportunity to comment on EPA’s a given taxon, may be transient since populations. A few other modifications analysis of how certain amendments to taxonomic categories may change as have been made to the text of the the FFDCA and FIFRA by FQPA information accrues. Others expressed exemptions, for purposes of affected this proposed exemption. concern that dietary risk may be clarification. A discussion of Copies of all comments received are presented by such a standard. modifications to other relevant available in the record for this rule as EPA received 37 comments on the use definitions, including an analysis of described in Unit X. of the process by which the genetic comments on those definitions, can be B. Exemption of Residues of Plant- material is introduced into the plant as found in a companion document Incorporated Protectants Derived an exemption criterion. Twenty of these published elsewhere in this issue of the Through Conventional Breeding from comments supported an approach based Federal Register on FIFRA regulations Sexually Compatible Plants on process, i.e., that those plant- for plant-incorporated protectants. incorporated protectants introduced by Discussion of all modifications can be On November 23, 1994 (59 FR 60535), rDNA would be regulated. The found in the documents summarizing EPA proposed to exempt from the arguments advanced by these public comments and EPA responses on FFDCA requirement of a tolerance, all commenters can be represented by the issues associated with plant- residues of a category of plant- comment that: incorporated protectants (Ref. 2) located incorporated protectants based on the Genetic engineering (particularly in the record for this rule as described premise that new dietary exposures would be unlikely if the genetic material recombinant DNA [rDNA] methodologies), in Unit X. represents a fundamental technical advance When EPA proposed the exemption in leading to the production of the plant- over traditional plant breeding in the ability 1994 at 40 CFR 180.1137(a), it also incorporated protectant is derived from to manipulate plants genetically. Genes stated its intention (59 FR at 60520) to a plant closely related to the recipient which code for production of plant- establish a new 40 CFR part 174 plant. EPA offered two options for pesticides can be readily turned ‘on’ or ‘off’ specifically for plant-incorporated. This defining plant-incorporated protectants to dramatically increase the existing levels of new 40 CFR part 174 is being derived from plants closely related to plant-pesticides within plants, turning plants the recipient plant. The options were into pesticide factories and delivery systems. established in a companion document . . . given the fact that rDNA technologies published elsewhere in this issue of the somewhat different approaches to represent such a fundamental technical Federal Register. EPA adds this describing a high degree of relatedness advance over plant breeding, and given that tolerance exemption to 40 CFR 174.479, between the genetic donor and the plant-pesticides are by their very nature toxic subpart W, rather than adding it to 40 recipient plant. Neither of the options substances, all plant-pesticides produced via CFR part 180 as proposed. was based on the process by which a rDNA methodologies should undergo some plant-incorporated protectant was form of review under both FIFRA and FFDCA VIII. Discussion of Final Rule and introduced into the recipient plant. . . . (Ref. 3). Public Comments Option 1, based upon sexual Several letters described quantitative In this unit, EPA discusses the final compatibility, was EPA’s preferred changes in the levels of plant- rule and summarizes the comments it option (59 FR 60542). Option 2, used incorporated protectants as specific
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instances in which the commenter techniques of modern biotechnology, information can be used in assessing believed risk would be better addressed e.g., recombinant DNA, from plants risk. by an approach based on process. One sexually compatible with the recipient Using sexual compatibility as a of these commenters did not agree with plant. The Agency is considering these standard affords a clear delineation of EPA’s analysis that levels of the plant- options in response to public comment whether the residues of a plant- incorporated protectants (and thus of on its earlier proposals. One of these incorporated protectant meet the their residues) are likely to fall, in the options would establish notification conditions of the exemption. In most vast majority of cases, within ranges procedures, and as the public has not cases, whether two plants are sexually currently found in safely consumed had an opportunity to comment on compatible is known; thus, testing to food from plants. Another of these either the procedures themselves, or the determine whether the plants are commenters urged EPA to modify the criteria on which EPA would base its sexually compatible is not likely to be proposed exemption so that the Agency regulatory decisions, the Agency necessary. If, in rare cases, it is not would be notified if levels of pesticidal believes it would be appropriate to seek known whether two plants are sexually substances are ‘‘deliberately increased additional public comment prior to compatible, the means of determining through the introduction or adopting a particular option. In sexual compatibility is straightforward modification of promoters or other addition, as these alternatives would and simple. Sexual compatibility is noncoding regulatory sequences or there distinguish between categories of empirically demonstrable. EPA believes is reason to believe that levels of a residues of plant-incorporated that the criterion of sexual compatibility plant-pesticide in food or feed derived protectants based solely on the provides a high level of regulatory from a particular crop will be increased processes by which they are derived, the clarity and the greatest ease of by an order of magnitude or more’’ (Ref. public will also have an opportunity to implementation, while at the same time 3). present comments on whether this is an presenting the lowest probability of In response to the May 16, 1997, appropriate distinction for regulatory novel dietary exposure. This standard supplemental document, EPA received purposes. allows the public, industry, and EPA to six comments. Five comments easily and readily identify those plant- supported exemption of residues of C. What is the Language of the incorporated protectants that meet the plant-incorporated protectants derived Exemption? criterion of being derived from plants from sexually compatible plants, with In this final rule, EPA is, at 40 CFR closely related to the recipient plant. i. Why is sexual compatibility limited four comments addressing specific 174.479, exempting only a subgroup of to conventional breeding? As explained questions posed by EPA. One the category of residues it proposed to in a companion document published commenter, however, opposed any exempt in 1994, pesticide chemical elsewhere in this issue of the Federal exemption that did not take into residues derived through conventional Register, EPA is soliciting additional account quantitative changes in the breeding from plants sexually comment on the various options it is levels of these residues, stating that compatible with the recipient plant. ‘‘current knowledge is certainly considering in response to the EPA discusses the language of the inadequate to sanction greatly increased significant comments it has received exemption as it applies to this levels of these substances’’ in food (Ref. raising issues specific to plant- subcategory. 4). incorporated protectants derived Some comments urging regulation 1. Why is sexual compatibility an through genetic engineering. Because based on whether rDNA had been used appropriate standard? EPA believes that none of the comments raised significant to introduced the plant-incorporated sexual compatibility is an appropriate issues relative to pesticide chemical protectant, supported exempting standard because sexually compatible residues of plant-incorporated conventional breeding. One commenter, plants share a common pool of genetic protectants derived through for example, stated ‘‘that a long record material, even though there may be conventional breeding, the Agency is of experience with the products of some variability among plants in finalizing its proposals with respect to natural evolution and traditional sexually compatible populations. Sexual residues of this subgroup of products. In breeding shows that they typically do compatibility, the ability to produce a final rule under FIFRA described not present new dietary exposures and viable offspring, is only possible in elsewhere in a companion document in should be exempt from tolerance nature for plants that possess many this issue of the Federal Register, EPA requirements’’ (Ref. 5). traits in common. Traits, and the genetic includes in the definition of sexually Based on the advice of the BSAC and material encoding them, can be passed compatible at 40 CFR 174.3 the clause SAP at the joint meeting held January through sexually compatible plant ‘‘through conventional breeding.’’ EPA 21, 1994, and the comments received in populations by hybridization, and the also provides a definition of response to the November 23, 1994 mixing of genetic material that occurs conventional breeding that equates it to Federal Register document, EPA has through this process of mating tends to the creation of progeny through either: determined that it is appropriate at this a situation where the members of The union of gametes, i.e., syngamy, time to exempt from the FFDCA sexually compatible population have brought together through processes such tolerance requirement those residues of similar traits and similar genetic as pollination, including bridging the pesticidal substance portion of material. This is particularly true with crosses between plants and wide plant-incorporated protectants, as well crop plants where generations of crosses; or vegetative reproduction. as any inert ingredients derived through selection and breeding have tended to Conventional breeding does not include conventional breeding from plants increase the homogeneity of traits used use of any of the following technologies: sexually compatible with the recipient to produce agriculturally important Recombinant DNA; other techniques plant. In a companion document cultivars. Sexual compatibility thus wherein the genetic material is extracted published elsewhere in this issue of the presents a natural grouping of plants from an organism and introduced into Federal Register, EPA solicits public which can be readily described and the genome of the recipient plant comment on alternative options for the used as a regulatory standard, and about through, for example, micro-injection, category of residues of pesticidal which a large amount of information macro-injection, micro-encapsulation; substances derived through the exists in the scientific literature. This or cell fusion. EPA believes that this
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definition addresses the residues of plant-incorporated iii. Will wide and bridging crosses be recommendation of the SAP/BSAC that protectants derived from plants sexually part of the definition of conventional ‘‘the Agency define methodologies in a compatible with the recipient plant. breeding? In the final rule under FIFRA way that clearly delineates to the EPA assumes this comment is directed described elsewhere in a companion scientific community and the public at both exemptions, and that the document in this issue of the Federal what is and is not included in the commenter’s suggestion is that EPA Register, EPA defines ‘‘conventional regulatory scope’’ (Ref. 6). ensure that the regulatory language breeding’’ to include wide and bridging In the 1994 proposed rule (59 FR at exempts from the FFDCA tolerance crosses. These definitions are also 60538) and in the 1997 supplemental requirements, residues of those plant- important to this FFDCA tolerance document (62 FR at 27135), EPA states incorporated protectants that normally exemption, and thus, EPA discusses that its proposed rule is based on occur in a plant (i.e., are ‘‘native’’ to the them in this preamble. ‘‘experience with the exposure of plant) and will be used in that plant. For In the final rule, wide crosses include human populations to crops developed example, if corn normally produced a use of surgical alteration of the plant through the breeding process, i.e., crops plant-incorporated protectant, the pistil, bud pollination, mentor pollen, developed through 50 to 100 years of regulatory text should be clear that the immunosuppressants, in vitro scientific breeding among sexually residues of the plant-incorporated fertilization, pre-pollination and post- compatible plant populations using protectant would be exempt when pollination hormone treatments, Mendelian genetics.’’ In its 1994 produced and used in corn. EPA manipulation of chromosome numbers, proposed rule, EPA calls this type of believes inclusion of the word embryo culture or ovary and ovule breeding, ‘‘traditional breeding’’ (see ‘‘pollination’’ as an example of a process cultures. Generations of artificial e.g., 59 FR 60519). When the Agency leading to syngamy in the definition of hybridizations through these techniques determined that it would exempt a conventional breeding addresses this have taken place in the well-established subgroup of residues of the sexually concern. EPA believes the word practices of plant breeding (Ref. 8). compatible grouping, while allowing ‘‘pollination’’ is appropriate because Wide crosses, have been in the past and additional comment on how the Agency pollination is the process through which are currently, commonly used to expand should treat the residues of those plant- traditional breeding occurs (see e.g., 59 the plant gene pool for varietal incorporated protectants introduced FR 60537) (Ref. 7). Inclusion of the word improvement, and a history of safe use into the plant through the techniques of ‘‘pollination’’ in the definition has been associated with plant varieties modern biotechnology, EPA chose to emphasizes that plant-incorporated developed through the use of wide cross describe the exempt group of residues in protectants that occur naturally in a techniques (Ref. 8). A fairly high degree the most straightforward manner, as plant growing from a viable zygote that of relatedness between the parental those derived through breeding in arises by the mating in conventional plants is indicated when a wide cross sexually compatible populations. breeding of one corn variety with produces a viable zygote. This high Recognizing that many consider the another, or the mating of a corn plant degree of relatedness indicates a low modern techniques of biotechnology as with a corn plant of the same variety, probability of new exposures. simply an extension of breeding are exempt. Agricultural plants safely consumed as techniques, EPA determined that an food have been developed in the past adjective was needed to modify the EPA recognizes that this same 100 years utilizing wide crosses in the word ‘‘breeding’’ to adequately describe concern also applies to plant- breeding process. the exempt group. Although the Agency incorporated protectants in plants that The definition of ‘‘bridging crosses used the word ‘‘traditional’’ in its 1994 are propagated vegetatively. EPA between plants’’ is intended to convey proposed rule, EPA chose the word believes inclusion of the phrase the concept that an intermediate plants ‘‘conventional’’ to describe this type of ‘‘vegetative reproduction’’ in the could be used in a cross to move traits breeding in this rule because the SAP/ definition of conventional breeding from a source plant into a desired BSAC in the report of their January 21, addresses this concern. The language of recipient plant. The intermediate plant 1994 joint meeting used the adjective the exemption for pesticide chemical can form viable zygotes with both the ‘‘conventional’’ in its advice to EPA residues derived through conventional source and recipient plants, whereas the (Ref. 6), and the word ‘‘conventional’’ breeding from sexually compatible source and recipient plant cannot form might more readily connote techniques plants specifically exempts residues in viable zygotes. The intermediate plant such as wide crosses. plants reproduced vegetatively. For serves as a bridge for gene flow between ii. Why is conventional breeding example, residues of a plant- the two incompatible plants. The result described by processes such as incorporated protectant in a plant of the bridging cross is the mixing of pollination and vegetative propagated only vegetatively, (e.g., genetic material of the first and third reproduction? One comment received bananas), are exempt. Also exempt are plant through the formation of an on the 1994 proposed rule suggested residues of a plant-incorporated intermediate zygote. No comments were that there is ambiguity in the proposed protectant in a plant propagated received on the proposed definition of regulatory language at 40 CFR 174.5(a) primarily vegetatively (e.g., potatoes), as bridging crosses between plants, also in the November 23, 1994, Federal long as, under conditions of part of the definition of conventional Register document (59 FR 60535). The reproduction through hybridization, the breeding for sexually compatible. EPA is commenter indicated the perceived plant donating the genetic material is adopting this definition as proposed. ambiguity could lead to questions about sexually compatible with the recipient iv. Will cell or protoplast fusion be whether plant-incorporated protectants plant as defined in at 40 CFR 174.3, and part of the definition of wide crosses? that are ‘‘native’’ to a food crop would the other conditions described at 40 EPA received one comment suggesting meet the criteria of exemption. CFR 174.479 are met. Inclusion of this that protoplast fusion should be Because of the use of the word ‘‘food’’ term in the definition of conventional included in the definition of wide in the comment, it was not clear breeding reflects EPA’s statement in the crosses between plants. That request whether the comment is directed toward 1994 proposed rule (59 FR 60524) on was made in the context of the proposal EPA’s proposed exemption under the status of crop plant varieties to exempt plant-incorporated FIFRA or that under the FFDCA for propagated vegetatively. protectants derived from plants sexually
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compatible with the recipient plant v. ‘‘Recombinant DNA’’ and genetic 2. Why is the concept of ‘‘functionally from FIFRA requirements, but as the material ‘‘extracted from an organism modified from the source’’ important definition of wide crosses is also and introduced into the genome of the and how does the definition of relevant for this FFDCA exemption, EPA recipient plant.’’ As explained conventional breeding address it? In the will discuss that comment in this previously, EPA restricted this November 23, 1994 Federal Register preamble. exemption to conventionally bred plant- document (59 FR at 60539), EPA In the technique of protoplast fusion, incorporated protectants while the explained that in proposing the protoplasts are made in the laboratory Agency solicits additional comment on exemptions the Agency did not intend through the removal of the cell walls of the alternatives it is considering in to exempt residues of a pesticidal somatic cells. A somatic cell is a type of response to the comments received on substance that is significantly different cell that forms plant vegetative tissues the 1994 proposal. Thus, in order to functionally, from the pesticidal and organs and is distinguished from a fully describe which plant-incorporated substance as it occurs in the source germ cell which undergoes meiosis to protectants are exempt under this plant. EPA believed this limitation is produce reproductive tissues (e.g., exemption, EPA includes limiting appropriate because rearrangements or pollen and egg cells). In the technique phrases. EPA in the 1994 Federal modifications of the genetic sequence of protoplast fusion, protoplast are made Register document (59 FR 60541, encoding a pesticidal substance made from the somatic tissues of two different November 23, 1994) discussion of the through the use of techniques such as plants. The membranes of the different advice of the joint SAP/BSAC at the rDNA could, for example, result in a protoplasts are then fused together January 21, 1994 meeting on the use of plant-incorporated protectant, and/or mechanically through processes such as a process-based criterion to define a residues of such a plant-incorporated treatment with polyethylene glycol, category of plant-incorporated protectant, with significantly different producing a hybrid somatic cell with a protectants that would be subject to functions from the function in the genetic make-up resulting from the review, stated that the Agency would source plant. For example, if the combination and sorting of the two define such a process-based criterion in pesticidal substance is an enzyme, it plant genomes. The somatic hybrid cell the following way: ‘‘The genetic could be modified so that it acts on a is then grown on specialized media into material that encodes for the pesticidal different substrate in the recipient plant a mature plant. substance or leads to the production of than it did in the source plant (Refs. 8 In support of the request, the the pesticidal substance is extracted and 9). Residues of such a significantly commenter argued that the from an organism and introduced into modified pesticidal substance would hybridization of somatic cells (i.e., the genome of the recipient plant or is not necessarily present risks similar to protoplast fusion) has a history of use to synthesized in vitro and introduced into the substance prior to modification, nor artificially induce sexual compatibility. the genome of the recipient plant.’’ EPA would the base of experience on which The commenter argued that movement in this action uses the language it put EPA relies for support of the exemption of genetic material by this means has forth in the 1994 Federal Register to necessarily be relevant. If the genetic historically been considered safe. fashion two of the exclusions from the material encoding the pesticidal EPA did not, in its 1994 proposed rule substance has been modified in such a include protoplast fusion in the conventional breeding definition at 40 CFR 174.3. One exclusion is for way that the pesticidal substance definition of wide crosses between functions differently in the recipient plants, nor did it perform an analysis of techniques involving the direct introduction into an organism of genetic plant than it did in the source plant, the the potential for new dietary exposures analysis performed to determine that when protoplast fusion is used to material extracted from the source and introduced into a recipient plant. there is a reasonable certainty that no perform wide crosses between plants. harm will result from aggregate The commenter did not provide such Processes such as micro-injection, macro-injection and micro- exposure to the residues of the plant- information in response to the 1994 incorporated protectant, would not proposed rule nor the 1997 encapsulation would be excluded from the conventional breeding definition apply. supplemental document. EPA does not In this final rule, this concern is because they are used to introduce such believe information currently in the addressed by the limitation placed on extracted genetic material into the record supports inclusion of protoplast the definition of sexually compatible. fusion in the definition of wide crosses. recipient plant. These processes have Under this definition, residues of Therefore, EPA does not include been included in the definition as pesticidal substances from sexually protoplast fusion in the definition of examples to assist in understanding the compatible plants are only exempt if the wide crosses and specifically excludes concept. genetic material is introduced into the cell fusion from the definition of The second exclusion from the plant through conventional breeding as conventional breeding. However, EPA conventional breeding definition uses defined at 40 CFR 174.3. The types of requests comment on whether the term ‘‘recombinant DNA’’ to changes discussed above (Refs. 8 and 9) protoplast fusion should be included in represent the concept of ‘‘extracted from that can be made through modern the definition of wide crosses in a an organism. . ., synthesized in vitro and molecular techniques, are very unlikely supplemental document published introduced into the genome of the to be made through conventional elsewhere in this issue of the Federal recipient plant.’’ To provide greater breeding as defined at § 174.3, and Register. EPA would welcome technical accuracy, EPA provides a residues of plant-incorporated submission of information on protoplast definition at 40 CFR 174.3 for protectants modified through modern fusion. If the Agency obtains sufficient recombinant DNA as follows: molecular techniques are not eligible for information demonstrating a low ‘‘Recombinant DNA means the genetic today’s exemption. probability of risk, EPA may initiate material has been manipulated in vitro 3. Why is the phrase ‘‘never derived notice-and-comment rulemaking under through the use of restriction from source not sexually compatible FIFRA section 25(b) and FFDCA section endonucleases and/or other enzymes with recipient plant’’ important? EPA 408 to include protoplast fusion in the that aid in modifying genetic material, discussed the relevance of this phrase to definition of wide crosses between and subsequently introduced into the the proposed exemption in the plants. genome of the plant.’’ November 23, 1994 Federal Register
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document (59 FR 60539). The phrase, substance not be present in food from substances are significantly increased. ‘‘has never been derived from a source the plant at levels that are injurious or EPA disagrees, however, with the that is not sexually compatible with the deleterious to human health. EPA is commenter’s suggestion that notification recipient plant,’’ was included in the including at 40 CFR 174.479, the be required only when levels of proposed regulatory text to clearly following condition to the language of pesticidal substances are increased by indicate that pesticide chemical the exemption: ‘‘(c) The residues of the 10 fold. There is natural variability in residues of a plant-incorporated pesticidal substance are not present in levels of expression in a plant of any protectant would not qualify for the food from the plant at levels that are substance, including plant-incorporated exemption if the genetic material is injurious or deleterious to human protectants, influenced by factors such introduced into a recipient plant from a health.’’ as genetic composition, soil sexually incompatible source and then If the residues of the plant- composition, climate and weather. subsequently introduced from this incorporated protectant do not meet this Humans are currently being exposed to recipient plant into other plants criterion, they are not exempt from the variation in the food they consume. The sexually compatible with the recipient requirement of a tolerance, nor would a commenter did not provide information plant. For example, the exemption does tolerance have been established for to support the suggestion that a 10-fold not extend to a situation where the them. A food containing residues of a increase would represent an genetic material encoding the Bacillus pesticide may not be moved in interstate unacceptable risk, and broad adoption thuringiensis delta endotoxin is commerce without either an appropriate of such a standard would be arbitrary. introduced into wheat, and the tolerance or an exemption from the The variations normally seen in food endotoxin-producing wheat is requirement of a tolerance. Should such from plants, such as the 20-fold subsequently hybridized with rye using an occurrence be identified, the variation for ascorbic acid in wide cross techniques to produce condition will allow expeditious muskmelon depending on variety triticale. The residues of the endotoxin removal of the offending food from the planted, and the variation in the levels produced in the triticale would not be market. EPA does not believe that such of carotene in carrots which can range eligible for the exemption because the an occurrence will result a priori in a from none detectable to 370 mg/100 g genetic material encoding the endotoxin reevaluation of the categorical tissue depending on the variety (Ref. 8), originated from a bacterium, a source exemption for pesticidal substances are greater than the 10-fold increase that is not sexually compatible with the derived through conventional breeding suggested by comment. Other examples original recipient plant (wheat in this from sexually compatible plants under can be offered where the variation falls example). FFDCA section 408 because any within a more narrow range, for One commenter suggested that the problem will likely be associated with a example, one researcher (Ref. 8) Agency delete this phrase from the single variety. reported that depending on maturity of regulatory text and instead include a Producers who wish to increase the the fruit, the level of ascorbic acid in period of time after which a plant- levels of pesticidal substances in plants tomato can range from 2.7 mg/100 g incorporated protectant would be in sexually compatible populations tissue to 7.6 mg/100 g tissue, a 2.8-fold treated as part of a plant’s ‘‘accessible’’ beyond the ranges of levels generally variation. The conditions on the gene pool. EPA disagrees and will seen in plant varieties currently on the exemption at § 174.479 and reporting continue to include this language in the market and known to produce food safe requirement at § 174.71, on the other final rule at 40 CFR 174.479. Further, for consumption are strongly hand, have no numerical standards. EPA disagrees with the commenter’s encouraged to consult with EPA to Nevertheless, the Agency believes that suggestion that a gene, derived from a determine whether their plant- the adverse effects reporting phylogenetically distant source and incorporated protectant is eligible for requirement will allow the Agency to successfully used in a crop, be treated the exemption from the requirement of monitor for any rare instances in which after a period of time as though it had a tolerance, or whether a tolerance, and significant increases in levels of plant- become part of the crop’s gene pool (i.e., therefore, a registration is necessary. incorporated protectants might present a equivalent to a gene that had evolved in Based on the record compiled for this hazard, and that the condition at a sexually compatible population of rulemaking on the historical safety of § 174.479 will allow EPA and FDA to plants). The commenter does not food from plants in sexually compatible act expeditiously. (The adverse effects suggest what an appropriate period of populations, as described in Unit IX.A. reporting requirement is described in a time would be nor how this would and Unit IX.B.1., EPA believes that such companion document published correlate with the potential for dietary a circumstance, will be extremely elsewhere in this issue of the Federal exposures. Without additional unlikely for residues derived through Register on FIFRA regulations for plant- information, EPA cannot find that there conventional breeding from plants incorporated protectants). is a ‘‘reasonable certainty that no harm sexually compatible with the recipient The historical safety of the food will result from aggregate exposure to plant. supply as described by the record EPA the pesticide chemical residue’’ as This condition makes EPA’s approach has compiled for this exemption, the required by FFDCA section 408(c). to plant-incorporated protectants more reporting requirement imposed as a 4. Why is EPA placing a condition on consistent with FDA’s regulatory condition of the FIFRA exemption, the exemption limiting the levels of approach, and allows the agencies to act taken in conjunction with the strong pesticidal substances? To address more expeditiously in the rare likelihood that manufacturers and concerns raised in comment on its circumstance that a risk associated with companies will choose to consult with original proposal concerning the higher levels of substances normally EPA rather risk seizure of their food by possibility that certain substances part of a plant in a sexually compatible FDA, cause EPA to believe that the normally present in plants in sexually population is identified in food. condition placed on the exemption compatible populations may in rare This condition, in conjunction with sufficiently address the commenters’ circumstances be present in food at the reporting requirement at 40 CFR concerns. levels that are hazardous, EPA is 174.71, is conceptually similar to the 5. Why does 40 CFR 174.479 include limiting this exemption by requiring suggestion of one commenter that the language limiting the recipient to food that the residues of the pesticidal Agency be notified if levels of pesticidal plants? In the preamble to the 1994
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proposed rule (see e.g., 59 FR 60537), compatible plants extends to any D. What Were the Other Potential EPA discussed the premise for this substance that is derived from plants Approaches to the Scope of Exemption? exemption; that ‘‘new dietary exposures sexually compatible with the recipient In the November 23, 1994 Federal would not likely arise for plant- plant, including substances such as a Register document (59 FR 60537), EPA pesticides produced in recipient food selectable marker, used to confirm or discussed the merits of an approach plants if the genetic material leading to ensure the presence of the active using taxonomy, along with sexual the production of the pesticidal ingredient. EPA’s analysis in Unit IX., compatibility (Option 2), as a standard substance is derived from closely applies equally to all the substances that for describing closely related plants, and related plants.’’ In addition, the BSAC normally are found in a population of received comment on use of such a in its report on the July 13, 1993 sexually compatible plants, including criterion. EPA also received a comment, meeting (Ref. 10) emphasized to the inert ingredients as long as these are made in the context of the FIFRA Agency that the focus of an exemption derived through conventional breeding regulations, suggesting that the criterion should be on plant-incorporated from plants sexually compatible with of sequence homology be used to limit protectants in food plants. They the recipient plant, and have never been the concept of sexual compatibility. In suggested that ‘‘plant-pesticides in derived from a source that is not light of the relevance of this comment plants commonly consumed by humans sexually compatible with the recipient to this FFDCA exemption, EPA as food be exempt as long as the plant’s plant. An example of such an inert discusses this suggestion, as well as the genetic material is derived from related ingredient in sexually compatible comments on taxonomy, here. EPA also plants within the same family that have populations could be tightly linked discusses a comment suggesting that contributed traits to the food plant traits, such as unusual leaf pigmentation EPA consider extending the exemption, through the mechanism of sexual always found with a pest resistance on a case-by-case basis, to residues of recombination (including wide crosses trait. plant-incorporated protectants derived and embryo rescue)’’ (59 FR 60540). In from plants unrelated to the recipient this final rule, EPA has revised EPA includes these residues at 40 plant, and a suggestion that exemptions § 174.479 to clearly state that the CFR part 174, subpart X, to ensure that should be based on a documented recipient plant must be a food plant by readers understand that any trait used as history of safe use. including the phrase ‘‘recipient food a selectable marker, and the genetic 1. Taxonomy. Two commenters plant’’ in the regulatory text at material necessary to produce it, that expressed reservation about using a § 174.479(a) and (b). In the final rule, occurs normally in a plant sexually taxonomic standard for describing EPA has revised the definition of ‘‘food compatible with the recipient plant or is closely related plants. They pointed out plant’’ proposed in the 1994 proposed introduced through conventional that taxonomic categories, and the rule at 40 CFR 180.1137 (59 FR at breeding, is exempt from the FFDCA relationship of a given plant species to 60542) to read: ‘‘Food plant means a section 408 requirement of a tolerance, a given taxon, may be transient since plant which, either in part or in toto, is as well as FIFRA requirements on inert taxonomic classification may change as used as food’’. EPA includes this ingredients when used with a plant- information accrues. EPA agrees. In the definition at 40 CFR 174.3. EPA also incorporated protectant derived through includes at § 174.3 the definition of food conventional breeding from a plant 1994 Federal Register document, EPA found in the FFDCA. Thus, for these sexually compatible with the recipient noted (59 FR at 60524) that a taxonomy- regulations for plant-incorporated plant. EPA believes this interpretation is based standard (e.g., Option 2) may be protectants: Food includes articles used a logical implication of the preamble artificial: classification of plants in for food or drink by humans or other discussion in the 1994 proposed rule different taxonomic genera is not fixed animals. (59 FR at 60538). and could change over time and between scientific authorities. 6. What is the status of substances Because the Agency recognizes that a within sexually compatible plant Taxonomy reflects current observations substance described in Unit IX.B.2. (i.e., about phenotypic, and to some extent, populations that might be used as inert a toxicant) could theoretically be used ingredients? In a companion document genotypic, differences between as an inert ingredient, EPA places the organisms. Currently, some plant genera published elsewhere in this issue of the same limiting condition on residues of Federal Register, EPA describes its are narrowly defined; for other plant the inert ingredient in food as is placed genera, membership is based on broader consideration of inert ingredients in on residues of the pesticidal substance light of existing regulations and criteria. These differences in portion of the active ingredient; i.e., the classification criteria may lead to comments received in response to both residues of the inert ingredient do not the November 23, 1994 Federal Register different probabilities between genera qualify for the exemption if they are document (59 FR 60534) and a 1996 that new exposures may occur when present in food from the plant at levels supplemental document (61 FR 37891) genetic material from one species in a that are injurious or deleterious to discussing the Agency’s treatment of genus is introduced into another species human health. selectable markers as inert ingredients in the genus. In recent years new tools for plant-incorporated protectants. In Discussion supporting this exemption have become available to taxonomists, the companion document published can also be found in a companion allowing them to better clarify elsewhere in this Federal Register on document published elsewhere in this phylogenetic relationships among FIFRA regulations, EPA describes its issue of the Federal Register on FIFRA organisms. New information, determination that it will apply the regulations for plant-incorporated particularly that obtained through the concept of inert ingredients to plant- protectants. Regulatory text has been use of new genetic tools, concerning incorporated protectants consistent with established at 40 CFR 174.485, subpart organisms’ properties and relationships the 1994 proposal. X, which is entitled ‘‘Inert ingredients may in the future alter current The preamble discussion in the 1994 from sexually compatible plant,’’in a taxonomic designations. In light of these Federal Register document (59 FR at companion document on FIFRA advances, EPA anticipates there may be 60523) of the rationale supporting the regulations for plant-incorporated some reorganizations among the proposal to exempt plant-incorporated protectants published elsewhere in this Plantae, and that these reclassifications protectants derived from sexually issue of the Federal Register. will better reflect the relationships
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among plants, and the probability of relatedness on the degree of sequence approximately the same (or lower) level, new exposures in intrageneric crosses. homology between the source and an exemption would be warranted.’’ A The possibility that taxonomic recipient plant. Sequence homology second commenter proposed that classification may change as refers to the extent that the sequence of exemptions should be based on a information accrues would add an extra deoxynucleotides in two pieces of documented history of safe use. layer of complexity to any regulations genetic material are the same. A With regard to the suggestion that based on a taxonomic standard, and deoxynucleotide is made up of a sugar, EPA consider extending exemptions on EPA probably would not be able to a phosphate, and one of four purine or a case-by-case basis to residues of structure an exemption to accommodate pyrimidine bases (adenine, cytosine, pesticidal substances of plant- for potential changes in classification. guanine, thymine). The sugars and incorporated protectants derived from The possibility of reclassification also phosphates of the deoxynucleotides are plants unrelated to the recipient plant, creates some uncertainty within the covalently linked by phosphodiester the Agency has the option to exempt regulated community about the future bonds to form the ‘‘backbone’’ of the residues of pesticides from the status of a product. deoxynucleotide polymer (DNA). One requirement of a tolerance on a case-by- Furthermore, under the FFDCA, an base is attached to each sugar in the case basis provided that the residues exemption must be examined sugar-phosphate backbone. The meet the exemption standard in FFDCA specifically within the context of the information encoded in the genetic section 408(c). In addition, any person food supply and dietary consumption. material is determined by the sequence may petition EPA to establish a Although some species in a genus might in which the bases are attached to the tolerance exemption pursuant to section be food plants, others in that genus sugar-phosphate backbone. The extent 408(d). Section 408(d)(2)(A) establishes might not. Moreover, in a genus to which two pieces of genetic material the minimum requirements for such a containing food plants, there may be have the same base sequence is often petition. As additional information such barriers to hybridization that some described in terms of percent homology, becomes available, EPA will consider, of the non-food species in that genus with 100% homology meaning the in future, exempting from the FFDCA would never have contributed to the pieces of genetic material have an requirement of a tolerance, residues of food supply. Thus, there may be no identical sequence. The Agency plant-incorporated protectants derived experience with the potential dietary currently believes that DNA sequence from plants unrelated to the recipient risks associated with such non-food homology is a less straightforward plant when these can be shown to meet species. In addition, knowledge of standard for regulatory purposes than a the FFDCA section 408 safety standard. whether substances such as naturally- standard such as sexual compatibility. EPA also has the option of exempting occurring toxicants are present is, in Sexual compatibility is known in most residues of plant-incorporated general, more limited for all the plant cases, and if it is not, it is less protectants based on a history of safe species constituting a genus than it is burdensome and simpler to demonstrate use where there is sufficient information for species used to produce the major than is relatedness based on DNA to meet the FFDCA section 408(c) test. food crops. Consequently, there is a sequence homology. Use of homology as greater degree of uncertainty in any IX. Statutory Finding a criterion presents the following finding applicable to all potential complex issues. First, where should A. What Methodology Did EPA Use to members of taxonomic categories. The homology be assessed? For example, Assess these Residues? large body of information supporting how many genes of the source and this exemption was generated for food For most pesticides (e.g., chemical recipient plants should be compared to crops in sexually compatible pesticides), EPA’s dietary risk determine the degree of homology? All populations (Refs. 8, 11, 12, 13, 14, 15, evaluation relies on data generated by 16, 17, 18, and 19, for example). Overall, the genes of both plants? A few genes? testing in laboratories using the base of dietary experience is not as If only a few, which genes? Second, representative animal models to broad or as deep for populations of what degree of homology would be estimate acute, subchronic or chronic plants described by the taxonomic sufficient to indicate a high degree of hazard end-points (e.g., acute toxicity, standard of genus as it is for populations relatedness? Third, under what carcinogenicity, developmental of plants described by sexual conditions should homology be toxicity). Conclusions from animal compatibility. EPA does not believe it measured? Fourth, appropriate test models are used to assess dose-response possesses sufficient information at this procedures would need to be developed and describe such endpoints for time to allow the Agency to issue an and validated in order to set a standard potential human hazard. Other exemption based on taxonomy. procedure for measuring homology. All information, including residue data and 2. Sequence homology. EPA received of these issues would need to be information generated by use of one comment suggesting that an resolved, and converted into regulatory mathematical models, are used to additional criterion be used to limit the text, in order to develop an exemption develop human exposure estimates. concept of sexual compatibility. While standard based on DNA sequence These exposure and hazard components this suggestion was made in the context homology. are combined to quantify the potential of a comment made on the proposal to 3. Other potential exemptions risk associated with the pesticide’s use. exempt plant-incorporated protectants suggested by comment. One comment Uncertainty factors are often used in the derived from plants sexually compatible suggested that EPA consider extending risk assessment to account for with the recipient plant from FIFRA the exemption, on a case-by-case basis, extrapolation from animal models to requirements, EPA discusses that to residues of the pesticidal substance human toxicity and from limited studies suggestion here because of its relevance portion of plant-incorporated using humans to the larger population. to EPA’s decision to exempt residues of protectants derived from plants The data requirements describing the pesticidal substances derived through unrelated to the recipient plant: types of information to be generated and conventional breeding from plants ‘‘Should a gene be taken from a other guidance for assessing dietary risk sexually compatible with the recipient commonly consumed food plant and are detailed in 40 CFR part 158. plant. The suggested criterion of inserted into another commonly used The questions posed as part of the risk sequence homology would base food plant, and the trait is expressed at assessment in evaluating residues of
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most pesticides (e.g., chemical residues of plant-incorporated Residues of plant-incorporated pesticides) can also be posed for the protectants derived through protectants derived through pesticide chemical residues that are the conventional breeding from sexually conventional breeding from sexually subject of this exemption, and 40 CFR compatible plants. Plant-incorporated compatible plants were evaluated for part 158 can be used as guidance in protectants are produced within the dietary risk within the context of the evaluating these residues for hazard living plant itself and the pesticidal food supply and dietary consumption end-points (including, for example, substance is used in situ in a living patterns. In performing its assessment, acute toxicity, carcinogenicity, and plant to protect against pests, in contrast the Agency considered that the diet developmental toxicity). To address the to most other pesticides which must be includes all of the food items that are hazard endpoints described in 40 CFR applied to the plant (Ref. 20). Because customarily eaten by human part 158 for residues of plant- a plant-incorporated protectant is populations or subpopulations as part of incorporated protectants derived produced and used within the plant, a normal diet. (EPA did not consider through conventional breeding from physiological constraints limit the that the normal diet includes plants or sexually compatible plants, EPA relied amounts of residues produced by the plant parts consumed in times of on a very large body of information plant (Ref. 20). Because the plant- deprivation, for religious reasons, in found, for the most part, in the public incorporated protectant is within the substance abuse or by misidentification. scientific literature. In performing the plant, routes by which other organisms The information base on which EPA assessment for this exemption from the may be exposed to the plant- relied in performing its risk assessment requirement of a tolerance, EPA did not incorporated protectant may be more (Refs. 8, 11, 12, 13, 14, 15, 16, 17, 18, need to rely as much on information limited, e.g., dietary exposure is likely and 19, for example) did not address generated from animal models as it to be the predominant route of such plants.) would in assessing other pesticides (e.g., exposure. EPA considered health risks to the chemical pesticides). A very large body EPA used experimental data derived general population, including infants of experience with actual human dietary from the science of phytopathology to and children. Children, and to some consumption over hundreds, if not characterize the disease and pest extent infants, have always and thousands, of years exists for the resistance mechanisms known to occur currently consume food containing substances that are the subject of this in plants (Ref. 21). EPA also considered residues that are the subject of this exemption. And thus, a large and varied information from the field of plant exemption. EPA’s risk assessment also amount of information developed physiology regarding plant metabolism, included subgroups as part of the through systematic scientific study the production of substances that may general population, (i.e., differences in exists in the literature, and can be used have pesticidal effects, and conditions diet due to the influence of culture), and for assessing the risk of exempting these that may limit the plant’s production of allowed for consumption pattern residues. Numerous epidemiological such substances (Refs. 7 and 20). This differences of such subgroups. The studies on humans show the health information also provided a basis for consumption of food plants is part of a benefits of consuming foods containing EPA’s estimation of the physiological balanced and varied diet. residues of the plant-incorporated limitations to production in plants of EPA believes that the numerous protectants that are the subject of this substances that may be pesticidal and epidemiological and nutritional exemption (Refs. 11, 12, 13, 14, 15, 16, thus to production of their residues. assessment studies found in the 17, 18, and 19). The epidemiological EPA also used information from the literature of human experience in studies in particular provide fields of biochemistry, microbial consuming food containing residues information on the effects of chronic ecology, and ecology (Refs. 7, 21, and that are the subject of this exemption, exposure of a far longer term than is 37). combined with information generated possible with animal model EPA’s conclusion that the vast from animal model testing and experimentation, given the large majority of plant varieties developed by biochemical studies and knowledge differences in life span between humans conventional breeding in sexually from the disciplines of plant genetics, and most animals used in animal model compatible populations produce foods plant physiology, phytopathology, testing. The results of many nutritional that are safe for human consumption is microbial ecology, ecology, assessment studies using human based on this information and the biochemistry, and plant breeding form volunteers are available on the effects of historical consumption of crops since the appropriate information base for either whole foods from plants in the prehistorical origins of agriculture. evaluating the potential risks of such sexually compatible populations or EPA also considered its knowledge of residues. isolated constituents from food from the practices that plant breeders B. What Factors Has EPA Considered in such plants (Refs. 11, 12, 13, 14, 15, 16, routinely employ in selecting and Making the Findings Required by 408(c) 17, 18, and 19). Studies have also been developing plant varieties in sexually of the FFDCA? performed using animal models to test compatible plant populations, such as the effects of either whole foods from chemical analyses, taste-testing, and FFDCA section 408(c)(2)(B) requires crops in sexually compatible visual analyses, and that such practices EPA to consider several factors in populations or constituents from food have historically proven reliable for determining whether to exempt a from such crops (Refs. 11, 12, 13, 14 15, ensuring the safety of food from such pesticide from the requirement of a 16, 17, 18, and 19). There is a large plants (Refs. 8 and 22). EPA also tolerance (21 U.S.C. 346a(c)(2)(B)). literature on constituents of food from considered that appropriate processing Information relevant to EPA’s plants in sexually compatible procedures are widely known and are consideration of these factors with populations accumulated by a century routinely used by consumers in regard to this exemption of the pesticide of systematic study (Ref. 8), and EPA preparation of food containing residues chemical residues of a plant- also used these sources of information. that are the subject of this exemption, incorporated protectant derived through EPA also considered other including those foods which require conventional breeding from sexually information in the literature in specific processing and/or preparation compatible plants, is contained in this evaluating the potential for exposure to steps to avoid dietary problems. document, as well as in other
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documents in the record for this rule as breeding. EPA concluded that this hyenanchin) are in honey, being ‘‘pass- described in Unit X. information was valid, complete and through’’ contaminants of honey The preamble discussion in the 1994 reliable, and adequately addressed the introduced by bees collecting pollen Federal Register document (59 FR at issues of hazard and exposure with from rhododendron, azalea, yellow 60538), and in the May 16, 1997, regard to residues in food of plant- jasmine, or the tutu tree. (The supplemental document (62 FR 27132), incorporated protectants derived substances from the tutu tree, tutin and of the rationale supporting the proposal through conventional breeding from hyenanchin, can cause delirium and to exempt residues of plant- sexually compatible plants. convulsions). Similarly, four (cicutoxin, incorporated protectants derived from 2. Nature of toxic effect. In light of coiinine, methylconiine, conhydrine) of sexually compatible plants extends to comments raising concern about the 21 substances capable of causing any substance that is normally a possible adverse effects from increases toxic effects in the normal diet are pass- component of a population of sexually in the levels of substances that naturally through contaminants in the milk of compatible plants. It thus, applies to occur at low levels in food from plants, cows that have consumed water any substance, such as a selectable EPA considered the nature of toxic hemlock or hemlock. These substances marker, used to confirm or ensure the effects shown by the data described in are nervous system stimulants. None of presence of the active ingredient, that is Unit IX.B.1., above to be caused by the plant sources of these 11 pass- also derived from plants sexually substances that might potentially be through contaminants are used or compatible with the recipient plant. residues of plant-incorporated intended to be used as food plants and EPA’s analysis in Unit IX., applies protectants derived through thus this section 408 exemption does equally to all the substances that are conventional breeding from sexually not apply to them. Another of the 21 normally a component of a population compatible plants, should these substances in the normal diet identified of sexually compatible plants, including substances be used as pesticides (i.e., if as potentially causing toxic effects is inert ingredients as long as these are humans intend to use these substances nitrate. Exposure to excessive amounts derived through conventional breeding for preventing, repelling or mitigating of nitrates can cause from plants sexually compatible with any pest) and present at high levels. The methemoglobinemia, a condition in the recipient plant, and have never been examination led EPA to conclude that as which some portion of the hemoglobin derived from a source that is not the vast majority of substances in plants molecules become incapable of binding sexually compatible with the recipient are not toxic, any of these nontoxic oxygen. Levels of nitrates high enough plant. substances, should they be used as to cause such effects can be found in 1. Validity, completeness and plant-incorporated protectants, would spinach and other green, leafy reliability of available data. As not present toxic effects. EPA has vegetables subjected to intensive described in Unit IX.A., EPA’s risk identified 21 substances of plant origin application of high-nitrate fertilizers. assessment for residues of plant- that are in foods that could be Nitrates that enter the plant through incorporated protectants derived considered part of a normal diet and uptake of fertilizer applied intensively through conventional breeding from could potentially present toxic effects if are not ‘‘produced’’ by the plant per se, sexually compatible plants was based present at high levels (Ref. 8). (The i.e., they are not biosynthesized by the primarily on an analysis of the long normal diet does not include plants, or plant. This exemption is not relevant to human experience with breeding and parts of plants, consumed in times of such nitrates. The toxic effect presented growing agricultural plants and deprivation, for religious reasons, in by high levels of nitrates is generally preparing and consuming food from substance abuse, or by addressed in agriculture by use of such plants, and associated misidentification. The normal diet is proper fertilization practices. epidemiological studies, nutritional considered to be balanced and varied Of the 21 substances originally assessments with human volunteers and and include food from a variety of identified (Ref. 8), nine of these animal model testing (Refs. 8, 11, 12, 13, sources.) This analysis is based on an (solanine, linamarin, lotaustralin, 14, 15, 16, 17, 18, and 19). EPA accumulation of millennia of human cucurbitacin, vicine, convicine, combined this information with experience and a century of systematic hypoglycin A, sparteine, beta-N- knowledge from the disciplines of plant scientific study of food constituents oxalylamino-L-alanine) are genetics, plant physiology, (Ref. 8). The conclusion of the analysis biosynthesized by plants that could be phytopathology, microbial ecology, described in Unit IX.B.2., for these 21 used as food in a normal diet ecology, biochemistry (including studies substances indicates that they are either: somewhere in the world, and, thus, if on the constituents of food), and plant Beyond the scope of the exemption; in used by humans for pesticidal purposes, breeding to evaluate the potential risks foods that are not part of the normal diet could potentially be pesticide chemical of pesticide chemical residues of plant- of the United States population; and/or, residues derived through conventional incorporated protectants derived millennia of human experience and use breeding from sexually compatible through conventional breeding from have given rise to procedures, on the plants. Three of these nine substances sexually compatible plants. EPA part of the plant breeder, the food (sparteine, hypoglycin A, beta-N- considered the validity, completeness processor and/or the consumer, that oxalylamino-L-alanine) are found in and reliability of the available combined with the condition food not customarily consumed as part information on human consumption of determining eligibility for this of the normal diet in the United States. food containing substances that are the exemption, adequately address the risk Their risks appear to be well known subject of this exemption including posed by these substances. locally where plants containing such epidemiological studies, nutritional These 21 substances, of the hundreds substances are consumed, and native assessments with human volunteers and of thousands of plant-produced methods of processing exist to reduce animal model testing, as well as substances in food, represent less than the potential for toxic effects (Ref. 22). information from the disciplines of one-tenth of 1% of the total number of Sparteine is a quinolizidine alkaloid plant genetics, plant physiology, constituents of food (Ref. 8). Of these 21 found in the lupines. The lupines are phytopathology, microbial ecology, substances, seven (acetylandromedol, forage or range crops, but can also be ecology, biochemistry (including studies andromedol, anhydroandromedol, cultivated for feed and have some on the constituents of food) and plant desacetylpireistoxin B, gelsamine, tutin, limited use in human food, primarily as
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a ‘‘traditional’’ grain used by indigenous present in edible squash and cucumbers some extent eggplant and peppers. A cultures in South America and the at very low levels. Cucurbitacins are related glycoalkaloid, tomatine, can be Mediterranean. The presence in the purgatives and impart a bitter taste to found in green tomatoes. The solanines plant of the quinolizidine alkaloids the fruit. Cucurbitacins if consumed at are membrane disruptors. Some appears to protect the plant against extremely high concentrations may members of the class have been shown fungal infection. Reduction of the levels cause stomach aches or cramps (Refs. 22 in vitro and through intraperitoneal and of quinolizidine alkaloids in the plant and 28). On rare occasions, in producing intravenous injection to be weak to can result in increased levels of seed for cultivated varieties, pollen from moderate cholinesterase inhibitors (Ref. potentially more hazardous mycotoxins. a wild relative may contaminate the 30). While solanine poisoning is very Toxic effects from consumption of food seed plot, resulting in seeds that may rare, in large doses solanine can cause containing higher levels of sparteine produce higher levels of cucurbitacin. gastrointestinal tract irritation, include breathing problems, weakness Breeding isolation is employed by seed including moderate nausea, vomiting and loss of motor control (Ref. 22, 23). producers to ensure that such and diarrhea, as well as headaches, These alkaloids can be removed by contamination does not occur (Refs. 7 drowsiness, sweating, changes in blood cooking, or by rinsing for several days and 22). pressure and heart rate, and edema (Ref. (Ref. 22, 24). Linamarin and lotaustralin (also 22). Solanine imparts a bitter taste to the Beta-N-oxalylamino-L-alanine is called phaseolutin) are cyanogenic tuber, and at high concentrations found in the seeds of the chickling glycosides (Refs. 8 and 22) solanine can leave a persistent irritation vetch. It is a neurotoxin that can cause biosynthesized by cassava and lima and burning sensation on the tongue spastic paralysis, probably by interfering beans. When the plant tissue is (Ref. 22). Potato varieties are bred and with the action of the neurotransmitter, damaged, enzymes are released that act monitored in the United States to ensure glutamate (Ref. 22, 25). Reported cases on the cyanogenic glycoside to produce that they produce only low levels of of toxicity are mostly confined to the hydrogen cyanide. The toxicity of solanine (Refs. 22 and 31). Monitoring Indian subcontinent. Most of the toxin cyanide is due to its ready reaction with for these glycoalkaloids also occurs can be leached out by soaking the seeds the iron atom of the enzyme, during the grading and shipping of in hot water for several minutes, cytochrome oxidase. The ability of the potatoes. Peeling or removing any followed by cooking. cell to utilize oxygen is inhibited by damaged portion of the potato is the Hypoglycin A is an amino acid formation of the cytochrome oxidase- best way to reduce solanine levels. In an analogue found in the immature ackee cyanide complex. Toxic effects undamaged, unsprouted potato, thirty to fruit that can result in severe associated with cyanide include eighty percent of the solanine is found hypoglycemia and vomiting. Ackee fruit neurological disorders, breathing in, and directly under, the skin. is primarily consumed in Africa and difficulties, and thyroid enlargement Cooking, e.g., boiling in steam or water Jamaica (Ref. 22). The primary method (Ref. 22). The lima bean varieties on the or deep frying in oil at 170 degrees, may of dealing with the potential adverse United States market today were bred lower solanine concentrations (Refs. 22 effect presented by hypoglycin A is and are monitored to ensure that they and 32). avoidance of (i.e., not consuming) produce very low levels of cyanogenic For the reasons described in the immature ackee fruit. glycosides (Refs. 22 and 29). Imported preceding paragraphs, EPA does not Of the remaining six substances, two lima beans are monitored to ensure only believe that this exemption would result (vicine and convicine) affect a small low levels of cyanogenic glycosides in levels in food of residues of these subpopulation of the United States (Refs. 22 and 29). Similarly, cassava four substances significantly different population. Vicine and convicine are used in the United States today comes from those observed in food currently found in the fava bean. Exposure of from varieties that were bred and are safely consumed. That there have been individuals with the Mediterranean monitored to ensure that they produce few instances in the United States of form of an inherited deficiency of the very low levels of cyanogenic toxic effects on humans due to enzyme, glucose-6-phosphate glycosides. Populations outside of the substances normally found in food from dehydrogenase (G6PD), to these United States (e.g., Africa) that consume plants in sexually compatible substances in the fava bean can result in cassava from varieties that produce populations in the past 50 years, despite an hemolytic anemia. The anemia is higher levels of cyanogenic the hundreds of food plant varieties manageable (Ref. 26). Physicians glycoalkaloids are aware of the risk from sexually compatible plant attempt to prevent hemolytic episodes associated with this food and use native populations going onto the market each by warning patients with the methods of processing (peeling, year (Ref. 8), supports a conclusion that Mediterranean form of G6PD deficiency chopping and grinding in running the probability of risk is low even for about the risks of consuming fava beans water, also boiling and fermentation) to the few substances discussed in this (Ref. 27). Thus, the primary strategy reduce the cyanogenic glycoside Unit. As an added protection, EPA has employed by persons with this G6PD content. Cases of toxicity are observed placed a condition limiting the deficiency with regard to food is primarily in these populations when the exemption to residues present in food avoidance of (i.e., not consuming) foods cassava is eaten without adequate from the plants at levels that are not containing fava beans. Drying the beans processing, because a scarcity of other injurious or deleterious to human or exposing them to sunlight reduces food items causes individuals to risk health. the potential for hemolytic episodes consuming inadequately processed 3. Relationship of studies to humans. (Ref. 22). cassava to ease their hunger (Ref. 26). EPA considered the available Several strategies, including breeding There are also ongoing breeding and information concerning the relationship for varieties that produce low levels of monitoring efforts to assist these to human risk of this information on the substances and monitoring, as well populations to reduce the cyanogenic residues in food of plant-incorporated as general knowledge in the population, glycoside content in cassava varieties protectants derived through reduce the potential for toxic effects to grown in their countries. conventional breeding from sexually occur with the remaining four toxicants The glycoalkaloids collectively compatible plants. The effect of these (cucurbitacin, linamarin, lotastralin, referred to in this document as solanine residues on humans was assessed in solanine). Cucurbitacins are naturally are biosynthesized by potatoes, and to light of the long history of human
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consumption of food derived from compatible plants, as well as other cumulatively when it addressed the plants, and from products such as meat substances present in food that may safety of food from plants in sexually and milk from animals that consume have a common mechanism of toxicity compatible populations. forage and other crops (e.g., corn and with such residues. Food from plants in sexually other grains), containing residues that i. What information is available on compatible populations is being safely are the subject of this exemption, and the cumulative effects of the residues consumed by humans either directly, or associated epidemiological studies, that are the subject of this exemption? indirectly in products such as meat and nutritional assessments with human A large amount of information exists for milk that are derived from animals that volunteers and animal model testing the residues that are the subject of this consume forage and other crops (e.g., (Refs. 8, 11, 12, 13, 14, 15, 16, 17, 18, exemption. The extensive information corn and other grains). The history of and 19). The epidemiological studies described in Unit IX.A. and Unit IX.B.1., safe consumption and the information and nutritional assessments performed e.g., epidemiological studies, nutritional base described in Unit IX.A. and Unit with human volunteers supply data assessment studies and animal model IX.B.1. indicates that any cumulative generated on humans and, thus, directly testing (Refs. 11, 12, 13, 14, 15, 16, 17, effects between substances in food that applicable to humans. Information from 18, and 19) indicates a very low may have a common mechanism with animal model testing as well as probability of harm. The few substances residues that are the subject of this information from the disciplines of occurring naturally in food from plants exemption present a very low plant genetics, plant physiology, that EPA has identified as being probability of harm. The analysis made phytopathology, microbial ecology, problematic are discussed in Unit in this preamble in Unit IX.B.6., ecology, biochemistry (including studies IX.B.2. A discussion of the variation in concerning potential increases in levels on the constituents of food) and plant the levels of substances that may be of residues apply equally to constituents breeding were also used to predict pesticide chemical residues and may of food that may have a common effects on humans. Because information occur naturally among the plants of a mechanism of action with residues that on human consumption of food derived sexually compatible population, and the are the subject of this exemption. from plants comprising sexually potential consequences of that variation Variations in the levels of these compatible populations was available are discussed in Unit IX.B.6. substances are not expected to be any and adequately addressed the issues of If information becomes available that different than those currently observed hazard and exposure for residues that indicates its analysis of cumulative in conventional breeding. Experience are the subject of this exemption, the effects in Unit IX.B.5., is no longer has shown that food from crop plants in Agency relied primarily on the consistent with the FFDCA exemption sexually compatible populations is safe epidemiological and other information standard for residues of a pesticidal for human consumption and/or generated directly from humans rather substance in this category, EPA will appropriate processing procedures are than relying on data generated in the consider the validity of the new widely known and routinely used by laboratory through animal testing. information and may act to amend this processors and consumers in preparing 4. Dietary consumption patterns. EPA tolerance exemption. food from such sources. Should EPA in considered the available information on ii. Are there substances that occur the future identify substances with a the varying dietary consumption naturally in food that may share a common mechanism of toxicity with the patterns of consumers and major common mechanism of toxicity with residues that are the subject of this identifiable consumer subgroups as it residues that are the subject of this exemption, both FIFRA and the FFDCA pertains to residues that are the subject exemption? Because of the conditions of give the Agency adequate authority to of this exemption. The consumption of this exemption, i.e., the genetic material take appropriate action to address any food from plants is part of a balanced leading to the production of the plant- risks these substances may present to and varied diet (Ref. 33). Humans have incorporated protectant is derived human health. Should substances in been consuming food containing through conventional breeding from food that may share a common substances that may be residues of plants sexually compatible with the mechanism of toxicity with residues plant-incorporated protectants derived recipient plant, the potential for new that are the subject of this exemption through conventional breeding from dietary exposures is low. Thus, EPA present cumulative effects resulting in sexually compatible plants and thus, all considered the effects of all the food safety concerns, the condition consumers, and all major identifiable substances in food from plants when it limiting this exemption at 40 CFR consumer subgroups, are, and have addressed the safety of food from plants 174.479 and the requirement to report been, exposed to the substances that are in sexually compatible populations, adverse effects at § 174.71 will provide the subject of this exemption. It is not including those that occur naturally in a mechanism to monitor the effects of anticipated that publication of this plants along with the substances that are this class of products and allow the EPA exemption from the requirement of a the subject of this exemption. Food from and FDA to act expeditiously. tolerance will affect current plants has hundreds of thousands of iii. Are there substances that do not consumption patterns of food from crop constituents, and EPA cannot rule out occur naturally in food that may share plants by consumers or major the possibility that in the foods humans a common mechanism of toxicity with identifiable consumer subgroups, and consume, common mechanisms of residues that are the subject of this thus no differences in exposure patterns action might exist between some of exemption? EPA examined two groups are anticipated. these substances and the various of substances to determine whether 5. Available information concerning residues that are the subject of this these substances have a common cumulative effects of the pesticide exemption. For example, the word mechanism of toxicity with residues chemical residue and other substances ‘‘solanine’’ generically refers to a group that could be the subject of this that have a common mechanism of of related steroid glycoalkaloids that exemption. toxicity. EPA examined available naturally occur in plants in the a. Do the organophophate and information on the cumulative effect of nightshade family such as potatoes, carbamate pesticides have a common residues of plant-incorporated eggplant, peppers and green tomatoes. mechanism of toxicity with the naturally protectants derived through EPA’s analysis considered the effects of occurring toxicants solanine? EPA conventional breeding from sexually these substances in food from plants examined certain of the
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organophosphate and carbamate consumed with raw agricultural constituent parts used as the building pesticides and the naturally-occurring produce. Certain microorganisms are blocks to make other biotic substances. toxicants, solanine (described in Unit deliberately consumed routinely in high Because of their biodegradable nature, IX.B.2.). EPA examined these substances numbers by humans with no ill effects the residues that are the subject of this because many members of these two (e.g., Marmite based on a yeast, natto exemption do not bioaccumulate classes of pesticides inhibit the based on the bacterium Bacillus subtilis, (bioaccumulation occurs when a cholinesterase enzymes (Refs. 30 and yogurt made with bacteria of the genus substance is taken into the body through 34), and some in vitro and Lactobacillus, cheese made with the processes such as eating, and as the intraperitoneal and intravenous fungus Penicillium roquefortii). This body is unable to either break the injection studies have shown that some base of experience with actual human substance down or eliminate it, the of the glycoalkaloids comprising the consumption indicates that should such substance accumulates in the tissues) or solanines also can inhibit these enzymes microbes have any metabolic pathways biomagnify in the tissues of living (Refs. 22 and 30). The solanines have in common with foodstuffs from plants, organisms (biomagnification occurs also been shown to disrupt cell the cumulative effect of substances from when a substance bioaccumulates in the membranes (Ref. 30). these pathways with residues that are bodies of organisms lower in the food EPA examined available information the subject of this exemption, presents chain, and as predators higher in the generated both in vitro and through in a very low probability of harm. food chain consume organisms lower in vivo animal studies on solanine. EPA c. Are there any other substances? the food chain, more and more of the gave greater weight in its analysis to EPA cannot rule out the possibility that substance accumulates in the bodies of information generated by animal studies there may be other substances outside of organisms higher in the food chain) as where the animals were exposed the food supply that may have a do such long-lived persistent substances through oral ingestion, as such studies common mechanism of toxicity with the such as DDT (Ref. 38). Humans are far more likely to provide residues that are the subject of this ingesting the substances that are the physiologically significant information. exemption, although it is not aware of subject of this exemption are likely to Animal studies performed with the any other such substances. Should EPA quickly degrade them and use their solanines administered to the animals in in future identify substances with a constituent elements as nutrients. similar manner that plant-incorporated common mechanism of toxicity other Because of these characteristics, the protectants would be presented in the than those found in food plants, both potential for exposures to the residues diet (i.e., through ingestion) show that FIFRA and the FFDCA give the Agency to occur, beyond direct physical death could not be attributed to adequate authority to take appropriate exposure to, or consumption of, the cholinesterase inhibition and its action. plant, is limited. This also contributes to neurotoxic consequences but was due to EPA’s conclusion that non-dietary 6. Aggregate exposures of consumers severe gastrointestinal necrosis from cell exposure (i.e., non-food oral, dermal including non-occupational exposures. membrane disruption (Ref. 35). and inhalation) in non-occupational Given this information, EPA has EPA considered the available settings is likely to be negligible. concluded that available information is information on the aggregate exposure i. Dietary exposures? As described in insufficient to create a presumption of level of consumers to the residues of Unit IX.A. and Unit IX.B.1., a large base the existence of a common mechanism plant-incorporated protectants derived of experience exists, including of toxicity between solanine and the through conventional breeding from information on human dietary exposure, organophosphate and carbamate sexually compatible plants, including for the residues exempted by this action. pesticides (Ref. 36), particularly as exposure to these substances in plants Moreover, dietary exposures other than animal studies suggest the solanines, when they are not intended to be used those for which a large base of when used as plant-incorporated as plant-incorporated protectants (i.e., information exists, are unlikely to result protectants, lead to the endpoint of when humans are not intending to use from this exemption for residues of death through membrane disruption. the substance for a pesticidal purpose). plant-incorporated protectants derived b. Do microorganisms have metabolic This evaluation included a through conventional breeding from pathways in common with plants? One consideration of exposures from dietary sexually compatible plants. Plants in a commenter, in response to the May 16, sources as well as from other non- sexually compatible population are 1997, supplemental document, occupational sources. Plant- likely to have similar genetic suggested that some microorganisms incorporated protectants and their information and have many traits in may have some metabolic pathways in residues are likely to present a limited common. Generations of directed common with plants, although the exposure to humans. In most cases, the breeding to produce improved crops for commenter was of the opinion that this predominant, if not the only, exposure cultivation have tended to increase the is not likely to be problematic. EPA route will be dietary. Exposure through relatedness, and reduce the genetic agrees that this route of exposure to any other routes is likely to be negligible variability, of populations of substances that may be related to because the substances are in the plant agricultural crop plants (Ref. 6). residues that are the subject of this tissue and thus are found either within Sexually compatible plants share a exemption is unlikely to be problematic, the plant or in close proximity to the common pool of genetic material, and and notes that possession of the same plant. movement of genetic material encoding metabolic pathways does not equate to In addition, the substances evolved by pesticidal substances between plants in expression of the same characteristics. populations of sexually compatible a sexually compatible population Raw plant foods commonly contain plants are part of the metabolic cycles through conventional breeding is hundreds to several million of these plants. These substances are unlikely to result in exposure of humans microorganisms per gram (Ref. 8). Some biotic and are subject to the processes of consuming food from such plants to of these microorganisms are biodegradation and decay that all biotic residues to which no humans commensals of the plant, others come materials undergo (Ref. 37). Biotic previously has been exposed and to from the natural environment of the materials are broken down to which the information base underlying plant (e.g., soil, water, air, other plants). constituent parts through the enzymatic this exemption cannot be applied. The Such microorganisms are routinely processes of living organisms, and these SAP Subpanel and the BSAC
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Subcommittee at the joint meeting held constraints on the extent to which because the exemption will not affect on January 21, 1994, supported this expression of any substance can be the ability of individuals to recognize conclusion and noted that genetic increased in highly managed food crop and avoid foods that cause them mapping of the genomes of both wild plants without unwanted effects on problems (Refs. 27, 39, and 40). For and crop plants reinforce the thesis that other, desirable characteristics of the example, the ability of persons who plants in sexually compatible plant such as yield or palatability. In have the Mediterranean form of the populations are likely to possess similar general, breeders balance a number of inherited G6PD deficiency to deal with genetic information (Ref. 6). It is likely characteristics (e.g., yield, palatability, their disease by avoiding (i.e., not that substances that are the subject of height, uniformity of seed drop) in consuming) fava beans or foods made this exemption are present at low developing marketable plant varieties. with fava beans will not be affected. The concentrations in the edible parts of Solanine and cucurbitacin, for example, substances in fava beans that can cause plants, and that such substances have affect palatability as they taste bitter to hemolytic anemias in such persons will long been part of the human diet. There humans. be exempt only if they are moved is no evidence at present in the many Moreover, in conventional breeding, through conventional breeding among studies performed on the relationship of plant breeders assess the new cultivar fava bean plants and plant varieties diet to health that food from plants in for food safety, based in part on sexually compatible with fava beans; a sexually compatible populations, knowledge of and familiarity with the population of plants in which such properly handled, has any significant characteristics of agricultural plants in substances normally occur, and the food adverse health effect (Refs. 8, 11, 12, 13, sexually compatible populations (Ref. of which individuals with the inherited 14, 15, 16, 17, 18, and 19). 22). EPA’s assessment of the likelihood G6PD deficiency avoid (Ref. 27). The primary exposure consideration of breeders ensuring that plants Similarly, the efficacy of the strategy of associated with the substances that are developed through conventional avoidance will not be affected for the subject of this exemption is whether breeding will continue to be safe for individuals suffering from food allergy the substances, identified in Unit IX.B.2. consumption is supported by the record (Ref. 39) or enteropathies such as celiac as toxic at higher concentrations, are of safety of the food products from disease (gluten-sensitive enteropathy) likely to be present in food from plants plants in sexually compatible (Ref. 40). Moreover, the efficacy of the in sexually compatible populations at populations. Although hundreds of new monitoring, processing, and preparation such concentrations. EPA carefully varieties come on the market each year, methodology which humans are familiar examined whether there are variations, within the past 50 years, conventional with and have been adequate in the past within and among food plant varieties plant breeding of plants in sexually to produce food safe for consumption in sexually compatible plant compatible populations has recorded will not be affected by publication of the populations, in levels of plant- very few instances of plant varieties exemption, e.g., the monitoring incorporated protectants and thus in the causing food safety problems. The two procedures for solanine used in the residues that are the subject of this identified instances (Ref. 8), high breeding and marketing of potatoes. exemption from the FFDCA requirement psoralen expressing celery that in the EPA believes the history of familiarity of a tolerance (Ref. 20). The amount of 1980s caused dermatitis in grocery with agricultural plants in sexually any substance produced by plants employees and the Lenape potato in the compatible populations, and thus with normally varies among members of a late 1960s with increased glycoalkaloid the likely progeny of genetic exchanges sexually compatible plant population levels, involved increases in the level of between plants in such populations because of the effects of conditions such known toxicants (which may or may not (Ref. 8), and the procedures currently as genetic constitution and environment be plant-incorporated protectants employed in plant breeding to screen (e.g., weather) (Refs. 8 and 20). Indeed, depending on whether humans intend out undesirable traits in such such variation is observed among plants to use these substances for preventing, populations, support a tolerance of the same variety. For example, one destroying, repelling or mitigating any exemption for residues of plant- researcher (Ref. 8) has shown a 20-fold pest). In both cases, the problem was incorporated protectants derived variation in the amount of ascorbic acid identified and the appropriate measures through conventional breeding from (3 to 61 mg/100g tissue) in different taken to protect the public health. In the sexually compatible plants. However, to varieties of muskmelon. Because such case of the Lenape potato, food ensure that the Agency can act variation is ubiquitous in populations, processors in routine screening detected expeditiously should any rare instances differences in the levels of exposure to the high levels of solanine and the of risk arise, EPA is placing at 40 CFR substances in plants are likely when potatoes were removed from the market 174.479 a condition on this exemption humans consume food from plants, before exposure of consumers (Ref. 8). from the requirement of a tolerance including differences in exposure to In contrast to these few problematic limiting the concentrations in food of residues that are the subject of this occurrences, there are many studies substances such as toxicants that may be exemption. Such variation is a natural indicating the health benefits of injurious or deleterious to human phenomenon common to all plants, consuming plant foods that likely health. EPA is also implementing an however, in controlled food production contain residues that are the subject of adverse effects reporting requirement at the variation in the substances this exemption (Refs. 8, 11, 12, 13, 14, § 174.71 that will serve to alert the identified in Unit IX.B.2. is limited (Ref. 15, 16, 17, 18, and 19). Agency to any such rare instances of 22). A second exposure consideration is risk. EPA also examined whether the levels whether this exemption will affect the One comment received in response to of substances any variety within a ability of individuals with food the May 16, 1997, supplemental sexually compatible population could sensitivities to manage these document (62 FR 27132), suggested that produce are likely to exceed the range sensitivities. To protect themselves, plant extracts might be used in some of low concentrations found in crop individuals with food sensitivities pharmaceutical preparations. The plant varieties safely consumed. For the generally avoid the food, and related commenter did not provide any following reasons, the Agency foods, that cause them problems (Ref. examples of these types of situations, concluded that such occurrences were 39). This exemption will not affect the nor any information on such extracts. unlikely. First, there are several efficacy of this strategy of avoidance, Without such additional information, it
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is difficult to determine whether the through the oral route has been unlikely to pass through the skin to extracts would contain substances examined in several animal species, and affect target organs. For those substances related to residues that are the subject it is estimated that the lethal dietary which possess to some degree properties of this exemption. However, even if dose for a 150 pound individual is 2.2 that allow some penetration of the skin, such related substances are present in kilograms (Refs. 22 and 45). Given the the potential amounts of such some pharmaceutical preparations, on a low toxicity of capsaicin, even if exposures, on a per person basis, are per person basis, the potential amounts capsaicin should penetrate through the likely to be negligible in comparison to involved in these exposures are likely to barrier of the skin, aggregate exposure potential exposure through the dietary be a negligible contribution to aggregate through the dermal and dietary routes is route, or do not cause adverse effects. exposure. The commenter also was of not anticipated to present harm. Dermal exposures are, thus, unlikely to the opinion that such uses are not likely A second substance examined contribute significantly to aggregate to be problematic. because of known effects beyond mild exposure. ii. Dermal exposure. With regard to dermatitis with dermal exposure are the One comment received in response to the dermal route of exposure, residues psoralens. These substances occur the May 16, 1997, supplemental of plant-incorporated protectants naturally in a wide range of plants but document (62 FR 27132) suggested that derived through conventional breeding occur in the highest concentrations in plant extracts might be used in some from sexually compatible plants may in celery, dill and parsley (Refs. 22 and cosmetic preparations. The commenter some cases be present in sap or other 41). Psoralens can be phototoxic to the was of the opinion that such uses are exudates from the plant or the food and skin in conjunction with sunlight (UV not likely to be problematic. The thus may present some limited light). Due to their relative solubility in commenter did not provide any opportunity for dermal exposure to oils, psoralens can penetrate into the examples of these types of extracts, nor persons coming physically into contact skin cells, where they intercalate into any information on the source or with the plant or raw agricultural food the genetic material of the skin cell composition of such extracts. Without from the plant. Individuals preparing (Refs. 22 and 41). Subsequent exposure such additional information, it is meals are those most likely to to sunlight (UV light) causes the genetic difficult to determine whether the experience dermal contact with the material to ‘‘cross link,’’ affecting the extracts would contain substances substances on a non-occupational basis. ability of the cell to further process its related to residues that are the subject Although contact dermatitis can occur genetic material. This may result in skin of this exemption. EPA is aware that from such exposure (Refs. 41 and 42), blisters and rashes. This UV-dependent some floral extracts are used in these reactions are generally mild, of a phototoxicity has also been implicated perfumes, e.g., lavender, jasmine, rose. self-limiting nature or self-diagnosed in mutations that may lead to skin However, lavender, jasmine and rose are and treated. cancer (Refs. 22 and 41). In spite of the not generally consumed as staple foods, Most of the substances that could be potential for this type of adverse effect although parts of these plants can be the subject of this exemption are with the psoralens, there are few brewed into teas or tisane. The amounts unlikely to pass through the skin to reported incidents for substances ingested through the tisane or by affect other organ systems (Refs. 41, 42, derived through conventional breeding passing through the skin from perfumes and 43). For those substances which from sexually compatible plants (Ref. 8). is likely to be very small. Further, EPA possess to some degree properties that Psoralens (supervised and in small is not aware of any reports of adverse allow some penetration of the skin, the doses) are also used in the treatment of effects from use of these flowers in potential amounts of such exposures, on a variety of skin diseases, including tisane or perfumes. Even if such a per person basis, are likely to be a vitiligo and psoriasis (Ref. 22), primarily substances are present in some cosmetic negligible contribution to aggregate through topical application. preparations, on a per person basis, the exposure, or do not present adverse The primary route through which potential amounts involved in these effects. humans in general are exposed to exposures are likely to be negligible. There are a few substances with the psoralens is dietary, and the psoralens EPA is also aware of other extracts ability to present an effect on dermal are not toxic when ingested. Given the used in perfumes from plants consumed exposure on a non-occupation basis, low oral toxicity, the supervised use of as food, e.g., carrot, fennel, garlic, that might be residues of plant- psoralen in medicine, the low lemon. Even if such substances are incorporated protectants, if humans concentrations of psoralen in celery, dill present in some cosmetic preparations, intend to use these substances as and parsley currently on the market, on a per person basis, the potential pesticides. For example, one substance and the condition EPA has placed on amounts involved in these exposures present in a food (condiment) this exemption limiting the amount of are likely to be a negligible contribution Americans might use in preparing meals substances in food that may have an to potential exposure through the and identified as a potential skin irritant injurious or deleterious effect on human dietary route. (Refs. 8 and 22) is the phenolic, health, EPA finds that for psoralen, were iii. Inhalation exposure. With regard capsaicin, found in cayenne pepper. this substance to be used as a plant- to exposure through inhalation, residues Capsaicin is used medically in a incorporated protectants derived of plant-incorporated protectants topically applied cream, which through conventional breeding from derived through conventional breeding facilitates passage of the capsaicin sexually compatible plants, there is a from sexually compatible plants may in across the barrier of the outer layer of reasonable certainty that no harm will some cases be present in pollen and the skin, at concentrations of 0.025 to result from aggregate exposure. some individuals (e.g., those living or 0.075% capsaicin. The cream is applied Those few substances from food working near enough to farms, nurseries up to four times daily for pain control plants discussed in Unit IX.B.2., which or other plant-growing areas to be and treatment of psoriasis (Refs. 22 and might be present in foods Americans exposed towind-blown pollen, or 44). Cayenne pepper can be used might use in preparing meals and which visiting such areas) may be exposed, liberally in the diet. Currently, cayenne at higher concentrations can cause through inhalation, to the pollen. On a pepper is exempt from the requirement adverse effects, do so when ingested per person basis, the potential amounts of tolerance when it is used on food (Refs. 22, 26, 29, and 31). Substances of pollen involved in these exposures crops (40 CFR 180.1165). Acute toxicity that are the subject of this exemption are are likely to be negligible in comparison
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to potential exposure through the the diet includes all of the food items tolerance. There is a long history of safe dietary route. Residues of the pesticidal that are customarily eaten by human human consumption of food containing substance will not in every case be populations or subpopulations. As residues that are the subject of this present in the pollen. When present in discussed in this preamble, this exemption, and of food derived from pollen, the residues are likely to be exemption will not affect the current animals that consume forage and other integrated into the tissue of the pollen pattern of exposure to residues that are crops containing these residues (e.g., grain. Pollen grains are solid, insoluble the subject of this exemption. corn and other grains). EPA thus was particles of sufficiently large diameter Individuals recognize and are familiar able to rely on epidemiological studies that they are filtered out in the with the plant-derived food they on humans, nutritional assessments nasopharynx or in the upper respiratory consume, and, based on prior with human volunteers and animal tract (Refs. 41 and 46). This exemption experience with food, individuals avoid model testing generated through a will not change current exposures nor consuming foods containing substances century of systematic scientific study affect strategies for dealing with they know, either through personal and available in the public literature residues that are the subject of the experience or through acquired (Refs. 8, 11, 12, 13, 14, 15, 16, 17, 18, exemption. (Ref. 41). knowledge, cause them problems (Refs. and 19). EPA also relied on knowledge iv. Drinking water. EPA also evaluated 8, 39, and 40). Because the exposure from the disciplines of plant genetics, potential non-occupational exposures in pattern will not be affected by plant physiology, phytopathology, drinking water. The substances in plants publication of this exemption, the microbial ecology, ecology, or parts of plants, including residues of efficacy of the current strategy whereby biochemistry (including studies on plant-incorporated protectants derived sensitive individuals recognize and plant constituents) and plant breeding. through conventional breeding from avoid foods known to cause them EPA believes that long-term evidence of sexually compatible plants, are problems will not be affected by this human consumption and the large base produced and used inside the living exemption (Ref. 39, 40). For example, of scientific data generated by plant itself. The residues are part of the the ability of persons who have the epidemiological studies on humans and living tissue of the plant. When the Mediterranean form of the inherited nutritional assessments with human plant dies or a part is removed from the G6PD deficiency to deal with their volunteers, with a more limited reliance plant, microorganisms colonizing the disease by avoiding (i.e., not on animal experimentation data, is the tissue immediately begin to degrade it, consuming) fava beans will not be appropriate information for evaluating using the components of the tissue affected. Thus, no subgroup should be whether residues of plant-incorporated (including any residues that are the adversely affected by the exemption. protectants derived through subject of this exemption in the tissue) 8. Estrogenic or other endocrine conventional breeding from sexually as building blocks for making their own effects. While there is some information compatible plants warrant exemption. cellular components or for fueling their on estrogenic effects from exposure to Because EPA was able to rely on data own metabolisms. The residues that certain pesticides, the data are limited. from humans, the Agency concluded EPA is exempting in this action, It is known that certain food plants (e.g., that a safety factor designed to account including those identified at Unit soybeans) contain estrogen mimics, for uncertainties in extrapolating from IX.B.2., as toxic at higher termed phytoestrogens. Such animal data would not be necessary. In concentrations, are subject to the same phytoestrogens are currently being addition, because the available processes of biodegradation and decay consumed by humans in food derived epidemiological and other information that all biotic materials undergo. This from plants and are part of the extensive generated on humans was based on turnover of biotic materials in nature history of safe human consumption of studies employing very large numbers of through a process of biodegradation food from plants. Although no individuals, the Agency concluded that occurs fairly rapidly (Ref. 37). There is information was submitted to EPA on a ten-fold safety factor to account for no indication that naturally-occurring this issue despite the Agency uncertainties in analyzing the human plant biotic materials, including the specifically soliciting it in the May 16, data would not be necessary. residues that are the subject of this 1997, supplemental document (62 FR 10. Infants and children. EPA exemption, are resistant to 27132), EPA cannot rule out the considered available information on biodegradation. Because of the fairly possibility that such phytoestrogens consumption patterns of infants and rapid turnover of these residues, even if could be used as plant-incorporated children, including special sensitivity, they reach surface waters (through protectants. Potential exposure of cumulative effects of residues of plant- pollen dispersal or parts of the plants humans via consumption of plant tissue incorporated protectants derived (leaves, fruits etc.) falling into bodies of to phytoestrogens exerting estrogenic through conventional breeding from water), they are unlikely to present effects and used as plant-incorporated sexually compatible plants with other anything other than a negligible protectants may need to be considered substances that may have a common exposure in drinking water drawn either as EPA examines the issue of endocrine mechanism of toxicity with these from surface or ground water sources. disruptors. If dietary exposure to residues, and the need for a margin of v. Residential exposure. EPA is not phytoestrogens (that are also plant- safety for infants and children. aware of any residential uses of plant- incorporated protectants) is discovered i. Dietary consumption patterns. EPA incorporated protectants that might to be a significant factor, the Agency considered available information on the result in exposure to residues that are will re-examine this exemption from the dietary consumption pattern of infants the subject of this exemption. requirement of a tolerance in light of and children as pertains to residues of 7. Sensitivities of subgroups. EPA that information. plant-incorporated protectants derived considered available information on the 9. Safety factors. EPA did not rely through conventional breeding from sensitivities of subgroups as it pertains solely on available animal data in sexually compatible plants. The range of to residues of plant-incorporated reaching its determination that residues foods consumed by infants and children protectants derived through of plant-incorporated protectants is in general more limited than the range conventional breeding from sexually derived through conventional breeding of foods consumed by adults. Most compatible plants. In performing its from sexually compatible plants can be newborns rely on milk products for assessment, the Agency considered that exempted from the requirement of a nutrition, although some infants are fed
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soy-based products. Soy-based products mechanism of toxicity. EPA examined containing residues of plant- may contain residues that are the the available information on the incorporated protectants derived subject of this exemption. Infants begin cumulative effect of residues of plant- through conventional breeding from as early as four months of age to incorporated protectants derived sexually compatible plants is safe for consume specific types of solid foods through conventional breeding from infants and children, and that a margin from plants that may contain residues sexually compatible plants as well as of safety need not be applied for these that are the subject of this exemption. other substances in food that may have residues in food. Subsequent to four months of age, apart a common mechanism of toxicity with 11. Analytical methods. EPA has from processing to facilitate swallowing, these residues. The Agency’s decided that there is no need to employ the diets of infants begin to be based on consideration of the effects of the a practical method for detecting and foods consumed by the general adult residues that are the subject of this measuring the levels of most of the population albeit in different exemption, and other substances that substances in plants that might be used proportions. As infants and children have a common mechanism of toxicity, as plant-incorporated protectants and mature, more and more of the foods in Unit IX.B.5. and Unit IX.B.6., thus might be residues of plant- normally consumed by adults become included consideration of effects on incorporated protectants derived part of their diets and the relative infants and children. through conventional breeding from proportions of the different types of iv. Margin of safety. In determining sexually compatible plants. It is not food consumed changes to more closely whether the residues of plant- anticipated that these substances would cause adverse effects. EPA has resemble an adult diet. The substances incorporated protectants derived identified nine substances of plant that are the subject of this exemption through conventional breeding from origin that are found in plants that are occur in the normal diet. They have sexually compatible plants are safe, part of the normal American diet and if been consumed by infants and children FFDCA section 408(b)(2)(C) directs EPA present at high levels can present toxic over very long periods of time and in the case of threshold effects to apply effects. These are discussed in Unit currently are being consumed by infants a tenfold margin of safety for the IX.B.2. Practical methods exist for and children. Exposure as part of a residues and other sources of exposure detecting and measuring the normal diet to these substances is highly to infants and children to account for unlikely to lead to harm to infants and concentration of these substances in potential prenatal and postnatal toxicity children. As the diets of humans change food (Ref. 22). EPA consulted with the and completeness of data effects with from infancy through childhood and Department of Health and Human respect to exposure and toxicity to into adulthood, there is some possibility Services (DHHS) in developing the infants and children, unless a different that the amount of the substances that proposed exemption and in issuing this margin will be safe (21 U.S.C. are the subject of this exemption being final rule. 346a(b)(2)(C)). For residues of plant- consumed may change with those incorporated protectants derived C. Determination of Safety for United consuming the greatest amounts of food through conventional breeding from States Population, and Infants and of plant origin receiving the highest sexually compatible plants, EPA has Children exposure to substances that are the subject of this exemption. There is no determined that a tenfold margin of Based on the information discussed in evidence that such changes are likely to safety is not necessary to protect infants this document today and that discussed result in disproportionately high and children. EPA reaches this in the 1994 Federal Register documents consumption of these residues in determination based on valid, complete and the supplemental documents and comparison to the general population. and reliable information. EPA based its the associated record as described in The evidence strongly suggests that assessment of exposure and toxicity Unit X., EPA concludes that there is a consumption of foods containing the upon the information base described in reasonable certainty that no harm will substances that are the subject of this Unit IX.A. and Unit IX.B.1. (Refs. 8, 11, result to the United States population in exemption, including changes in 12, 13, 14, 15, 16, 17, 18, and 19) that general, and infants and children in the exposure because of changes in the arose through the long history of human United States, from aggregate exposure relative proportions of the different consumption of food containing to any residues of the pesticidal types of food consumed from infancy substances which are the subject of this substance portion, or inert ingredients, through childhood and into adulthood, exemption, and other animals that of plant-incorporated protectants is highly unlikely to lead to any harm. consume plants containing these derived through conventional breeding ii. Special susceptibility. EPA substances, and other substances in food from plants sexually compatible with considered available information on the that may have a common mechanism of the recipient plant, including all potential for special susceptibility of toxicity (Ref. 8). EPA also relied upon anticipated dietary exposures and all infants and children, including prenatal knowledge from the disciplines of plant other exposures for which there is and postnatal toxicity, to residues of genetics, plant physiology, reliable information. This finding is plant-incorporated protectants derived phytopathology, microbial ecology, based on extensive use and experience, through conventional breeding from ecology, biochemistry (including the and the large associated literature on sexually compatible plants. The constituents of food) and plant breeding. epidemiological studies, nutritional substances that are the subject of this Based on all of this information, EPA assessments with human volunteers and exemption occur in the normal diet, and concludes that it is unlikely that animal model testing of foods from there is no evidence that exposure to consumption of food containing plant varieties developed by moving such residues, as components of food, residues that are the subject of this traits among plants in sexually present a different level of dietary risk exemption, including changes in compatible populations. This for infants and children, in light of exposure because of changes in the information shows that adverse effects neurological differences between infants relative proportions of the different due to aggregate exposure through the and children and adults, than they types of food consumed from infancy dietary, non-food oral, dermal and would present for the adult population. through childhood and into adulthood, inhalation routes are highly unlikely for iii. Cumulative effects of residues with would lead to any harm. Thus, EPA has pesticidal substances, or inert other substances with a common concluded that consumption of food ingredients, derived through
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conventional breeding from plants New York Academy of Sciences. Vol. bladder cancer in a male prospective sexually compatible with the recipient 672. The New York Academy of cohort. Journal of the National Cancer plant. And in the unlikely event such Sciences. New York, New York. Institute. Apr7;91(7):605–13. adverse effects do occur, EPA has 10. Environmental Protection Agency. 20. Environmental Protection Agency implemented mechanisms to ensure that Meeting of the EPA Biotechnology issue paper. 1994. FIFRA: Benefit and it will be notified, and that FDA will be Science Advisory Committee (BSAC); environmental risk considerations for able to seize the adulterated food; i.e., Subcommittee on plant-pesticides. July inherent plant-pesticides. the adverse effects reporting 13, 1993. Final Report. 21. Agrios, George. 1988. Plant requirement at 40 CFR 174.71 and the 11. World Cancer Research Fund and Pathology. Third Edition. Academic condition limiting this exemption at American Institute for Cancer Research. Press. New York, New York. § 174.479. 1997. Food, Nutrition and the 22. Environmental Protection Agency Prevention of Cancer: A Global issue paper. 2000. Natural toxicants in X. Documents in the Official Record Perspective. BANTA Book Group, food. As indicated in Unit I.B.2., the official Menasha, Wisconsin. 23. USDA Agricultural Research record for this rule has been established 12. Lampe, J. M. 1999. Health effects Service Poisonous Plant Research under docket control number OPP– of vegetables and fruit: assessing Laboratory. Bulletin 415: Poisonous 300368B, the public version of which is mechanisms of action in human plants of the western United States: available for inspection as specified in experimental studies. American Journal Neurotoxic and mycotoxic plants. Unit I.B.2. of Clinical Nutrition. Sep;70(3 [http://www.pprl.usu.edu/bulletin.htm] Suppl):475S–490S. 24. Hernando, J. E. and J. Leon (eds) A. References 13. Ogomoto, I. A. Shibata and K. Neglected Crops: 1492 from a different The following books, articles and Fukuda. 2000. World Cancer perspective. FAO Plant production and reports were used in preparing this final ResearchFund/American Institute of protection series No. 26. Rome Italy, p. rule and were cited in this document by Cancer Research 1997 recommendation: 131–148. 1994. the number indicated: applicability to digestive tract cancer in 25. Shibamoto, T. And L.F. Bjeldanes. 1. Whittaker, R. H. 1969. New Japan. Cancer Causes Control 1993. Introduction to Food Toxicology. concepts of kingdoms of organisms. Jan;11(1):9–23. Academic Press, Inc. San Diego, New Science, 163:150–160. 14. Joseph, J. A., B. Shukitt-Hale, N. York, Boston. 2. Environmental Protection Agency. A. Denisova, D. Bielinski, A. Martin, J. 26. Ellenhorn, M. J. S. Schonwald, G. 2000. Summary of public comments and J. McEwen and P. C. Bickford. 1999. Ordog and J. Wasserberger. 1997. EPA responses on issues associated with Reversals of age-related declines in Ellenhorn’s Medical Toxicology: plant-incorporated protectants (formerly neuronal signal transduction, cognitive, Diagnosis and Treatment of Human plant-pesticides) for docket OPP– and motor behavioral deficits with Poisoning. Second Edition. Williams 300368 and OPP–300368A. blueberry, spinach, or strawberry and Wilkins. Baltimore, MD 3. Hanson, M., and J. Halloran. In a dietary supplementation.Journal of 27. Cooper, R. A., and H. F. Bunn. letter dated February 22, 1995 on Neuroscience. Sep 15;19(18):8114–21. Hemolytic anemias. 1980. In: Harrison’s dockets OPP–300367 through OPP– 15. Segasothy, M. and P. A. Phillips. Principles of Internal Medicine. Edited 300371. 1999. Vegetarian diet: panacea for by. K. J. Isselbacher, R. D. Adams, E. 4. Goldburg, R. In a letter dated modern lifestyle diseases? QJM Monthly Braunwald, R. G. Petersdorf and J. D. February 6, 1995 on dockets OPP– Journal of the Association of Physicians. Wilson. McGraw-Hill Company. 300367 through OPP–300371. Sep;92(9):531–44. 28. Coulston, F., and A. C. Kolbye. 5. Rissler, J., and M. Mellon. In a letter 16. Joshipura, K. J., A. Ascherio, J. E. 1990. (Eds) Regulatory Toxicology and dated January 23, 1995 on dockets OPP– Manson, M. J. Stampfer, E. B. Rimm, F. Pharmacology. 12(3), S20–S30. 300367 through OPP–300371. E. Speizer, C. H. Hennekens, D. 29. Concon, J. M. 1988. Food 6. Environmental Protection Agency. Spiegelman and W. C. Willett. 1999. Toxicology: Principles and Concepts. 1994. Joint meeting of the FIFRA Fruit and vegetable intake in relation to Marcel Decker Inc. New York and Basel. Scientific Advisory Panel (SAP); risk of ischemic stroke. Journal of the 30. Environmental Protection Agency Subpanel on plant-pesticides, and the American Medical Association. issue paper. 2000. The glycoalkaloid EPA Biotechnology Science Advisory Oct6;282(13)1233–9. class; solanine and chaconine: Committee (BSAC); Subcommittee on 17. Thompson, H. J., J. Heimendinger, Mechanisms of action. plant-pesticides. January 21, 1994. Final A. Haegele, S. M. Sedlacek, C. Gillette, 31. D’Mello, J. P. F. 1997. Handbook Report. C. O’Neill, P. Wolfe and C. Conry. 1999. of Plant and Fungal Toxicants. CBC 7. Raven, P. H., R. F. Evert, and S. E. Effect of increased vegetable and fruit Press. Boca Raton, New York. Eichhorn. 1992. Biology of Plants. Fifth consumption on markers of oxidative 32. Tice, R. 1998. Chacoline and Edition. Worth Publishers, New York, cellular damage. Carcinogenesis. solanine: Review of the Toxicological New York. Dec;20(12):2261–6. Literature. Prepared for E. Zeiger, 8. International Food Biotechnology 18. New, S. A., S. P. Robins, M. K. National Toxicology Program, National Council. 1990. Biotechnologies and Campbell, J. C. Martin, M. J. Garton, C. Institute of Environmental Health food; Assuring the safety of foods Boltin-Smith, D. A. Grubb, S. J. Lee and Sciences, National Institutes of Health. produced by genetic modification. In: D. M. Reid. 2000. Dietary influences on [http://ntp-server.niehs.nih.gov/htd. Regulatory Toxicology and bone mass and bone metabolism: further ...und/ExecSumm/ Pharmacology. Vol 12. Academic Press, evidence of a positive link between fruit ChaconineSolanine.html New York, New York. and vegetable consumption and bone 33. Environmental Protection Agency. 9. Wilks, H. M., A. Cortes, D. C. health?American Journal of Clinical 2000. Benefits of fruits and vegetables. Emery, D. J. Halsall, A. R. Clarke and J. Nutrition. Jan;71(1):142–51. 34. Taylor, P. 1996. J. Holbrook. 1992. Opportunities and 19. Michaud, D. S., D. Spiegelman, S. Anticholinesterase agents. In: Goodman limits in creating new enzymes. In: K. Clinton, E. B. Rimm, W. C. Willett and Gilman’s The Pharmacological Enzyme Engineering XI. Edited by D. S. and E. L. Giovannucci. 1999. Fruit and Basis of Therapeutics. Ninth Edition. Clark and D. A. Estell. Annals of the vegetable intake and incidence of Edited by J. G. Hardman, L. E. Limbird,
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P. B. Molinoff, and R. W. Rudden. B. Additional Information Notice of Proposed Rulemaking’’ (62 FR McGraw-Hill Health Profession The complete official record for this 27149, May 16, 1997) (FRL–5716–6). Division. New York, New York. rulemaking includes: The docket identified by the docket 35. Baker, D. C., R. F. Keeler, and W. The docket identified by the docket control number OPP–30069A for the P. Gaffield. 1988. Mechanism of death control number OPP–300370 for the document entitled ‘‘Plant-Pesticides, in syrian hamsters gavaged potato document entitled ‘‘Proposed Policy: Supplemental Notice of Availability of sprout material. Toxicologic Pathology. Plant-Pesticides Subject to the Federal Information’’ (64 FR 19958, April 23, Vol. 16:333 Insecticide, Fungicide, and Rodenticide 1999) (FRL–6077–6). The docket identified by the docket 36. Environmental Protection Agency. Act and the Federal Food, Drug, and control number OPP–300371B for the 1999. Guidance for identifying pesticide Cosmetic Act’’ (59 FR 60496, November companion document entitled chemicals and other substances that 23, 1994) (FRL–4755–2). ‘‘Exemption from the Requirement of a have a common mechanism of toxicity. The docket identified by the docket Tolerance Under the Federal Food, FAX-on-Demand Number : (202) 401– control number OPP–300369 for the Drug, and Cosmetic Act for Residues of 0527. Item: 6055. document entitled ‘‘Plant-Pesticides Nucleic Acids that are Part of Plant- 37. Atlas, R. and R. Bartha. 1987. Subject to the Federal Insecticide, Incorporated Protectants (Formerly Microbial Ecology. Benjamin/Cummings Fungicide and Rodenticide Act; Plant-Pesticides)’’ (FRL–6057–5) Publishing Company, Inc. Menlo Park, Proposed Rule’’ (59 FR 60519, published elsewhere in this issue of the California. November 23, 1994) (FRL–4755–3). The docket identified by the docket Federal Register. 38. National Research Council. 1999. The docket identified by the docket control number OPP–300368 for the Hormonally Active Agents in the control number OPP–300369B for the document entitled ‘‘Plant-Pesticides; Environment. National Academy Press. document entitled ‘‘Regulations Under Proposed Exemption From the Washington DC. the Federal Insecticide, Fungicide, and Requirement of a Tolerance Under the 39. Yunginger, J. W. 1991. Food Rodenticide Act for Plant-Incorporated Federal Food, Drug, and Cosmetic Act’’ Antigens. In: Food Allergy: Adverse Protectants (Formerly Plant-Pesticides)’’ (59 FR 60535, November 23, 1994) Reactions to Foods and Food Additives. (FRL–6057–7)published elsewhere in (FRL–4758–8). Edited by D. D. Metcalfe, H. A. this issue of the Federal Register. The docket identified by the docket Sampson, and R. A. Simon. Blackwell The docket identified by the docket control number OPP–300371 for the Scientific Publications. Cambridge, control number OPP–300368B for this document entitled ‘‘Plant-Pesticides; Massachusetts. document (FRL–6057–6). 40. O’Mahony, S. And A. Ferguson. Proposed Exemption From the Also include in the complete official 1991. Gluten-Sensitive Enteropathy Requirement of a Tolerance Under the public record are: (Celiac Disease). In: Food Allergy: Federal Food, Drug, and Cosmetic Act 1. Public comments submitted in Adverse Reactions to Foods and Food for Nucleic Acids Produced in Plants’’ response to the proposals and Additives. Edited by D. D. Metcalfe, H. (59 FR 60542, November 23, 1994) supplemental documents cited in this A. Sampson, and R. A. Simon. (FRL–4755–5). Unit X.B. Blackwell Scientific Publications. The docket identified by the docket 2. Reports of all meetings of the Cambridge, Massachusetts. control number OPP–300367 for the Biotechnology Science Advisory 41. Environmental Protection Agency document entitled ‘‘Plant-Pesticides; Committee and the FIFRA Science issue paper. 2000. Dermal and Proposed Exemption From the Advisory Panel pertaining to the inhalation exposure to plant substances. Requirement of a Tolerance Under the development of this final rule. Federal Food, Drug, and Cosmetic Act 42. Lovell, C. R. 1993. Plants and the 3. The Economic Analysis (EA) for the for Viral Coat Proteins Produced in skin. First edition. Oxford, Blackwell final rule on FIFRA regulations for Plants’’ (59 FR 60545, November 23, Scientific Publications. plant-incorporated protectants, and 1994) (FRL–4755–4). documents supporting the EA (Ref. 47). 43. Guy, R. H., and J. Hadgraft. 1991. The docket identified by the docket Principles of skin permeability relevant 4. Support documents and reports. control number OPP–300370A for the 5. Records of all communications to chemical exposure. In: Dermal and document entitled ‘‘Plant-Pesticide Ocular Toxicology: Fundamentals and between EPA personnel and persons Subject to the Federal Insecticide, outside EPA pertaining to the final rule. Methods. Edited by D. W. Hobson. CRC Fungicide, and Rodenticide Act and the Press Boca Raton, Florida. (This does not include any inter-agency Federal Food, Drug, and Cosmetic Act; and intra-agency memoranda, unless 44. Murray, M. T. 1995. The Healing Reopening of Comment Period’’ (61 FR specifically noted in the Indices of the Power of Herbs. Prima Publishing, 37891, July 22, 1996) (FRL–5387–4). dockets). Rocklin, California. The docket identified by the docket 6. Published literature that is cited in 45. Glinsukon, T., Stitmunnaithum, control number OPP–300368A for the this document. V., Toskulkao, C., Buranawuti, T., and document entitled ‘‘Plant-Pesticides; 7. The response to comments V. Tangkrisanavinont. Acute toxicity of Supplemental Notice of Proposed document pertaining to the capsaicin in several animal species. Rulemaking’’ (62 FR 27132, May 16, development of this final rule (Ref. 2). Toxicon. 18(2):215–20. 1980. 1997) (FRL–5717–2). 46. Environmental Protection Agency. The docket identified by the docket XI. Regulatory Assessment 1997. Exposure Factors Handbook. control number OPP–300371A for the Requirements Volume 1. National Center for document entitled ‘‘Plant-Pesticides; This final rule establishes an Environmental Assessment. EPA/600/P– Nucleic Acids; Supplemental Notice of exemption from the tolerance 95/002Fa. Proposed Rulemaking’’ (62 FR 27142, requirement under FFDCA section 408 47. Environmental Protection Agency. May 16, 1997) (FRL–5716–7). and does not impose any other 2000. Economic analysis of the plant- The docket identified by the docket regulatory requirements. As such, The incorporated protectant regulations control number OPP–300367A for the Office of Management and Budget under the Federal Insecticide, document entitled ‘‘Plant-Pesticides; (OMB) has exempted these types of Fungicide, and Rodenticide Act. Viral Coat Proteins; Supplemental actions from review under Executive
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Order 12866, entitled Regulatory any substantial direct effect on States, submit a rule report, which includes a Planning and Review (58 FR 51735, on the relationship between the national copy of the rule, to each House of the October 4, 1993). government and the States, or on the Congress and to the Comptroller General This action does not contain any distribution of power and of the United States. EPA will submit a information collections subject to OMB responsibilities among the various report containing this rule and other approval under the Paperwork levels of government, as specified in required information to the U.S. Senate, Reduction Act (PRA), 44 U.S.C. 3501 et Executive Order 13132, entitled the U.S. House of Representatives, and seq., nor does it require OMB review or Federalism (64 FR 43255, August 10, the Comptroller General of the United any Agency action under Executive 1999). This rule directly regulates States prior to publication of this final Order 13045, entitled Protection of growers, food processors, food handlers rule in the Federal Register. This final Children from Environmental Health and food retailers, not States. This rule is not a ‘‘major rule’’ as defined by Risks and Safety Risks (62 FR 19885, action does not alter the relationships or 5 U.S.C. 804(2). distribution of power and April 23, 1997). List of Subjects in 40 CFR Part 174 This action does not require any responsibilities established by Congress special considerations under Executive in the preemption provisions of FFDCA Environmental protection, Order 12898, entitled Federal Actions to section 408(n)(4). Administrative practice and procedure, Address Environmental Justice in Pursuant to section 605(b) of the Agricultural commodities, Pesticides Minority Populations and Low-Income Regulatory Flexibility Act (RFA) (5 and pests, Plants, Reporting and Populations (59 FR 7629, February 16, U.S.C. 601 et seq.), the Agency hereby recordkeeping requirements. 1994), nor does it involve any technical certifies that this final rule will not have standards that would require Agency a significant economic impact on a Dated: July 12, 2001. consideration of voluntary consensus substantial number of small entities. Christine T. Whitman, standards pursuant to section 12(d) of The Agency’s determination is based on Administrator. the National Technology Transfer and the fact that an exemption from the requirement of a tolerance under Therefore, 40 CFR chapter I is Advancement Act of 1995 (NTTAA), amended as follows: Public Law 104–113, section 12(d) (15 FFDCA section 408, such as that U.S.C. 272 note). contained in this rule, will not PART 174—[AMENDED] adversely affect any small businesses. This action does not impose any Additional information about the enforceable duty or contain any 1. The authority citation for part 174 Agency’s determination may be found unfunded mandate, and will not continues to read as follows: in the small entity impact analysis otherwise significantly or uniquely prepared as part of the economic Authority: 7 U.S.C. 136–136y and 21 affect small governments as described analysis for the FIFRA rulemaking, U.S.C. 346a and 371. under Title II of the Unfunded Mandates which is available in the public version 2. Section 174.479 is added to subpart Reform Act of 1995 (UMRA) (Public of the official record under OPP– W to read as follows: Law 104–4). This rule does not 300368B (Ref. 47). The Agency has also significantly or uniquely affect the previously assessed whether § 174.479 Pesticidal substance from communities of Indian trial establishing tolerances, exemptions sexually compatible plant; exemption from the requirement of a tolerance. governments, nor does it involve or from tolerances, raising tolerance levels impose any requirements that affect or expanding exemptions might Residues of a pesticidal substance that Indian Tribes. Accordingly, the adversely impact small entities and is part of a plant-incorporated protectant requirements of section 3(b) of concluded, as a general matter, that from a sexually compatible plant are Executive Order 13084, entitled there is no adverse economic impact exempt from the requirement of a Consultation and Coordination with associated with these actions. See 46 FR tolerance if all the following conditions Indian Tribal Governments (63 FR 24950, May 4, 1981. are met: 27655, May 19, 1998), do not apply to This rule is not subject to Executive (a) The genetic material that encodes this rule. Executive Order 13175, Order 13211, entitled Actions for the pesticidal substance or leads to entitled Consultation and Coordination Concerning Regulations That the production of the pesticidal with Indian Tribal Governments (65 FR Significantly Affect Energy Supply, substance is from a plant that is sexually 67249, November 6, 2000), which took Distribution, or Use (66 FR 28355, May compatible with the recipient food effect on January 6, 2001, revokes 22, 2001), because this action is not plant. Executive Order 13084 as of that date. expected to affect energy supply, (b) The genetic material has never EPA developed this rulemaking, distribution, or use. been derived from a source that is not however, during the period when XII. Submission to Congress and the sexually compatible with the recipient Executive Order 13084 was in effect; food plant. thus, EPA addressed tribal Comptroller General (c) The residues of the pesticidal considerations under Executive Order The Congressional Review Act, 5 substance are not present in food from 13084. For the same reasons stated for U.S.C. 801 et seq., as added by the Small the plant at levels that are injurious or Executive Order 13084, the Business Regulatory Enforcement deleterious to human health. requirements of Executive Order 13175 Fairness Act of 1996, generally provides do not apply to this rule either. For the that before a rule may take effect, the [FR Doc. 01–17983 Filed 7–16–01; 11:42 am] same reasons, this rule does not have agency promulgating the rule must BILLING CODE 6560–50–S
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