Premarket Notice Concerning Bioengineered Foods

FDA, HHS Proposed Rule [Docket No. 00N-1396] RIN 0910-AC15

Published in the Federal Register 18jan01

Comments due 20feb01

Federal Register 66 FR 4706 January 18, 2001
Premarket Notice Concerning Bioengineered Foods
(Proposed Rule)
[Federal Register: January 18, 2001 (Volume 66, Number 12)]
[Proposed Rules]
[Page 4706-4738]
From the Federal Register Online via GPO Access [ wais.access.gpo.gov  ]
[DOCID:fr18ja01-29]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
21 CFR Parts 192 and 592
[Docket No. 00N-1396] RIN 0910-AC15
Premarket Notice Concerning Bioengineered Foods
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to require the submission to the agency of data and information regarding plant- derived bioengineered foods that would be consumed by humans or animals. FDA is proposing that this submission be made at least 120 days prior to the commercial distribution of such foods. FDA is taking this action to ensure that it has the appropriate amount of information about bioengineered foods to help to ensure that all market entry decisions by the industry are made consistently and in full compliance with the law. The proposed action will permit the agency to assess on an ongoing basis whether plant-derived bioengineered foods comply with the standards of the Federal Food, Drug, and Cosmetic Act (the act).

DATES: Submit written comments on the proposed rule by April 3, 2001. Submit written comments on the information collection provisions by February 20, 2001. See section XIV of this document for the proposed effective date of a final rule based on this document.

ADDRESSES: Submit written comments to the Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit written comments on the information collection provisions to the Office of Information and Regulatory Affairs, OMB, New Executive Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, Attn: Desk Officer for FDA.

FOR FURTHER INFORMATION CONTACT: Regarding human food issues: Linda S. Kahl, Center for Food Safety and Applied Nutrition (HFS-206), Food and Drug Administration, 200 C St. SW., Washington, DC 20204, 202-418-3101. Regarding animal feed issues: William D. Price, Center for Veterinary Medicine (CVM) (HFV-200), Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855, 301-827-6652.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background A. The 1992 Policy B. Consultations Under the 1992 Policy and the 1996 Procedures C. Public Meetings II. Legal Authority III. Scope IV. Definitions V. Requirement for Premarket Biotechnology Notice A. Foods That Are Subject to the Requirement B. Origin of Data and Information C. Timing VI. Recommendation for Presubmission Consultation A. Presubmission Consultation Program B. Public Disclosure C. Standard Procedures VII. Premarket Biotechnology Notice: Administrative Information A. Submissions to CFSAN for Use in Human Food, Animal Feed, or Both B. Paper Copies C. Electronic Copies D. English Language Translations, Incorporation by Reference, and Available Guidance Documents E. Opportunity to Withdraw VIII. Premarket Biotechnology Notice: Required Parts A. Part I: Letter

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1. Statements Regarding the Notifier's Responsibility and the Balanced Nature of the Notice 2. Statements Regarding the Availability of Data and Information for FDA's Review 3. Statement Regarding Public Disclosure B. Part II: Synopsis C. Part III: Status at Other Federal Agencies and Foreign Governments D. Part IV: Method of Development E. Part V: Antibiotic Resistance F. Part VI: Substances in the Food 1. Covered Substances 2. Identity, Function, Level, and Dietary Exposure 3. Allergenicity 4. Other Safety Issues G. Part VII: Data and Information About the Food 1. Comparable Food 2. Historic Uses of the Comparable Food 3. Comparing the Composition and Characteristics of the Bioengineered Food to That of Comparable Food 4. Other Relevant Information 5. Narrative IX. Agency Administration of a Premarket Biotechnology Notice A. Filing Decision B. Acknowledgment Letter C. Response Letter 1. General Categories for FDA's Response a. Letter That Extends FDA's Evaluation b. Letter That the Notice Does Not Provide a Basis c. Letter That FDA Has No Questions d. Letter That a Notifier Has Withdrawn the Notice 2. Status of the Bioengineered Food at EPA X. Public Disclosure A. Existence of the Notice B. Content of the Notice C. Disclosure of FDA's Evaluation of, and Response to, a Notice XI. Proposed Regulations Regarding Bioengineered Foods That Would Be Used in Animal Feed XII. Paperwork Reduction Act A. Hourly Burden to Prepare a Report (Proposed Sec. 192.20(a) through (b)(1) and Sec. 192.25 B. Hourly Reporting Burden Associated With Confidential Information in a Report (Proposed Sec. 192.20(b)(2)(i) and (b)(2)(ii) C. Hourly Reporting Burden Associated With Electronic Copies of the Report (Proposed Sec. 192.20(c)(1) and (c)(2) D. Hourly Reporting Burden Associated With English Language Translations, Authorization to Incorporate Information by Reference, and Withdrawal (Proposed Sec. 192.20(d), (e), and (g) E. Hourly Reporting Burden Associated With a Voluntary Presubmission Consultation Program (Proposed Sec. 192.10(e) through (g), (h)(2), (h)(3)(i), and (h)(3)(ii) F. Hourly Recordkeeping Burden (Proposed Sec. 192.25(a)(2) XIII. Analysis of Economic Impacts A. Cost-Benefit Analysis B. Background 1. Benefits 2. Costs C. Regulatory Flexibility Act D. Unfunded Mandates Reform Act XIV. Effective Date XV. Environmental Impact XVI. Comments XVII. References

I. Background

A. The 1992 Policy

In the Federal Register of May 29, 1992 (57 FR 22984), FDA published its ``Statement of Policy: Foods Derived From New Plant Varieties'' (the 1992 policy). The 1992 policy clarified the agency's interpretation of the application of the act with respect to human foods and animal feeds derived from new plant varieties, including varieties that are developed using recombinant deoxyribonucleic acid (rDNA) technology. This proposal refers to foods derived from plant varieties that are developed using in vitro manipulations of DNA (generally referred to as rDNA technology) as ``bioengineered foods.'' The 1992 policy provided guidance to industry on scientific and regulatory issues related to plant-derived foods, including bioengineered foods. In developing the 1992 policy as it relates to bioengineered foods, FDA focused on modifications to foods that were likely to result in commercial products and did not attempt to predict future changes in foods that could result from technological advances. Instead, FDA intended to modify its policy as circumstances warranted (57 FR 22984 at 22985). In announcing the 1992 policy, FDA invited interested persons to submit written comments. Comments received from the scientific community generally have supported the scientific guidance articulated in the 1992 policy, including the scientific guidance as it relates to bioengineered foods. In addition, the views expressed by the members of FDA's Food Advisory Committee (Ref. 1) and the joint meeting of FDA's Food Advisory Committee and Veterinary Medicine Advisory Committee (Ref. 2), generally supported the scientific guidance in the 1992 policy. However, many consumers, a number of public interest groups, and some State officials have expressed concern about or opposed the regulatory guidance articulated in the 1992 policy, particularly regarding the ability of the regulated industry to make market entry decisions. Frequently, those comments suggested, as an important adjunct to the 1992 policy, that FDA require an administrative process, such as premarket notification, to ensure that the agency remains aware of new bioengineered foods entering commercial distribution.\1\ ---------------------------------------------------------------------------

\1\ This document defines ``commercial distribution'' as the introduction, or delivery for introduction, into interstate commerce for sale or exchange for consumption in any form by humans or other animals. ---------------------------------------------------------------------------

FDA is confident that the guidance articulated in the 1992 policy adequately addressed both the scientific and regulatory issues raised by the products that were approaching commercialization in 1992. FDA is aware, however, that rDNA technology continues to evolve and that it is not possible for the agency to anticipate all of the novel scientific and regulatory issues that may arise as the number and types of foods developed using this technology expands. As discussed more fully below, this proposed rule would modify the regulatory guidance laid out in the 1992 policy by requiring the submission to the agency of data and information regarding plant-derived bioengineered foods at least 120 days prior to the commercial distribution of such foods.

B. Consultations Under the 1992 Policy and the 1996 Procedures

In the 1992 policy, FDA explained that, under the act, developers of new foods have a responsibility to ensure that the foods they offer to consumers are safe and in compliance with all requirements of the act (57 FR 22984 at 22985). In light of this responsibility, FDA has long regarded it to be a prudent practice for producers who use new technologies in the manufacture or development of foods and food ingredients to work cooperatively with FDA to ensure that the products of these new technologies are safe and comply with all applicable legal requirements (57 FR 22984 at 22991). Historically, the food industry generally has initiated consultation with FDA during the pioneer stages of a new technology, even if there is no legal obligation to do so. These consultations have served to make FDA aware of foods and food ingredients before these products are distributed commercially, and have provided FDA with the information necessary to address any questions regarding the safety, labeling, or regulatory status of the food or food ingredient. As such, these consultations have provided assistance to both industry and the agency in exercising their mutual responsibilities under the act. In the 1992 policy, FDA noted that the agency expected this practice of consultation to continue with respect to bioengineered foods (57 FR 22984 at 22991). One early example of such a

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consultation involved FLAVR SAVRTM tomatoes.\2\ In developing FLAVR SAVTM tomatoes, Calgene used rDNA technology to introduce an antisense polygalacturonase gene, which was derived from tomatoes, and the kanamycin resistance gene (the kan r gene), which encodes the enzyme aminoglycoside-3'- phosphotransferase II (APH(3')II). The enzyme APH(3')II confers resistance to the clinically used antibiotics kanamycin and neomycin in the selection of new plant varieties developed using rDNA technology. The use of APH(3')II raised several issues that had not previously been evaluated by the agency in the context of food safety. The initial consultation between the agency and Calgene about the intended use of APH(3')II, which in this instance resulted in the filing and approval of a food additive petition (59 FR 26700, May 23, 1994), was an effective mechanism to fully explore and resolve these issues. ---------------------------------------------------------------------------

\2\ This consultation was concluded in May 1994 (59 FR 26647 at 26700, May 23, 1994). ---------------------------------------------------------------------------

The resolution of these and other scientific issues entailed the use of nontraditional approaches to the evaluation of food safety. For example, traditional evaluation of the safety of a food additive frequently includes toxicological tests conducted in accordance with the principles outlined in the agency's ``Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food'' (Redbook (Ref. 3)).\3\ In addition to guidance on when certain tests may be appropriate, the Redbook includes specific recommendations on the protocols for conducting such tests. ---------------------------------------------------------------------------

\3\ In 1993, the Center for Food Safety and Applied Nutrition (CFSAN) released a revised Redbook for public comment (58 FR 16536, March 29, 1993). Following its evaluation of comments on each draft chapter of the Redbook, CFSAN is making revised chapters available on its Internet site (Ref. 4). ---------------------------------------------------------------------------

In contrast, issues raised during the consultations on APH(3')II and the FLAVR SAVRTM tomato required evaluation of data generated using procedures that had only rarely been used in the evaluation of food safety. For example, Calgene used ``Southern blots'' to determine which DNA sequences had been transferred to FLAVR SAVRTM tomatoes, ``Northern blots'' to demonstrate the intended technical effect in FLAVR SAVRTM tomatoes, and ``Western blots'' to determine the amount of APH(3')II present in FLAVR SAVRTM tomatoes. The use of nontraditional strategies in the evaluation of food safety likely will become the norm as the use of rDNA technology expands, and further consultations between industry and the agency would foster the identification and design of reasonable test procedures to evaluate the composition and safety of whole foods. Consultations are an appropriate forum for industry and the agency to address proactively issues that are relevant to bioengineered foods, and developers have actively consulted with FDA about their products since the issuance of the 1992 policy. In June 1996, FDA provided guidance to industry on procedures for these consultations (the 1996 procedures (Ref. 5)).\4\ Under that process, a developer who intends to commercialize a bioengineered food meets with the agency to identify and discuss relevant safety, nutritional, or other regulatory issues regarding the bioengineered food prior to marketing it. Depending on the experience the agency and the developer have with the kind of modification being considered, a developer may initiate such a consultation early or late in the development of the food. When the developer believes that it has accumulated adequate data or information to address any issues raised during the consultation, the developer begins the ``final consultation'' by submitting to FDA a summary of its scientific and regulatory assessment of the food. To date, the agency has completed its evaluation of data or other information from more than 45 such consultations (Ref. 6). FDA believes that, to date, all developers of bioengineered foods commercially marketed in the United States have consulted with the agency prior to marketing the food. ---------------------------------------------------------------------------

\4\ In October 1997, FDA made administrative revisions to these procedures to reflect reorganizations within the Office of Premarket Approval, CFSAN, and the Center for Veterinary Medicine (CVM). In this document, FDA refers to these procedures as ``the 1996 procedures'' to reflect the year that the agency made them available. ---------------------------------------------------------------------------

FDA continues to believe that the consultation process is appropriate for bioengineered foods. Accordingly, this proposed rulemaking includes FDA's recommendation that developers consult with the agency to identify and discuss relevant safety, nutritional, or other regulatory issues regarding a bioengineered food (see proposed Sec. 192.10 and section VI of this document).

C. Public Meetings

In 1999, FDA announced that the agency would hold three public meetings, each in a different region of the United States (64 FR 57470, October 25, 1999). The purpose of those meetings was for the agency to share its current approach and experience over the past 5 years regarding bioengineered foods, to solicit views on whether FDA's policies or procedures should be modified, and to gather information to be used to assess the most appropriate means of providing information to the public about bioengineered products in the food supply. In the notice announcing the public meetings (64 FR 57470), FDA requested comments on specific questions regarding bioengineered foods. As a result of those meetings and the request for comments, the agency subsequently received more than 35,000 written comments about its policy regarding bioengineered foods. At those meetings, and in the comments, FDA heard three messages very clearly. First, there does not appear to be any new scientific information that raises questions about the safety of bioengineered foods currently being marketed. Second, some of the public is concerned about FDA's existing guidance and regulatory approach to overseeing the safety of these products. These concerns include whether FDA's guidance and regulatory approach will be adequate for future developments and whether firms will continue to inform FDA about new bioengineered foods under the present program. In addition, there was a concern that the current regulatory process lacks transparency (e.g., because FDA discloses each consultation about a bioengineered food only at the end of the process). Third, there are very strongly held but divergent views as to whether bioengineered foods should bear special labeling. However, there was general agreement that providing more information to consumers about bioengineered foods would be useful \5\ (Ref. 8). ---------------------------------------------------------------------------

\5\ In May 2000, FDA announced that it intended to issue for public comment draft labeling guidance to aid manufacturers who wish to voluntarily label their products as made with or without the use of bioengineering or bioengineered ingredients (Ref. 7). The development of that draft guidance is outside the scope of this document. ---------------------------------------------------------------------------

II. Legal Authority

FDA is responsible for ensuring that all foods \6\ in the American food supply conform to the applicable provisions of the law. The act provides FDA with broad authority to regulate the safety and wholesomeness of food. In particular, the act prohibits the adulteration of food under section 402 of the act (21 U.S.C. 342) and the misbranding of food under section 403

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of the act (21 U.S.C. 343). The act also requires that all food additives (as defined by section 201(s) of the act (21 U.S.C. 321(s))) be approved by FDA before they are marketed (sections 409 and 402 of the act (21 U.S.C. 348(a) and 342(a)(2)(C))). FDA is authorized to seek sanctions against foods that do not adhere to the act's standards, through seizure of foods that violate the act under section 304 of the act (21 U.S.C. 334); the agency is also authorized to seek an injunction against, or criminal prosecution of, those responsible for introducing such foods into commerce under sections 302 and 303 of the act (21 U.S.C. 332 and 333). ---------------------------------------------------------------------------

\6\ There are certain exceptions to this jurisdiction pertaining to meat, poultry, and egg products that are not relevant to this rulemaking. ---------------------------------------------------------------------------

All plant breeding techniques have the potential to alter food source crops in ways relevant to the legal status of food derived from such crops. However, rDNA technology greatly facilitates, relative to traditional breeding techniques, both the introduction of specific new substances into foods and the directed modification of the composition of foods. This is in part because the technology expands the range of sources of new substances that can be introduced into plants, relative to those that can be introduced with traditional techniques, due principally to rDNA technology's ability to permit the transfer to a food crop of genetic material from virtually any organism. Similarly, at the present time, information related to the genomes of many organisms is rapidly expanding, with the result that newly identified genes are now available to breeders. In addition, rDNA technology increases the speed by which traits can be introduced into food crops, by allowing the introduction of specific, well-characterized genetic material and by reducing the need for backcrossing to remove undesirable traits. Given the efficiencies of rDNA techniques, the advances in these techniques, and the rapidly expanding information related to genomes, FDA expects that these techniques are likely to be utilized to an increasingly greater extent by plant breeders and that the products of this technology are likely in some cases to present more complex safety and regulatory issues than seen to date. Alterations in food source plants accomplished using rDNA technology, with resulting changes in the foods derived from such plants, can present a range of regulatory issues (57 FR 22984 to 23005). For example, such alterations may present questions as to the food additive status of the substances introduced into the food as a result of the genetic transformation. As noted, bioengineering permits the introduction into food of substances from any source, and the number and types of genes available for use in rDNA technology are rapidly increasing. Thus, increasingly, substances may be introduced into food using rDNA techniques that cannot be introduced by traditional breeding. FDA noted in the 1992 policy that a nonpesticidal substance introduced into food by way of breeding is a food additive if the substance is not generally recognized as safe (GRAS) within the meaning of 21 U.S.C. 321(s). Because of the greater range of sources of substances that can be introduced into plants via rDNA technology, there is a greater likelihood that some of the new substances will be significantly different from substances that have a history of safe use in food or may otherwise not satisfy the GRAS standard in section 201(s) of the act(s). Thus, there is a greater potential for foods developed using rDNA technology to contain substances that are food additives. The agency reiterates its view, as stated in the 1992 policy (57 FR 22990), that transferred genetic material can be presumed to be GRAS. Likewise, FDA is not altering its view, as set forth in the 1992 policy, that there is unlikely to be a safety question sufficient to question the presumed GRAS status of the proteins (typically enzymes) produced from the transferred genetic material, or of substances produced by the action of the introduced enzymes (such as carbohydrates, fats, and oils), when these proteins or other substances do not differ significantly from other substances commonly found in food and are already present at generally comparable or greater levels in currently consumed foods. However, FDA recognizes that because breeders utilizing rDNA technology can introduce genetic material from a much wider range of sources than previously possible, there is a greater likelihood that the modified food will contain substances that are significantly different from, or are present in food at a significantly higher level than, counterpart substances historically consumed in food. In such circumstances, the new substances may not be GRAS and may require regulation as food additives (57 FR 22990). To date, FDA has not seen multiple examples of food additive substances introduced into food using rDNA technology. However, the agency recognizes that the potential for introducing such substances is real. There are, for example, certain plant-derived proteins that have a sweetening effect but whose biochemical function is not known.\7\ In addition, they are found in plants that have not been used for food. Thus, in contrast to other proteins introduced into foods by genetic engineering, which have been presumed GRAS, there is little or no apparent basis for a GRAS presumption for such substances. Genes encoding the protein sweetener could be introduced into a fruit to enhance sweetness. In such circumstances, FDA should be made aware of the intended marketing of the modified food and have access to relevant information to evaluate whether the protein sweetener is a food additive within the act's definition under section 201(s) of the act. If the protein sweetener is a food additive, premarket approval of the substance would be required under section 409 of the act before the altered food could be lawfully marketed. ---------------------------------------------------------------------------

\7\ The proteins apparently do not make the plants more attractive to insects or animals, and thus would not likely function as natural sweeteners in plants in the wild. ---------------------------------------------------------------------------

Another potential consequence of transferring genetic material from one source into another is the possibility of introducing a food allergen that would not be expected to be in a particular food, a change that would be relevant to the legal status of such food. This is because genes code for proteins, and virtually all allergens are proteins (although only a small subset of proteins are allergens). Thus, by increasing the range of potential proteins that can be introduced into food over that possible by traditional breeding, there is an increased potential for introducing an allergen into a food developed using rDNA technology. Also, rDNA technology can be used to express proteins at higher concentrations than they would otherwise be expressed; these higher concentrations may increase the potential for such proteins to be allergenic. One implication of being able to transfer genes between unrelated plants using rDNA techniques is that it is possible to transfer genes from one food plant to another quite unrelated food plant, thereby allowing the potential transfer of an allergen from the first plant to the second. In such a case, food from the bioengineered plant could have an allergenic characteristic completely different from that of its conventional counterpart. Such a change would not be evident to the consumer. For example, a gene from a Brazil nut plant was introduced into a soy plant to improve the protein content of soy beans for use in animal feed. The seed was never commercialized, however, because when the company tested the

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soy beans for allergenicity, they found that people allergic to Brazil nuts were also allergic to the bioengineered soy (Refs. 9 and 10). Given the potential consequences to sensitive consumers of eating soy products containing a Brazil nut allergen, such a food would likely be considered misbranded within the meaning of sections 201(n) and 403(a)(1) of the act, unless the presence of the new allergen were disclosed to consumers. Further, in certain circumstances, labeling may not be adequate or practical to ensure that consumers are aware of the presence of unexpected allergens. FDA would likely consider such food containing an unexpected allergen to be adulterated within the meaning of section 402(a)(1) of the act because the unexpected allergen rendered the food possibly injurious to health. With alterations of this type, FDA should be made aware of the modification and have an opportunity to assess whether and how the food could legally be marketed. Specifically, FDA should have the opportunity to consider whether any labeling proposed by the developer would ensure that the engineered food is not misbranded within the meaning of sections 201(n) and 403(a)(1) of the act, and whether, even with labeling, the food would be adulterated because it may be injurious to health within the meaning of section 402(a)(1) of the act. Compositional changes in foods created through breeding may also present regulatory status issues. Although traditional breeding techniques can be used to alter significantly the compositional characteristics of food, rDNA technology enhances that ability because rDNA technology enables breeders to make targeted changes in plant components such as proteins and other constituents. For example, rDNA techniques would facilitate a breeder's ability to modify a soy plant so that the composition of oil derived from the plant would more closely resemble that of a tropical oil than that of conventional soy oil. In these circumstances, the name ``soy oil'' would likely not be suitable for the oil derived from the altered soy plant because the composition of the new oil is significantly different from what is customarily understood to be ``soy oil''. Thus, a new common or usual name would likely be required for this new oil to ensure that the oil is not misbranded under section 403(i)(1) of the act. FDA should be made aware of compositional changes of this type so that the agency may consider whether a new common or usual name is required and, if so, what that new name should be. Additionally, rDNA technology has recently begun to be used to introduce multiple genes to generate new metabolic pathways (Ref. 11). New metabolic pathways are intended to result in the synthesis of substances not normally present in the host plant. Such modifications may alter the composition of the food in a significant manner that may raise nutritional or safety issues or that would require use of a new common or usual name. In addition to enabling breeders to introduce desired new characteristics into foods, all breeding methods used to develop new plant varieties have a potential for unintentionally introducing undesired new characteristics into foods (57 FR 22986). Broadly speaking, a breeding method's potential for introducing unintended changes to the characteristics of a food results either from bringing into a food plant extraneous genetic material encoding trait(s) additional to the desired trait(s), or from introducing mutations (such as deletions, amplifications, insertions, rearrangements, or DNA base- pair changes) into the plant's native genetic material that alter some characteristic(s) of the food. The most commonly used breeding method is a ``narrow cross,'' which is hybridization between varieties of the same species. Hybridization between related species or genera that cannot be cross-fertilized is a ``wide cross.'' Wide crosses are useful for expanding the range of genetic source material that can be introduced into food crops, but are performed relatively infrequently because of technical and logistical difficulties. Both wide and narrow crosses will introduce into plants extraneous genetic material along with the genetic material encoding the desired traits. Breeders then attempt to remove any undesired traits through extensive backcrossing. Plant breeders also use mutagenic techniques to modify plants. These techniques include random mutagenesis using a mutagenic agent and somaclonal variation. (Somaclonal variation refers to the process of growing a plant up from tissue culture and observing for phenotypic changes, which are often due to chromosomal rearrangements or other mutations.) Both techniques can introduce undesirable mutations along with possible desirable mutations. As with hybridization, breeders perform backcrosses to eliminate any undesirable traits. Cell fusion poses similar issues to those posed by wide crosses (because it generally is performed between cells of different species of plants) and posed by somaclonal variation (because it involves growing a plant up from tissue culture). Recombinant DNA technology greatly reduces the likelihood of introducing extraneous genetic material, as compared with hybridization, because it enables breeders to introduce only the gene or genes of interest, with little or no extraneous deoxyribonucleic acid (DNA). However, it shares with mutagenesis techniques a potential for introducing unintended effects through mutations. In part, this is because rDNA technology involves growing plants from tissue culture, which can exhibit somaclonal variation, and, more significantly, because breeders using this technology generally cannot control the location in the plant genome at which genetic material will insert when introduced into a plant. Thus, with rDNA technology, the introduced genetic segment may insert into a genetically active chromosomal location. Such insertion may disrupt or inactivate an important gene or a regulatory sequence that affects the expression of one or several genes, thereby potentially affecting adversely the safety of the food or raising other regulatory issues. Such an occurrence is referred to as an insertional mutation. FDA believes that in the future, plant breeders will increasingly use rDNA techniques to achieve more complicated compositional changes to food, sometimes introducing multiple genes residing on multiple vectors to generate new metabolic pathways. FDA expects that with the increased introduction of multiple genes, unintended effects may become more common. For example, rice modified to express pro-vitamin A was shown to exhibit increased concentrations of xanthophylls (Ref. 11), and rice modified to reduce the concentration of a specific protein was found to exhibit an increased concentration of prolamine (Ref. 12). FDA believes that the use of rDNA techniques in plant breeding may lead to unintended changes in foods that raise adulteration or misbranding questions. These unintended changes may cause a food to be adulterated because the food may be rendered injurious to health within the meaning of section 402(a)(1) of the act, or, in the absence of a new common or usual name, cause the food to be misbranded under section 403(i)(1) of the act. Because of its role in ensuring the safety of the U.S. food supply, FDA needs to be aware of the modifications to food source plants from the application of rDNA technology and any unintended effects in food that result so that the agency can evaluate whether the foods

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from such plants are adulterated or misbranded. Because some rDNA-induced unintended changes are specific to a transformational event (e.g., those resulting from insertional mutagenesis), FDA believes that it needs to be provided with information about foods from all separate transformational events, even when the agency has been provided with information about foods from rDNA-modified plants with the same intended new trait and has had no questions about such foods. Similarly, the agency believes that it needs to be provided with information about foods from rDNA-modified plants whose intended change is the introduction of a pesticidal protein subject to oversight by the Environmental Protection Agency (EPA) rather than by FDA, because the transformational event that is used to introduce the pesticidal trait may also cause unintended changes to the food that would raise adulteration or misbranding questions subject to FDA jurisdiction. In contrast, the agency does not believe that it needs to receive information about foods from plants derived through narrow crosses (including narrow crosses between different rDNA-modified lines). Narrow crosses, because they generally are performed between varieties that are themselves used in food or are very closely related to varieties used in food, are unlikely to introduce extraneous DNA that encodes traits that have not been in food before. In addition, plant lines used for narrow crosses generally have been subject to extensive backcrossing and field testing to ensure genetic stability (including lack of any active transposons that could cause insertional mutagenesis). Finally, because the plant lines are closely related to each other, crosses between them will involve homologous recombination and thus are unlikely to be subject to insertional mutagenesis. Therefore, narrow crosses are unlikely to result in unintended changes to foods that raise safety or other regulatory questions. The agency recognizes that unintended changes associated with other non-rDNA breeding methods may pose regulatory questions similar to those posed by rDNA methods. For example, wide crosses, especially between a food plant variety and an undomesticated nonfood plant variety, have much greater potential than do narrow crosses for introducing unintended traits that may alter the safety of the food; undomesticated plants frequently produce toxins at levels unsafe for human consumption, and may also produce substances not found in food. The agency has not found it necessary to assess routinely the safety of foods derived from such breeding methods, because over the last 50 to 60 years that some of these techniques have been used in plant breeding, breeders have used well-established practices successfully to identify and eliminate, prior to commercial use, plants that exhibit unexpected adverse traits. The agency is not aware of a basis for additional FDA oversight of foods derived from plants modified by such techniques, given that there has not been such a need in the past and that there do not appear to be any significant changes in breeders' use of such techniques that would warrant new FDA oversight. Rather, because of the technical advantages of rDNA methods over these other techniques, FDA anticipates that, in the future, breeders will likely use non-rDNA methods less frequently to introduce new characteristics into food plants as they increasingly utilize rDNA techniques. Likewise, despite the similar potential for unintended effects, FDA believes that declining to propose a requirement that the agency be notified about the commercialization of food source plants transformed using techniques other than rDNA is consistent with its current conclusion that, unexpected effects aside, rDNA techniques have a greater potential, relative to conventional methods of breeding, to result in the development of foods that present legal status questions. The agency therefore is not proposing to include foods from crops modified by methods other than rDNA techniques within the scope of this proposed notification rule. The agency requests comment as to whether it should include foods from crops developed by wide crosses or other breeding methods in the scope of any final rule based upon this proposal. FDA recognizes that whether there is a change in the legal status of a food resulting from a particular rDNA modification depends almost entirely on the nature of the modification, and that not every modification accomplished with rDNA techniques will alter the legal status of the food. In other words, many modifications will result in a food that does not contain an unapproved food additive, does not contain an unexpected allergen, and does not differ significantly in its composition compared with its traditional counterpart or otherwise require special labeling. For this reason, FDA is neither proposing to require premarket approval for all foods developed using rDNA technology nor is the agency proposing an across-the-board requirement that all such foods bear special labeling. There is substantial basis to conclude, however, that there is greater potential for breeders, using rDNA technology, to develop and commercialize foods that are more likely to present legal status issues and thus require greater FDA scrutiny than those developed using traditional or other breeding techniques. It was in part for this reason that, in 1994, the agency initiated a consultation process. Since that time, developers have actively consulted with FDA regarding their new plant varieties; under this process, the agency has completed its evaluation of data and other information from some 45 consultations. As noted, FDA believes that, to date, the developer of each rDNA variety commercially marketed in the United States has consulted with the agency prior to marketing food from the new variety. But these products represent only a small fraction of the potential products of rDNA technology.\8\ Additionally, in general, the introduced traits have been agronomic in nature (i.e., directed at the characteristics of the plant and not at the characteristics of the food produced by the plant). However, this picture is rapidly changing. The current list, which is provided by the Animal and Plant Health Inspection Service (APHIS) in the U. S. Department of Agriculture (USDA), of field tests of plants being developed using rDNA technology shows that the plants under development have a broader variety of introduced traits (Ref. 13). Additionally, that list shows that many such traits are not simply agronomic, but are intended to modify the food itself, and thus would be more likely than in the past to raise regulatory issues falling under FDA's purview.\9\ Finally, as noted previously, FDA believes that, given the efficiencies of rDNA techniques, the advances in these techniques, and the rapidly expanding information related to genomes, these techniques are likely

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to be utilized by plant breeders to an increasingly greater extent. ---------------------------------------------------------------------------

\8\ For example, in the 45 consultations completed under the 1992 policy, only 11 different commodities are represented, including 12 consultations on corn, 7 on canola, 6 on tomatoes, 5 on cotton, and 4 on potatoes. Moreover, the 45 consultations do not represent 45 separate types of modifications; rather, these 45 consultations represent only 9 general types of modifications. These modifications were herbicide resistance, insect and virus resistance, delayed ripening or softening, male sterility or fertility restorer, high phosphorus availability, and modified oil. \9\ These include modifications for altered protein quality, increased carotenoid content, increased fruit solids, altered fiber quality, and increased fruit sweetness, among others. ---------------------------------------------------------------------------

The confluence of the increasingly broader use of rDNA techniques to develop foods for human and animal use and the globalization of the world's food supply also suggest that FDA needs to be aware of the various foods developed using rDNA technology. Currently, approximately 45 percent of the United States' plant-derived food is imported, and that percentage continues to increase. The agency expects that rDNA techniques may, over time, be used increasingly by plant breeders and developers in countries that export foods to this country. In such circumstances, the accuracy of FDA's knowledge about the presence in the U.S. food supply of foods developed using rDNA techniques is likely to decrease. In addition, the awareness of particular food allergies is not uniform throughout the world because the diets of some populations do not contain sufficiently large amounts of a food such that the allergic potential has been demonstrated; in these circumstances, it is particularly important that FDA be aware of imported foods modified using rDNA techniques that may unexpectedly contain a substance that is an allergen. For all these reasons, FDA believes that the food products of rDNA technology are appropriately made subject to greater regulatory scrutiny by FDA in the form of enhanced agency awareness of all such foods intended for commercial distribution. This increased agency awareness will ensure that at this stage of this continuously evolving technology, all market entry decisions about new bioengineered foods, including those intended for import into the United States, are made consistently and in full compliance with the law. Similarly, in order for the agency to evaluate fully and consistently the possible regulatory consequences of the alterations made possible using rDNA technology, FDA must be made aware of the bioengineered foods entering commercial distribution. Section 701(a) of the act (21 U.S.C. 371(a)) authorizes the Secretary of the Department of Health and Human Services (the Secretary) to issue regulations for the efficient enforcement of the act; under section 903(d)(2) of the act (21 U.S.C. 393(d)(2), the Secretary is responsible for executing the act, including section 701(a), through the Commissioner of Food and Drugs. The authority under section 701(a) of the act to issue regulations under the act extends to both regulations that supplement a specific statutory mandate as well as regulations that are justified by the statutory scheme as a whole. (See National Confectioner's Association v. Califano, 569 F.2d 690, 693 (D.C. Cir. 1978), citing Toilet Goods Association v. Gardner, 387 U.S. 158, 163 (1967).) In assessing a regulation issued under section 701(a), it is important to consider both the statutory purpose as well as the practical aspects of the situation, including the possible enforcement problems that may be encountered by FDA. (See National Confectioner's Association v. Califano, 569 F.2d 690, 693 (D.C. Cir. 1978), citing Toilet Goods Association v. Gardner, 387 U.S. 158, 163 (1967).) To ensure that FDA has the maximum amount of information about foods from bioengineered plants, the agency has tentatively concluded that, prior to initiation of commercial distribution in the United States of a bioengineered food, FDA must be notified of the intent to market such food, including foods intended for import into the United States. Notification will ensure that the agency is aware of all bioengineered foods entering commercial distribution that are subject to FDA's jurisdiction and will help to ensure that all market entry decisions by the industry are made consistently and in full compliance with the law. This will permit the agency to assess on an ongoing basis whether foods developed using rDNA technology comply with the standards of the act. FDA believes that it is essential that all those developing and marketing bioengineered foods participate fully and completely in the proposed notification program. Therefore, the agency is proposing that the notification program that is described in this document be mandatory. Accordingly, for the reasons set forth above concerning the special circumstances of bioengineered foods, to enforce the act efficiently, and in particular, to administer efficiently the act's various provisions that relate to food as such provisions apply to bioengineered food, including section 301 of the act (21 U.S.C. 331) and sections 402, 403, and 409 of the act, FDA is proposing regulations to require that the agency be notified at least 120 days prior to the initiation of commercial distribution in the United States of a bioengineered food. The elements of FDA's proposed program are discussed in detail below.

III. Scope

FDA is proposing to require the submission to the agency of data and information regarding plant-derived bioengineered foods that would be consumed by humans or animals. FDA's proposal also includes a recommendation that prospective notifiers participate in a presubmission consultation program. The regulations regarding bioengineered foods that would be consumed by humans would be codified in new part 192. The regulations regarding bioengineered foods that would be consumed by animals would be codified in new part 592. The proposed regulations regarding bioengineered foods that would be consumed by animals parallel the proposed regulations regarding bioengineered foods that would be consumed by humans. For ease of discussion, in this proposed rule, FDA describes each of the regulations that would be codified in part 192, without describing the parallel regulations in part 592. Following this discussion, FDA describes areas of importance in the proposed animal feed regulations (section XI of this document).

IV. Definitions

FDA is proposing to codify five definitions that are associated with the proposed notification program (proposed Sec. 192.1). These terms are bioengineered food, commercial distribution, notifier, premarket biotechnology notice (PBN or notice), and transformation event. FDA invites comments on these proposed definitions. FDA is particularly interested in comments on the proposed definitions of bioengineered food and transformation event. Specifically, FDA is requesting comment on whether these proposed definitions are consistent with the agency's intent (described in section V of this document) that the proposed notification program apply to a particular subset of plant-derived foods. Such comments may result in a modification to the proposed definitions. Under the proposed definitions, a required PBN may be submitted by any person who is responsible for the development, distribution, importation, or sale of a bioengineered food. Based on the agency's experience, FDA expects that it ordinarily will be the seed developers and purveyors who notify the agency about a bioengineered food.

V. Requirement for Premarket Biotechnology Notice

FDA is proposing to require a submission to the agency of data and information regarding a plant-derived bioengineered food at least 120 days prior to the commercial distribution of the food (proposed Sec. 192.5). The proposed regulation would include a bioengineered food derived from a new

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plant variety modified to contain a pesticidal substance, and would exclude a bioengineered food that meets three specified criteria. The rationale for this proposed notification requirement is discussed in section II of this document. FDA specifically requests comment on the scope of the proposed notification requirement and on the proposed conditions for exclusion from the notification requirement. Such comments may result in a modification to the proposed regulation.

A. Foods That Are Subject to the Requirement

FDA is proposing that the notification requirement apply to a bioengineered food derived from a new plant variety modified to contain a pesticidal substance (proposed Sec. 192.2(a)). Under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) (7 U.S.C. 136 et seq.), EPA has authority to regulate all pesticides, regardless of how they are made or their mode of action. Under the act, EPA has authority to regulate pesticide residues in foods and FDA has authority to regulate a nonpesticidal substance that may be introduced into a new variety and that is expected to become a component of food. Given this statutory framework, both FDA and EPA agree that any food safety questions beyond those associated with the pesticide, such as those raised by unexpected or unintended compositional changes, are under FDA's jurisdiction (57 FR 22984 at 23005). FDA's proposal to include in its notification program new plant varieties that contain a pesticidal substance will facilitate consultation between EPA and FDA on the scientific and regulatory issues that are not within the scope of EPA's authority under FIFRA and the act. FDA is proposing to exclude from the notification requirement a bioengineered food that satisfies three conditions. The first condition is that the food derives from a plant line that represents a transformation event that has been addressed in a notice previously submitted to FDA (proposed Sec. 192.5(a)(1)). Under Sec. 192.5(a)(1), a separate notice would be required for distinct plant lines that are derived from separate transformed cells, even when those cells were transformed during a single transformation procedure. The second condition is that the use or application of the bioengineered food has been addressed in a notice previously submitted to FDA (proposed Sec. 192.5(a)(2)). Under Sec. 192.5(a)(2), a separate notice would be required, for example, if herbicide tolerance introduced into a variety of sweet corn that is used solely for human food is subsequently transferred, using traditional plant-breeding techniques, to a variety of field corn that would also be used in food intended for consumption by animals. The third condition is that a letter from FDA demonstrates that FDA has evaluated the use or application of the bioengineered food and has no questions about it (proposed Sec. 192.5(a)(3)). Under Sec. 192.5(a)(3), a notice would be required if, for example, a prior notice about another use of a bioengineered food is still pending or if the agency's response to a prior notice demonstrates that FDA did not consider the prior notice as providing a basis to conclude that the bioengineered food was in compliance with all applicable requirements of the act. As mentioned, FDA believes that all developers of bioengineered foods that already are commercially marketed in the United States have consulted with the agency prior to marketing the food. FDA believes that any legal status questions that pertain to the applicable bioengineered foods have been identified and resolved through that consultation process. Therefore, the notification requirement would not extend to bioengineered food obtained from a plant line (or series of plant lines) that derives from a particular transformation event, as long as both the applicable transformation and the use or application of the bioengineered food has been addressed satisfactorily in a completed consultation under the voluntary program. It is likely that some final consultations received under the 1996 procedures would still be pending on the date of a final rule based on this proposal. The proposed regulations include no specific provisions regarding a bioengineered food that is the subject of a pending final consultation under the 1996 procedures. FDA specifically requests comment on how FDA should administer such submissions. FDA also specifically requests comment on whether the process for administering a final consultation that is pending on the date of a final rule based on this proposal should be included in these regulations. Such comments may result in a modification to the proposed regulation. FDA specifically requests comment on the scope of proposed notification requirement and on the proposed conditions for exclusion from the notification requirement. Such comments may result in a modification to the proposed regulation.

B. Origin of Data and Information

FDA is proposing that the data or information that a notifier submits to FDA regarding a bioengineered food must be generated from a plant line whose derivation can be traced to the transformation event

Note: The text ended here but it appears that there may be more that has not been included by the FDA website.

source: http://vm.cfsan.fda.gov/~lrd/fr010118.html 27jan01