Guidance for Industry: Foods Derived from Plants Produced Using Genome Editing (February 2024)

Contains Nonbinding Recommendations

Food

s Derived from Plants Produced

Using Genome Editing: Guidance for

Industry

You may submit electronic or written comments regarding this guidance at any time. Submit

electronic comments to http://www/regulations.gov. Submit written comments to the

Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane,

rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number

FDA-2019-D-4658 and with the title of the guidance document.

For questions regarding this document contact the Center for Food Safety and Applied

Nutrition (CFSAN) at 240-402-1200 or the Center for Veterinary Medicine (CVM) at 240-

402-7002.

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Food Safety and Applied Nutrition

Center for Veterinary Medicine

February 2024

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Table of Contents

I. Introduction ............................................................................................................................... 3

II. Background .............................................................................................................................. 4

III. Discussion and Recommendations ........................................................................................ 5

A. Plant breeding ..................................................................................................................... 5

B. Unintended changes ............................................................................................................ 6

C. Considerations specific to food for animals ........................................................................ 8

D. Potential allergenicity of food for humans .......................................................................... 9

E. Regulatory status of foods from plants produced using genome editing .......................... 10

F. Legal authority .................................................................................................................. 10

G. Voluntary premarket consultations and meetings ............................................................. 11

H. Early food safety assessment ............................................................................................ 18

I. Regulatory status at other federal agencies ....................................................................... 19

IV. References ............................................................................................................................. 19

Contains Nonbinding Recommendations

Foods Derived from Plants Produced

Using Genome Editing: Guidance for

Industry

This guidance represents the current thinking of the Food and Drug Administration’s (FDA or

we) on this topic. It does not establish any rights for any person and is not binding on FDA or

the public. You can use an alternative approach if it satisfies the requirements of the applicable

statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible

for this guidance as listed on the title page.

I. Introduction

A purpose of this guidance is to clarify how FDA’s policy statement “Statement of Policy: Foods

Derived from New Plant Varieties” (NPV policy) (57 FR 22984, May 29, 1992) applies to

foods

derived from new plant varieties produced using genome editing.

The NPV policy

provides scientific and regulatory guidance on foods from new plant varieties. The NPV policy

lays out broad, risk-based principles for ensuring the safety of foods from new plant varieties.

These principles are sufficiently flexible to accommodate foods from new plant varieties

developed using a wide range of techniques. This guidance explains that the principles outlined

in the NPV policy apply to foods from genome-edited plant varieties. This guidance also

reminds developers of new plant varieties (developers) of their obligations under section 403(w)

of the Federal Food, Drug, and Cosmetic Act (FD&C Act), which was enacted after the issuance

of our NPV policy. In addition, this guidance describes two processes through which developers

may voluntarily inform FDA of the steps they have taken to ensure the safety of foods from their

new genome-edited plant varieties: voluntary premarket consultations and voluntary premarket

This guidance has been prepared by the Office of Food Additive Safety, Division of Science and Technology in the

Center for Food Safety and Applied Nutrition and the Office of Surveillance and Compliance, Division of Animal

Food Ingredients in the Center for Veterinary Medicine at the U.S. Food and Drug Administration.

For the purpose of this guidance, unless otherwise specified, “food” means human food and animal food.

Genome editing methods are methods that can be used to produce new plant varieties by creating genetic changes

at specific sites in the plant genome. Using deoxyribonucleic acid (DNA) sequence information from a plant, plant

breeders can make targeted changes to a plant’s DNA sequence to alter expression of traits in the plant. These

methods include processes using targeted nucleases (clustered regulatory interspaced short palindromic repeat

(CRISPR) associated nucleases, zinc-finger nucleases, meganucleases, and transcription activator-like effector

nucleases (TALENs)) or targeted oligonucleotides (oligonucleotide-directed mutagenesis) intended to modify a

plant’s DNA sequence by insertion, deletion, or substitution of nucleotides at a specific site in a plant’s genome.

The process of producing these targeted DNA sequence alterations is often referred to as “genome editing.”

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meetings. The voluntary process we recommend for a new food is based on the objective

characteristics of the new food, especially those related to food safety.

In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

Instead, guidances describe FDA’s current thinking on a topic and should be viewed only as

recommendations, unless specific regulatory or statutory requirements are cited. The use of the

word should in FDA guidances means that something is suggested or recommended, but not

required.

II. Background

In the Federal Register of May 29, 1992, we issued a policy statement titled, “Statement of

Policy: Foods Derived from New Plant Varieties” (NPV policy; 57 FR 22984). The NPV policy

clarifies our interpretation of the FD&C Act as it applies to foods derived from new plant

varieties. The NPV policy lays out broad risk-based principles for ensuring the safety of foods

from new plant varieties and is sufficiently flexible to accommodate foods from plants developed

using a wide range of techniques. The NPV policy discusses scientific issues and provides

guidance relevant to the safety assessment of foods derived from new plant varieties. Since

issuance of the NPV policy, scientists have gained a greater knowledge of plant biology,

genomics, and genetics. At the same time, new methods have been developed to modify the

deoxyribonucleic acid (DNA) sequences of plants and to characterize such modifications. In

addition, new DNA sequencing methods have made it easier to obtain the DNA sequences of

plant genomes. Using a plant’s DNA sequence information, plant breeders can now make

targeted changes to the plant’s DNA sequence to alter traits in the plant (see for example, Yin et

al., 2017). These newer methods, collectively referred to as genome editing, include the use of

nucleases and/or oligonucleotides intended to modify the plant’s DNA sequence by insertion,

deletion, or substitution of nucleotides at specific locations in a plant’s genome. These methods

can be used to produce a range of changes from as little as a single base-pair to the introduction

of a gene from an exogenous source.

In the Federal Register of January 19, 2017, we published a notice titled “Genome Editing in

New Plant Varieties Used for Foods,” in which we invited public comment to help inform our

regulatory approach to foods derived from plants produced using genome editing (82 FR 6564).

We asked for data and information in response to questions about the safety of foods from

genome-edited plants, such as the ways in which food safety risks associated with foods from

genome-edited plants are the same as or different from those associated with other development

methods (e.g., hybridization, chemical or radiation mutagenesis, and non-targeted genetic

modifications using in vitro recombinant-DNA technologies). We also asked for information

about how best to engage small businesses that may be considering using genome editing to

produce new plant varieties for food use. We received more than 580 comments in response to

While this guidance does not apply to the safety or legal status of plant incorporated protectants (PIPs) themselves,

which are regulated by the Environmental Protection Agency (EPA), this guidance does apply to PIP-containing

foods. Specifically, this guidance applies to food safety aspects of a PIP-containing food in the event that a food

safety concern is not associated with the PIP. For example, this guidance applies to food-safety-related changes in

the food that are not due to the presence of the PIP. Consequently, developers producing plants that contain a PIP

should consider this guidance as they develop new genome-edited plants intended for food use.

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the notice. Given our experience with foods from genetically engineered plants under the NPV

policy—including the more than 200 evaluations we have completed through the voluntary

premarket consultation program for foods from such plants that we have operated since 1994—

and the information in the comments, we have determined that the risk-based principles laid out

in the NPV policy are applicable to foods produced from genome-edited plant varieties.

III. Discussion and Recommendations

A. Plant breeding

Plant breeders have a long history of using genetic variability to develop new varieties that

produce safe and nutritious foods. Regardless of technique(s) used in plant development, only

very rarely have new plant varieties been identified as the source of food safety concerns. Based

on a history of new plant varieties producing safe food, FDA has not found it necessary to

conduct routine premarket food safety reviews of whole foods derived from new plant varieties

produced through traditional breeding practices (57 FR 22984 at 22988).

Plant breeders require genetic variability to create new plant varieties. Traditional plant breeding

relies on genetic variation within a species that may arise spontaneously during cultivation or

may be introduced through techniques such as hybridization (including wide-crosses), chemical

or irradiation mutagenesis, or other methods (e.g., somaclonal variation). These traditional

breeding practices have been shown to create new varieties with genomes containing large-scale

rearrangements, deletions, insertions, and substitutions. Spontaneous, chemical, or irradiation

mutagenesis alters the plant’s DNA at random sites in the genome. Changes at specific locations

in the DNA cannot be prescribed as part of the breeding process using these methods. As a

result, desirable traits occur at low frequencies, and many rounds of selection are needed to

separate desired traits from undesired traits. Beginning in the 1980’s, plant breeders began using

recombinant-DNA technology as a tool to further expand the genetic variability that can be used

in developing new plant varieties. Recombinant DNA technology can be used to introduce

genetic material (variation) from any source into plant genomes to create new plant varieties.

Genome editing techniques are more recent techniques that can be used to produce new plant

varieties by creating genetic changes at specific sites in the plant genome. In addition, genome

editing techniques may make it easier for plant breeders to introduce desirable traits in plants that

are typically propagated vegetatively and those plants whose breeding cycles or number of sets

of chromosomes (ploidy) pose logistical challenges (National Academies of Sciences,

Engineering, and Medicine, 2016).

Genome editing methods enable modifications directed to specific DNA sequences within the

genome. This allows for greater control over where the genetic modification occurs in the

plant’s genome and provides plant breeders greater precision in the types of genetic

modifications they are producing. Genome editing techniques may be used to mediate directed

changes to a single base-pair, several base-pairs, an entire gene, or possibly to direct the

While foods from genetically engineered plant varieties have customarily been the subject of a voluntary

premarket consultation with FDA before marketing, these plant varieties represent a small portion of all new plant

varieties used for food. Food from plant varieties produced using other plant breeding methods have not historically

been the subject of voluntary premarket consultations.

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introduction of a gene from an exogenous source to a specific site in the genome (Hilscher et al.,

2017). Because genome editing techniques allow for greater control over the site of a genetic

modification, new plant varieties produced using genome editing can produce foods with

characteristics similar to or even identical to foods from traditionally-bred plants; thus, food from

these genome-edited varieties may have the same characteristics as foods from traditionally-bred

plants that have been safely consumed in the past.

B. Unintended changes

Plant breeding relies on genetic variability to introduce new traits. In some cases, introducing

genetic variability may result in unintended changes to the plant’s phenotype

and/or to the

characteristics of the foods derived from the plant. Some scientists may refer to such changes as

“unintended effects” or “unexpected effects.” Unintended changes can occur with all plant

breeding techniques and their occurrence does not necessarily result in a food safety concern

(Institute of Medicine and National Research Council, 2004; National Academies of Sciences,

Engineering, and Medicine, 2016; Schnell et al., 2015).

Addressing unintended changes from plant breeding is not new. Plant breeders are experienced

with unintended characteristics arising during the breeding process and use practices to eliminate

from the variety development process individual plants with characteristics that would negatively

affect food safety or nutrition. For example, plant breeders are aware of substances produced by

certain plants that can cause harm when consumed in food and take concentrations of these

substances into account when developing new plant varieties (Institute of Medicine and National

Research Council, 2004; Organisation for Economic Co-Operation and Development 1993a).

Plant breeders have historically screened new plant varieties for toxins that are typical of the

plant group (i.e., species, genus, family) from which a crop was domesticated and have excluded

from commercialization plants that have high concentrations of the compounds (National

Academies of Sciences, Engineering, and Medicine, 2016; Glenn et al., 2017). Using this

screening process, plant breeders have historically generated new plant varieties that produce

food that complies with the safety requirements of the FD&C Act. This screening process also is

applicable to ensuring the safety of foods from genome-edited plant varieties. FDA expects that

developers will incorporate this screening process in their variety development process for

genome-edited plants used for food.

Among the plant varieties used to produce food, only very rarely have foods from new plant

varieties raised food safety concerns (Rymal et al., 1984; Kirschman and Suber, 1989; Zitnak

The term “phenotype” refers to an organism’s physical or observable traits.

It has been reported that traditional breeding techniques such as chemical and radiation mutagenesis and natural

variation result in a greater frequency and randomness of mutations compared to those resulting from genome

editing tools (see Graham et. al., 2020 and Sturme et. al., 2022).

When developing new varieties, breeders consider naturally occurring substances that may potentially be harmful

including, for example, solanine in potatoes, cyanogenic glycosides in cassava, and cucurbitacin in cucurbits (e.g.,

cucumber and squash). In some instances, routine preparation is necessary and sufficient to produce safe food and

the need for such preparation is well-known. For example, cassava is typically prepared by cooking or soaking

because of harmful cyanogenic glycosides in the root, and soybean meal used as animal food must be toasted before

consumption to inactivate proteinase inhibitors (Organisation for Economic Co-operation and Development, 1993b.;

Organisation for Economic Co-Operation and Development, 1993a).

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and Johnston, 1970; Hellanäs et al., 1995). As of 2023, we have completed voluntary premarket

consultations on food from more than 200 new biotechnology-derived plant varieties intended

for commercialization to ensure an unintended characteristic causing a food to be unsafe under

the FD&C Act in these varieties is not present (Food and Drug Administration, 2023).

Based

on available scientific data and information related to the use of genome editing in plants,

unintended changes potentially resulting from genome editing are likely to fall within the scope

of unintended changes associated with all other plant breeding practices that have historically

produced safe food.

The scientific literature regarding genome editing techniques has referred to certain unintended

changes as “off-target effects” of genome editing — that is, modifications that occur at genomic

locations other than the intended location(s)

(see for example Tsai and Joung, 2016).

Traditional plant breeding practices routinely introduce non-targeted DNA modifications. While

off-target modifications can occur, the relevant question for FDA is whether the safety or

nutritional characteristics of the resulting food have been impacted (see 57 FR 22984 at 22984).

It is possible that off-target effects have no impact on the safety of food from the new plant

variety. Moreover, if off-target modifications result in varieties (and derived foods) that have

undesirable characteristics, we anticipate that the premarket selection process routinely

performed by plant breeders would identify such plants and eliminate them from further

development (57 FR 22984 at 22991 to 23004; Organisation for Economic Co-Operation and

Development, 1993a; Organisation for Economic Co-Operation and Development, 1993b;

Schnell et al., 2015; Glenn et al., 2017; Graham et. al., 2020).

Intended genetic modifications also can result in unintended characteristics in plants. This can

arise from pleiotropic

effects and from secondary effects of gene insertion or disruption (Joint

FAO/WHO Consultation on the Assessment of Biotechnology in Food Production and

Processing as Related to Food Safety, 1991). For example, intentionally increasing levels of a

metabolite can unintentionally alter levels of other metabolites in related metabolic pathways.

When targeted genetic modifications are made through genome editing, such unintended

characteristics are largely predictable and, therefore, can be evaluated on a case-by-case basis.

Pleiotropy and secondary effects also occur from non-targeted genetic changes arising from

traditional plant breeding methods. Historically, the premarket selection process routinely

performed by plant breeders has successfully ensured such changes do not negatively impact

food safety (57 FR 22984 at 22990; Organisation of Economic Co-Operation and Development,

1993a (see Chapter II); Kaiser et. al., 2020).

Ultimately, developers are responsible for ensuring that plant-derived human and animal foods

are safe and comply with all applicable legal and regulatory requirements. We encourage plant

breeders to continue adhering to accepted scientific standards of practice and sound agricultural

In our NPV policy, we recommended that developers consult with us about foods from new plant varieties

developed using biotechnology. Since we issued the policy in 1992, developers have routinely done so. FDA

maintains an inventory of completed Consultations on Food from New Plant Varieties

“On-target” effects are modifications that occur at the intended genomic location(s) but are not the intended

modification(s). The impact on food safety of an on-target effect would be assessed in the same manner as any other

modification.

“Pleiotropy” refers to the condition where a single gene may have multiple effects.

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practice as described in the NPV policy (57 FR 22984 at 22991 to 23004) as well as any

additional practices that have been implemented since we published the NPV policy.

In addition to the standard premarket selection process performed on new plant varieties by plant

breeders, we expect that foods from some plants produced using genome editing may have

characteristics that warrant additional molecular, chemical, and/or nutritional analyses.

Examples of such foods may include those that contain new proteins that raise toxicological or

allergenicity questions, produce substances that have not normally occurred in that food, have an

increased/decreased level of a substance typically found in that food,

and/or have modified

nutritional content.

C. Considerations specific to food for animals

There are several considerations that are specific for plants and their products used in food for

animals, including those intended for companion animals such as cats and dogs. Unlike a food in

the human diet, an animal food derived from a single plant variety may constitute a significant

portion of the animal diet. For instance, 50 percent of the diet of many domestic livestock

species consists of field corn, while soybean meal may be included at 30 percent of the diet. In

addition, animals may be fed the same or a similar type of diet for their entire lives. Therefore, a

change in nutrient or toxicant composition that is considered insignificant for human

consumption may be a very significant change in the animal diet. For example, plant breeders

routinely evaluate the lignin content in traditionally-bred new varieties of alfalfa (a plant

commonly used as food for livestock) because increased lignin content may decrease the

digestibility of food from the variety (Organisation for Economic Co-Operation and

Development, 1993b). Thus, nutrient composition and availability in animal food are important

safety considerations for animal health.

Further, animals consume plants, plant parts, and plant by-products that humans do not consume.

For example, gossypol, a plant toxicant, is concentrated in cottonseed meal during the production

of cottonseed oil. Animals consume cottonseed meal, whereas humans primarily consume

cottonseed oil, thus necessitating different safety considerations. For plants primarily grown for

human food, plant by-products as well as produce and grains that do not meet production

Information on substances typically produced in different plants for use in food can be found, for example, in the

scientific literature, Organisation for Economic Co-Operation and Development (OECD) Crop Composition

documents (Consensus documents: work on the safety of novel foods and feeds - OECD), the National Research

Council’s (NRC’s) Nutrient Requirement series (Nutrient Requirements of Animals | The National Academies Press

(nap.edu)), Feedstuffs (www.feedstuffs.com), and the American Oil Chemists’ Society (AOCS) Monograph Series

on Oilseeds (Academic Press and AOCS Press). There are multiple database sources that also provide information

on quantities of substances produced in foods obtained from plants, including the U.S. Departments of Agriculture’s

(USDA’s) FoodData Central (

https://data.nal.usda.gov/dataset/fooddata-central) and the Agriculture and Food

System Institute’s Crop Composition Database (https://www.cropcomposition.org/).

The OECD publishes documents (Consensus documents: work on the safety of novel foods and feeds - OECD)

containing data on the range of values for nutrients in non-genetically engineered plants. These documents can be

used as references regarding nutrient content of various plant-derived foods. Because OECD documents do not

always address the typical uses of plants in animal food,

the nutrient requirement series published by the NRC also

is helpful in establishing average nutrient composition of non-genetically engineered plant varieties, and also typical

inclusion rates of different plants, plant parts, or by-products derived from new plant varieties in livestock, poultry,

aquaculture, and pet food diets.

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standards for human food often become components of animal food. Because plants and their

by-products represent an important food source for animals, it is important to determine if

significant concentrations of toxicants or other harmful plant constituents are present in new

plant varieties.

An additional consideration for animal food is the effect on human food derived from animals

that have consumed the animal food (i.e., meat, milk, and eggs). The safety of these resulting

human foods is an important safety consideration in the evaluation of the safety of foods derived

from new plant varieties.

As with food for humans, plant breeders have historically considered the animal food uses of

their new plant varieties and have typically produced new varieties whose products are safe and

lawful for use as animal food.

D. Potential allergenicity of food for humans

In the NPV policy, we expressly raised concerns about the potential that a known food allergen

could be transferred from one food source to another (57 FR 22984 at 22987). FDA explained in

the NPV policy that if an allergen were moved into a variety of a plant species that never before

produced that allergen, the susceptible allergic population would not know to avoid food from

that variety, and that labeling of such foods may be needed to inform consumers (57 FR 22984 at

22987). These scenarios continue to be a very serious concern for FDA. To date, developers

have not commercialized plant varieties for human consumption in which a known allergen was

transferred from one source to another (Nordlee et al., 1996; National Academies of Sciences,

Engineering, and Medicine, 2016). In April 2023, we issued a letter to industry reminding

developers and manufacturers of new plant varieties who intend to transfer genes for proteins

that are food allergens (including allergens from foods identified as major food allergens) into

new plant varieties used for food of the food safety risks of doing so and the relevant legal

requirements for these products.

When we developed the NPV policy in 1992, we were unaware of any practical method to

predict or assess the potential for new proteins in food to induce an allergic response in humans

and we requested comments on this issue (57 FR 22984 at 22987). Since 1992, there have been

several initiatives regarding the assessment of potential allergenicity of proteins that are new to

the food supply.

These initiatives resulted in the adoption by the Codex Alimentarius

Commission of the “Guideline for the Conduct of Food Safety Assessment of Foods Derived

from Recombinant-DNA Plants (CAC/GL 45-2003)” (the Codex Plant Guideline; Codex

Alimentarius Commission, 2003 with amendments in 2008). The Codex Plant Guideline

includes an annex titled the “Assessment of Possible Allergenicity” (the allergenicity annex) that

represents a culmination of work to develop harmonized criteria for the assessment of potential

allergenicity of new proteins. The annex acknowledges that, while there is no definitive test that

can be relied upon to predict human allergic response to a protein new to the food supply, a

“weight of evidence” approach can be used to assess the possible allergenicity of a protein new

to the food supply.

FDA Issues Letter to Industry on the Food Safety Risks of Transferring Genes for Proteins that are Food

Allergens to New Plant Varieties Used for Food (April 13, 2023).

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In our 2006 “Guidance for Industry: Recommendations for the Early Food Safety Evaluation of

New Non-Pesticidal Proteins Produced by New Plant Varieties Intended for Food Use,” we

provide recommendations for assessing the potential allergenicity of a new protein and

encourage developers to use the allergenicity annex in the Codex Plant Guideline. We continue

to find this approach valuable in assessing the potential allergenicity of proteins new to the food

supply and encourage developers to use this approach when assessing the potential for new

proteins to induce an allergic response in humans.

Due to the potential safety concerns, we strongly recommend that developers consult FDA

before: (1) transferring genetic material from an organism known to produce food allergens into

a different food source; (2) modifying the genetic material of an organism to produce proteins

similar or identical to those from an organism known to produce food allergens; (3) attempting to

change the levels of specific allergens in crops producing foods subject to labeling under section

403(w) of the FD&C Act; and (4) adding to food a new protein whose potential allergenicity is

not known.

E. Regulatory status of foods from plants produced using genome editing

FDA explained in the NPV policy that the regulatory status of a food, irrespective of the method

by which it is developed, is dependent upon objective characteristics of the food and the intended

use of the food (or its components) (57 FR 22984 at 22984).

While modern molecular biology

methods can provide detailed information about the genetic changes in a new plant variety, the

objective characteristics of the food ultimately are most relevant to food safety, rather than the

breeding method by which the plant was produced or the type of genetic modification introduced

(single base pair mutations, deletions, insertions, etc.). Consistent with the NPV policy, the

regulatory status of foods derived from plant varieties produced using genome editing will, like

that of food from other plant varieties, be based on the objective characteristics of the food and

the intended use of the food (or its components). Under the NPV policy, foods (such as fruits,

vegetables, grains, and their by-products) derived from plant varieties developed by the new

methods of genetic modification are regulated within the existing framework of the FD&C Act,

FDA’s regulations, and current practice, utilizing an approach identical in principle to that

applied to foods developed by traditional plant breeding (57 FR 22984 at 22984).

F. Legal authority

FDA regulates the safety of foods derived from new plant varieties, including varieties produced

using genome editing techniques, under the applicable food safety provisions of the FD&C Act.

We explain in the NPV policy that sections 402(a)(1), 403, and 409 of the FD&C Act are

adequate to ensure the safety of new food ingredients and foods derived from new varieties of

plants, regardless of the process by which such foods and ingredients are produced (emphasis

added). We have considered our authority under the FD&C Act as it relates to new methods of

modification and have concluded that sections 402(a)(1), 403, and 409 of the FD&C Act

FDA explained in the NPV policy that the method by which food is produced or developed may, in some cases,

help to understand the safety or nutritional characteristics of the finished food. However, the key factors in

reviewing safety concerns should be the characteristics of the food product (57 FR 22984 at 22984).

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continue to provide the primary authority to oversee the safety and labeling of foods derived

from new plant varieties, including those produced using new methods of modification. We

refer readers to section V of the NPV policy where we discuss our legal authority under sections

402(a)(1), 403, and 409 of the FD&C Act.

After we issued the NPV policy, Congress amended the FD&C Act to make it easier for food

allergic consumers and their caregivers to identify and avoid foods that contain major food

allergens. Section 403(w) of the FD&C Act requires that the label of a human food containing

an ingredient that is, or contains protein derived from, a “major food allergen” declare the

presence of the allergen in the manner described by the law. Section 201(qq) of the FD&C Act

identifies nine foods or food groups as major food allergens. They are milk, eggs, fish (e.g.,

bass, flounder, cod), Crustacean shellfish (e.g., crab, lobster, shrimp), tree nuts (e.g., almonds,

walnuts, pecans), peanuts, wheat, soybeans, and sesame. Developers should consider their

obligations under section 403(w) of the FD&C Act.

G. Voluntary premarket consultations and meetings

The FD&C Act places an obligation on those marketing foods to ensure that the products they

offer for sale are safe and lawful. When a food contains an unapproved food additive or color

additive, developers must obtain premarket approval from FDA for use of the food additive or

color additive (see sections 409 and 721 of the FD&C Act). While there is no FDA premarket

approval requirement for new plant varieties as a class, historically, developers of biotechnology-

derived new plant varieties have nonetheless voluntarily consulted FDA before marketing

because this enables FDA to help developers ensure that foods are safe and legal before

marketing.

Below, we lay out two processes through which developers may voluntarily inform FDA of the

steps they have taken to ensure the safety of foods from their new genome-edited plant varieties.

Which voluntary process we recommend is based on the objective characteristics of the new

food, especially those related to food safety. As described below, we recommend a voluntary

premarket consultation, using our current consultation process, for foods from genome-edited

plants that may be more likely to raise food safety questions or regulatory considerations because

they have one or more of the characteristics identified in this guidance. For those foods from

genome-edited plants that do not have any of these characteristics and, therefore, are less likely

to raise food safety questions or regulatory considerations, we recommend a voluntary premarket

meeting.

Participation in these programs is not required by law, but these programs can help developers

ensure that they are meeting their legal obligation to market only safe and lawful food. Such

consultations or meetings also would provide FDA with an awareness of the genome-edited plant

products potentially on the market. This awareness would help inform our knowledge about the

general safety of these foods and our oversight of food safety for specific foods from these

For more information related to allergens, including the food allergen labeling requirements of the FD&C Act,

please see

http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/Allergens/default.htm

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plants. Regardless of whether a developer participates in the consultation or meeting processes,

developers have a legal obligation to market only safe and lawful foods.

a. Voluntary premarket consultations

Since 1994, we have operated a voluntary premarket consultation program for foods from new

plant varieties. We intend to continue to offer voluntary premarket consultations on foods from

new plant varieties, including those from genome-edited plant varieties. As has been our

practice for previous consultations on foods from new plant varieties, when conducting

consultations on foods from genome-edited plant varieties, we will use a science-based, case-by-

case approach to food safety assessment that considers the objective characteristics of the food

and its similarity to foods that have been safely consumed. We are not aware of data or

information indicating that the general food safety assessment principles used in previous

consultations would not be applicable to consultations on foods from new plant varieties

developed through genome editing. Additionally, we are not aware of data or information

indicating that the use of genome editing in the development of new plant varieties would raise

novel safety concerns regarding the resulting foods. As in the past, the data and information

needed to establish the identity, safety, and regulatory status of the resulting food product will

vary depending on the nature of the changes, if any, to the food itself.

Our voluntary premarket consultation process provides a mechanism that can be used to help

developers determine the regulatory status of food from new plant varieties and ensure that any

safety concerns have been resolved prior to marketing. In general, we encourage developers to

consult with us to help ensure the safety of food from plants produced using modern

biotechnology and foster continued public confidence and transparency in the use of such

technologies. In addition, the information we obtain during voluntary premarket consultations

enables us to speak confidently about the safety of these foods. The information and experience

gleaned from voluntary premarket consultations also informs FDA’s work in multilateral

standard-setting bodies and other international fora where the safety of these foods, and the

scientific assessments supporting their safety, are discussed.

Using a series of flow charts with explanatory notes, the NPV policy provides guidance to

developers regarding safety questions that should be considered prior to marketing. We advise

developers to consider the flowcharts and explanatory notes in the NPV policy statement when

determining whether food from a new plant variety—including one produced using genome

editing—is likely to raise a safety or other legal question.

In addition, for foods from genome-edited plants, voluntary premarket consultations may be

especially useful when genome editing is used to make any of the types of modifications

described below. Foods from varieties with such modifications may raise safety questions or

regulatory considerations that put the legal status of the food in question—including whether an

added substance, such as a newly expressed substance resulting from genome editing, is an

unapproved food additive. Thus, we strongly recommend that developers of genome-edited

plants with any of the following modifications engage in a voluntary premarket consultation:

Contains Nonbinding Recommendations

1. Modifications to endogenous genes that create significant homology to a known

allergen

that is relevant to human health or a toxin that is relevant to human or animal

health. One example would be editing DNA sequences in a gene in corn such that the

protein expressed from the modified gene now encodes a protein that has significant

amino acid sequence homology to a known allergen in soybeans.

Another example would be editing DNA sequences in a gene in peanuts that expresses a

non-allergenic protein such that the protein expressed from the modified gene now

encodes a protein that has significant amino acid sequence homology to another peanut

protein that is a known allergen. In this case, even though people allergic to the known

allergen might already know to avoid peanuts, the genome edit might, for example, result

in more people having allergic reactions to peanuts.

2. Modifications that cause a non-negligible increase in levels of potentially harmful

components, including toxicants, allergens, anti-nutrients, and other components that can

exhibit non-nutritive physiological effects on humans or animals (e.g., wheat with

increased gluten content, a tomato with increased levels of tomatine, fruits with increased

levels of substances that are neurotransmitters or hormones in humans or animals, fruits

with significantly increased levels of bio-active phytoconstituents).

Intended genetic modifications can cause unintended characteristics in plants. Therefore,

we recommend developers consider whether intentional changes to crop composition

unintentionally increase levels of potentially harmful components. Some examples may

include: (1) reducing levels of one allergenic storage protein in a food could

unintentionally cause compensatory increases in levels of other allergenic storage

proteins; (2) inhibiting production of one toxicant could shunt metabolic flow into a

different pathway, resulting in greater production of a different toxicant; and (3)

enhancing accumulation of an essential mineral in a food could enhance accumulation of

heavy metals also.

3. Modifications that cause a non-negligible change in the nutritional value (level of nutrient

and/or bioavailability) of the food.

Examples of modifications that would cause a non-negligible change in the nutritional

value (level of nutrient and/or bioavailability) in food for humans:

• Modifications that result in the food containing, at a nutritionally meaningful

level, a nutrient found at negligible levels in food from its traditional counterpart

When considering whether a modification has resulted in significant homology to a known allergen, FDA

recommends applying the amino acid sequence homology criteria in the annex titled “Assessment of Possible

Allergenicity” to the

Guideline for the Conduct of Food Safety Assessment of Foods Derived from Recombinant-

DNA Plants (CAC/GL 45-2003; the Codex Plant Guideline) or other appropriate criteria.

We strongly suggest that developers contact us if they have questions about whether an intended change to a food

would result in a change to the nutritional value of the food that might warrant a voluntary consultation. In some

cases, it may be important for us to have specific details about the intended nutritional change and the magnitude of

the change for us to assess whether we would recommend a voluntary consultation or a voluntary premarket

meeting.

Contains Nonbinding Recommendations

(e.g., wheat

containing significantly increased amounts of iron, fruits modified

such that they become sources of vitamin D or preformed vitamin A).

• Modifications that result in nutritionally meaningful reductions to the levels of

nutrients (e.g., significant reductions in vitamin C content of oranges, significant

reductions in vitamin E in sunflower).

• Modifications that result in increases to the levels of nutrients such that a safety

concern may be raised (e.g., increases in the selenium content of Brazil nuts,

increases in the content of folate in cereal grains).

• Modifications that introduce nutrients to the food that are limited by regulation in

similarly used foods (e.g., introducing docosahexaenoic acid (DHA) or

eicosapentaenoic acid in canola

• Modifications intended to change the fatty acid profile of the food (e.g., oilseeds

with increased levels of monounsaturated fatty acids or omega-3 fatty acids).

• Modifications expected to affect the bioavailability of nutrients in the food (e.g.,

increased expression of a protein known to bind certain essential minerals,

making them unavailable during digestion and absorption).

For food for animals, in assessing whether a voluntary consultation may be appropriate,

developers should consider the following: nutrient levels in the food; the relative

sensitivity of individual animal species and stage of life, with respect to nutritional

requirements and toxicity; as well as the potential need for diet reformulation.

Developers also should consider the anticipated inclusion rate of a plant in an animal’s

diet because, although a nutrient may only be present at a low level in food from a new

plant variety, that food may still be an important source of that nutrient. The examples

below involve changes in the nutrient or anti-nutrient content of new plant varieties and

the direct impact of such nutrients in diet formulation. However, we note that changes in

the nutrient profile of new plant varieties also may indirectly impact other areas of animal

nutrition, and the developer also should consider if this raises potential safety concerns.

Examples of modifications that would cause a non-negligible change in the nutritional

value (level of nutrient and/or bioavailability) in food for animals:

Paragraphs (a)(3) and (a)(4) of the Generally Recognized as Safe (GRAS) affirmation regulation for menhaden oil

(21 CFR 184.1472) establish limits on the use of menhaden oil to avoid total dietary intake of eicosapentaenoic acid

or DHA above 3.0 grams/person/day. Paragraph (a)(3) limits maximum use levels of menhaden oil in specific food

categories; paragraph (a)(4) restricts use of menhaden oil in combination with any other added oil that is a

significant source of eicosapentaenoic acid or DHA.

Contains Nonbinding Recommendations

• Modifications that result in the food containing, at a nutritionally meaningful level, a

nutrient found at negligible levels in food from its traditional counterpart (e.g.,

elevated levels of vitamin D and calcium,

elevated methionine levels

• Modifications that result in nutritionally meaningful reductions to the levels of

nutrients (e.g., significant reductions in essential and/or limiting amino acids).

• Modifications that result in increases to the levels of nutrients such that a safety

concern may be raised (e.g., introducing or increasing ferroxidase enzymes, which

participate in iron metabolism and are also copper-carrying proteins

• Modifications that introduce nutrients to the food that are limited by regulation in

similarly used foods (e.g., introducing DHA and other omega-3 fatty acids such as

eicosapentaenoic acid

• Modifications intended to change the fatty acid profile of the food (e.g., oilseeds with

increased levels of monounsaturated fatty acids or omega fatty acids

• Modifications that can introduce residues to edible tissues, milk, and eggs from

animals fed the new plant variety (e.g., the inclusion of omega long-chain fatty acids

in the diet of animals may lead to the accumulation of these fatty acids in eggs, milk,

and edible tissues of animals).

• Modifications that affect the bioavailability of nutrients in the food (e.g., phytase

expression

The calcium and vitamin D requirements for broiler chicken diets are significantly lower than the requirements of

these nutrients in layer chicken diets. Thus, modification of vitamin D (or a precursor of vitamin D) or calcium

levels in corn, for example, could lead to toxicity in broiler chicken diets, while having minimal effect in layer

chicken diets.

Formulated diets for monogastric animals often do not have an ideal amino acid balance without the addition of

specific synthetic amino acids, such as methionine (Katz and Baker, 1975). Modification of amino acids profile in

corn, soybeans, and wheat could alter the amount of essential amino acids that are added to diets to provide a

balanced amino acid profile. However, methionine also can be toxic at high levels.

Sheep are more sensitive to copper levels in the diet when compared to other livestock species. Thus, the

developer should discuss the impact of sheep exposure to the new plant variety expressing a mineral-binding protein

that accumulates copper in the plant.

Our regulation at 21 CFR 573.615 addresses the use of marine microalgae as a food additive permitted in dry

adult maintenance food for dogs as a source of DHA and other omega-3 fatty acids. The regulation, at 21 CFR

573.615(e)(2)(i), limits maximum use level of the food additive to 16.5 pounds per ton of complete, dry, adult

maintenance dog food.

Our regulation at 21 CFR 573.492 addresses the use of gamma-linolenic acid safflower oil as a food additive

permitted in dry adult maintenance food for dogs and complete dry adult maintenance food for cats as a source of

gamma-linolenic acid and other omega-6 fatty acids.

Phytases degrade phytic acid, which leads to increased bioavailability of phosphorus, cationic minerals, and other

feed components. If a genome-edited corn variety that expresses high levels of phytase in the grain is used as a

substitute for commodity corn, this may alter nutrient digestion in the gut and lead to mineral imbalances or mineral

toxicities.

Contains Nonbinding Recommendations

• Modifications that elevate antinutrient levels of animal food (e.g., elevated levels of

tannins, such as in sorghum or clover

• Modifications that disrupt the normal digestive physiology when present at high

levels (e.g., elevated levels of lectin in soybeans,

modification of fatty acid profile

to increase long-chain polyunsaturated fatty acids

4. Modifications that change how the plant or food from the plant is used, including

modifications that:

• Enable new or different uses in food, including use of plant tissues with no history of

safe use in food (e.g., cotton with reduced levels of gossypol in seed such that

roasted kernels can be used in food for humans).

• Render inappropriate certain historical uses of food from the plant (e.g., an oilseed in

which the fatty acid composition is modified such that the oil is no longer suitable

for frying; or a forage crop with increased lignin content to prevent lodging,

but

that renders the crop unsuitable for animal food).

• Alter the manufacturing properties of a food for animals (e.g., modification of

resistant starch content in corn would alter the pet food extrusion process and

characteristics of the kibble).

• Alter properties of food in the animal digestive tract (e.g., modification impacting

glucanase, which alters viscosity of digesta in digestive tract; modification impacting

xylanase, which alters resistant fiber levels in digestive tract).

5. Modifications that introduce: (a) new genes and/or genetic elements that do not naturally

occur in that species; or (b) additional copies of endogenous genes that are retained in the

genome once genome editing is complete. We would ordinarily consider genes and/or

Condensed tannins are a class of secondary plant metabolites that are found in several forage plants and sorghum

grain. Condensed tannins possess various antimicrobial, anti-parasitic, anti-oxidant, and anti-inflammatory

activities. However, condensed tannins at high levels are considered antinutrients because they can impair the

digestion of various nutrients, especially proteins, and can inactivate digestive enzymes such as trypsin and

chymotrypsin (Barry, 1989).

The alteration of plant architecture or modification of the expression of a transcription factor in the plant could

lead to higher levels of lectin in the plant. This could alter availability of carbohydrates or glycol-conjugates

(glycoproteins, glycolipids, and polysaccharides), resulting in an alteration in carbohydrate metabolism, and impact

digestive physiology (Popova and Mihaylova, 2019).

The addition of high levels of polyunsaturated long-chain fatty acids to diets for ruminant animals may cause

disruption of rumen fermentation (Niwinska et al., 2011).

We recognize that traditional plant breeding has resulted in foods with new uses and that such foods may have

historically been safely consumed. In cases where genome editing is used to make the same modifications, a

voluntary premarket consultation would not ordinarily be warranted. Examples of such modifications would be

those resulting in foods such as sweet corn and waxy maize from varieties not previously associated with these

characteristics. Sweet corn (Walker, 2018) and products of waxy maize (e.g., cornstarch) (Schwartz and Whistler,

2009) have been safely used in foods in the United States for decades.

Lodging is when a plant falls over and does not return to a standing position.

Contains Nonbinding Recommendations

genetic elements introduced into the genome through a transformation event and retained

in the final product to be examples of these types of modifications.

New genes and/or genetic elements may come from organisms that have not historically

been used in the food supply and/or may have chemical functions new to the food supply

such that their use in food is more likely to raise questions about whether the expressed

protein or new substance would be an unapproved food additive. FDA also recognizes

that a possible 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. For example, it is possible to transfer genes from one food organism to

an unrelated food plant, thereby allowing the potential transfer of an allergen from the

first organism to the second. The transfer of an allergen from one food organism to

another could raise significant food safety concerns because consumers would not

ordinarily expect the new food to contain an allergen from a different food.

We recognize that there may be instances in which new genetic elements are inserted into

the genome of a plant that are non-functional and inconsequential to food safety (e.g.,

components of border sequences used in Agrobacterium-mediated transformation;

incomplete and non-functional regulatory components such as promoters, enhancers, or

transcriptional terminators). In such cases, a voluntary premarket consultation may not

be warranted, and a voluntary premarket meeting may be appropriate. If a product

presents such a case, we suggest the developer talk to us about the specific product and

whether a consultation would be warranted.

If there are questions about whether a product has any of the above characteristics, we encourage

developers to contact us.

b. Voluntary premarket meetings

For those foods from genome-edited plants that do not have any of the characteristics described

above, we strongly recommend that developers schedule a voluntary premarket meeting with us

to share information about the food and its food safety characteristics. The purpose of a

voluntary premarket meeting is to familiarize us with the types of foods from genome-edited

plants entering the market and the steps developers have taken to ensure their safety and

lawfulness. During these meetings, developers should describe the safety characteristics of

human and animal food from their new variety (including whether the food has characteristics

that would suggest a voluntary premarket consultation instead of a voluntary premarket meeting)

and explain the steps they have taken to ensure that food from their new variety is safe and

lawful. We intend to summarize each voluntary premarket meeting in a memorandum of

meeting that we will store in our files.

Voluntary premarket meetings are not intended to substitute for a voluntary premarket

consultation when foods have characteristics, such as those laid out above, that may raise food

safety questions or regulatory considerations not amenable to resolution during a simple meeting.

Along the same lines, a voluntary premarket meeting is not intended to represent an FDA

evaluation of a developer’s food safety assessment similar to the evaluation we conduct as part

of a completed voluntary premarket consultation. To inform stakeholders of our activities in this

Contains Nonbinding Recommendations

area, we intend to maintain on our website a list of voluntary premarket meetings. However, if

safety and/or regulatory questions arise based on information presented during the developer’s

narrative, we intend to discuss those with the developer during the meeting or through follow-up

communications.

Voluntary premarket meetings are within the spirit of the long-standing practice of voluntary,

informal consultations between developers and FDA before marketing food from biotechnology-

derived plant varieties. These meetings provide an opportunity for FDA to help developers

ensure that foods from genome-edited plants are safe and legal before marketing and, as in the

case of voluntary premarket consultations, provide us with an awareness of the genome-edited

plant products potentially on the market.

Developers have an obligation under the FD&C Act to ensure that the foods they offer to

consumers are safe and comply with all applicable legal requirements. Because, in some cases, a

developer may have questions about the regulatory status of a food from a genome-edited plant,

developers can informally meet with FDA before marketing a food from genome-edited plants to

ensure that the food’s safety and regulatory status is properly resolved.

c. Initiating a voluntary premarket consultation or a voluntary premarket

meeting with FDA

Developers can begin engaging us in a voluntary premarket consultation or voluntary premarket

meeting by contacting us at: plantbiote[email protected]. We encourage developers to meet with

us early in their product development process and as often as necessary to resolve any concerns.

Early engagement with FDA about food from a specific new plant variety may help identify the

data and information most relevant to food safety or other concerns specific to food from the new

variety. Developers with limited regulatory experience may find engagement with FDA early in

their product development process especially beneficial. Developers interested in participating

in the voluntary premarket consultation process may wish to view completed consultations on

FDA’s website.

H. Early food safety assessment

Separate from premarket consultations or meetings, we recommend that developers consult,

when relevant, FDA’s 2006 guidance on the early food safety assessment of new

non-

pesticidal

proteins expressed in new plant varieties (see “Guidance for Industry:

Recommendations for the Early Food Safety Evaluation of New Non-Pesticidal Proteins

Produced by New Plant Varieties Intended for Food Use,” June 2006). In the 2000s, we

developed an early food safety assessment program, referred to as the New Protein Consultations

program (NPC program), whereby developers can consult us in the early stages of development

about the potential toxicity and allergenicity of new non-pesticidal proteins intended to be

expressed in new plant varieties. The NPC program helps ensure that new, non-pesticidal

proteins are not toxins or allergens, and provides guidance about the assessment of potential

In this context, “new” refers to a protein that has not been evaluated through either an early food safety evaluation

or a biotechnology consultation, regardless of the plant species into which the protein is introduced.

This 2006 guidance does not apply to PIPs, which are regulated by EPA.

Contains Nonbinding Recommendations

allergenicity for new proteins. While the early food safety evaluation guidance was intended to

address food safety concerns associated with the inadvertent low-level presence of new varieties

in the food supply, our experience has been that the safety assessment performed during an

evaluation in the NPC program may address relevant food safety issues associated with the

intended presence of the protein in the food supply as well. We encourage developers producing

varieties with new non-pesticidal proteins to continue engaging in the NPC program before

material from the variety might inadvertently be present in the food supply, such as during field

testing.

I. Regulatory status at other federal agencies

The Coordinated Framework for the Regulation of Biotechnology (51 FR 23302, June 26, 1986),

most recently updated in 2017, explains that new plant varieties and products derived from them

may be regulated by more than one federal agency based on the nature of the alteration and

applicable legal authority. For example, plants and their products may be subject to regulatory

oversight by USDA’s Animal and Plant Health Inspection Service (APHIS), the Environmental

Protection Agency (EPA), as well as FDA. APHIS enforces the Plant Protection Act and

regulates organisms that may pose a risk to plant health. EPA’s enforcement of the Federal

Insecticide, Fungicide, and Rodenticide Act as well as EPA’s authority to establish tolerances

under section 408 of the FD&C Act, are focused on the safe use of pesticides in the environment

as well as the safety of any pesticide chemical residues in or on food.

The fact that a plant and

the products derived from it comply with applicable laws and regulations enforced by APHIS

and/or EPA does not mean that food from the plant will necessarily comply with all applicable

food safety laws and regulations enforced by FDA. Moreover, the types of data and information

necessary to address plant pest issues considered by APHIS and pesticide safety issues

considered by EPA may differ from the data and information necessary to address food safety

issues considered by FDA. We encourage developers to engage FDA before marketing when

they have questions about whether food from their new plant variety presents any food safety or

other legal issues.

IV. References

The following references marked with an asterisk (*) are on display at the Dockets Management

Staff (see ADDRESSES) and are available for viewing by interested persons between 9 a.m. and

4 p.m., Monday through Friday; they also are available electronically at

https://www.regulations.gov. References without asterisks are not on public display at

https://www.regulations.gov because they have copyright restriction. Some may be available at

the website address, if listed. References without asterisks are available for viewing only at the

Dockets Management Staff. FDA has verified the website addresses, as of the date this

document publishes in the Federal Register, but websites are subject to change over time.

1. Barry, T.N. “Condensed tannins: Their role in ruminant protein and carbohydrate digestion

and possible effects upon the rumen ecosystem.” In: Nolan, J.V., Leng, R.A. and Demeyer,

FDA is responsible for enforcing tolerances for pesticide chemical residues in or on domestic foods shipped in

interstate commerce and foods offered for import into the U.S., except for meat, poultry, Siluriformes fish (including

catfish), and certain egg products that are regulated by the U.S. Department of Agriculture.

Contains Nonbinding Recommendations

D.I. The roles of Protozoa and Fungi in Ruminant Digestion: proceedings of an international

seminar held at the University of New England, Armidale, Australia, 26-29th September,

1988. Penambul Books, Armidale, NSW Australia. pp. 153-169, 1989.

2. Codex Alimentarius Commission. Guideline for the Conduct of Food Safety Assessment of

Foods Derived from Recombinant-DNA Plants (CAC/GL 45-2003), Food and Agriculture

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amendments in 2008.*

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Accessed at

https://www.cfsanappsexternal.fda.gov/scripts/fdcc/?set=NewPlantVarietyConsultations

December 6, 2023.*

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Souder, C., Sparks, O., Urquhart, W., Ward, J. M., Vicini, J. L. “Bringing New Plant

Varieties to Market: Plant Breeding and Selection Practices Advance Beneficial

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S., Lindbo, J. A., Maas, L., May, G. D., Vega-Sanchez, M. E., Stupar, R. M., & Morrell, P.

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6. Hellanäs, K. E., Branzel, C., Johnsson, H., Slanina, P. “High levels of glycoalkaloids in the

established Swedish potato variety Magnum Bonum.” Journal of the Science of Food and

Agriculture, 68: 249-255, 1995.

7. Hilscher, J., Bürstmayr, H., Stoger, E. “Targeted modification of plant genomes for precision

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8. Institute of Medicine and National Research Council. 2004. Safety of Genetically

Engineered Foods: Approaches to Assessing Unintended Health Effects. Washington, DC:

The National Academies Press. https://doi.org/10.17226/10977.

9. Joint FAO/WHO Consultation on the Assessment of Biotechnology in Food Production and

Processing as Related to Food Safety. “Strategies for assessing the safety of foods produced

by biotechnology- Report of a Joint FAO/WHO Consultation.” World Health Organization,

Geneva, 1991.

10. Kaiser, N., Douches, D., Dhingra, A., Glenn, K. C., Herzig, P. R., Stowe, E. C., Swarup, S.

“The role of conventional plant breeding in ensuring safe levels of naturally occurring toxins

in food crops.” Trends in Food Science & Technology, 100: 51-66, 2020.

11. Katz, R.S. and Baker, D.H. “Methionine toxicity in the chick: nutritional and metabolic

implications.” Journal of Nutrition 105(9): 1168-75, 1975

Contains Nonbinding Recommendations

12. Kirschman, J. C., Suber, R. L. “Recent Poisonings from Cucurbitacin in Traditionally Bred

Squash.” Food and Chemical Toxicology, 27: 555-556, 1989.

13. National Academies of Sciences, Engineering, and Medicine. 2016. Genetically Engineered

Crops: Experiences and Prospects. Washington, DC: The National Academies Press.

14. Niwinska, B., Bilik, K., Andrzeuewski, M. “Factors influencing rumenic and vaccenic acid

content in cow’s milk fat.” Annals of Animal Science. 11: 3-16, 2011.

15. Nordlee, J. A., Taylor, S. L., Townsend, J. A., Thomas, L. A., Bush, R. K. “Identification of

a Brazil-Nut Allergen in Transgenic Soybeans.” The New England Journal of Medicine,

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16. Organisation for Economic Co-Operation and Development. Safety evaluation of foods

derived by modern biotechnology: concepts and principles. Paris, 1993a.

17. Organisation for Economic Co-Operation and Development. Traditional crop breeding

practices: an historical review to serve as a baseline for assessing the role of modern

biotechnology. Paris, 1993b.

18. Popova, A. Mihaylova, D. “Antinutrients in plant-based foods: A review.” The Open

Biotechnology Journal, 13: 68-76, 2019.

19. Rymal, K. S., Chambliss, O. L., Bond, M. D., Smith, D. A. “Squash Containing Toxic

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Protection, 47: 270-271, 1984.

20. Schnell, J., Steele, M., Bean, J., Neuspiel, M., Girard, C., Dormann, N., Pearson, C., Savoie,

A., Bourbonnière, L. Macdonald, P. “A comparative analysis of insertional effects in

genetically engineered plants: considerations for pre-market assessments.” Transgenic

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21. Schwartz, D. and Whistler, R. L. “History and Future of Starch.” Starch: Chemistry and

Technology, Third Edition. Elsevier, Inc., 2009.

22. Sturme, M. H. J., van der Berg, J. P., Bouwman, L. M. S., De Schrijver, A., de Maagd, R. A.,

Kleter, G. A., Battaglia-de Wilde, E. “Occurrence and Nature of Off-Target Modifications by

CRISPR-Cas Genome Editing in Plants.” ACS Agricultural Science & Technology, 2 (2):

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23. Tsai, S. Q., Joung, J. K. “Defining and improving the genomewide specificities of CRISPR–

Cas9 nucleases.” Nature Reviews Genetics, 17: 300-312, 2016.

24. Walker, S. “Home and Market Garden Sweet Corn Production-Guide H-223.” Cooperative

Extension Service, College of Agricultural, Consumer and Environmental Sciences, New

Contains Nonbinding Recommendations

Mexico State University, 2018 (available online at: https://pubs.nmsu.edu/_h/H223.pdf;

accessed June 16, 2023).

25. Yin, K., Gao C, Qiu J. L. “Progress and prospects in plant genome editing.” Nature Plants,

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26. Zitnak A., Johnston, G. R. “Glycoalkaloid content of B5141-6 potatoes.” American Potato

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