Contains Nonbinding Recommendations 
Foods 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 
1  Contains Nonbinding Recommendations 
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 
2  Contains Nonbinding Recommendations 
Foods Derived from Plants Produced 
Using Genome Editing: Guidance for 
Industry1
This guidance represents the current thinking of the Food and Drug Administrations (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 FDAs policy statement Statement of Policy: Foods 
Derived from New Plant Varieties (NPV policy) (57 FR 22984, May 29, 1992) applies to 
foods2 derived from new plant varieties produced using genome editing.3  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 
1 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.   
2 For the purpose of this guidance, unless otherwise specified, food means human food and animal food. 
3 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 plants 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 
plants DNA sequence by insertion, deletion, or substitution of nucleotides at a specific site in a plants genome.  
The process of producing these targeted DNA sequence alterations is often referred to as genome editing. 
3  Contains Nonbinding Recommendations 
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.4    
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe FDAs 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 plants DNA sequence information, plant breeders can now make 
targeted changes to the plants 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 plants DNA sequence by insertion, 
deletion, or substitution of nucleotides at specific locations in a plants 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 
 
4 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. 
  4  Contains Nonbinding Recommendations 
the notice.  Given our experience with foods from genetically engineered plants under the NPV 
policyincluding 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).5   
 
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 plants 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 1980s, 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 
plants 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 
 
5 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.     
  5  Contains Nonbinding Recommendations 
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 plants phenotype 6 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).7     
 
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).8  
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 
 
6 The term phenotype refers to an organisms physical or observable traits. 
7 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). 
8 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).   
  6  Contains Nonbinding Recommendations 
and Johnston, 1970; Hellanas 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).9  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)10 (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 pleiotropic11 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 
 
9 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. 
10 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. 
11 Pleiotropy refers to the condition where a single gene may have multiple effects. 
  7  Contains Nonbinding Recommendations 
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,12 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.13 
 
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 
 
12 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 
Councils (NRCs) 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 Agricultures 
(USDAs) FoodData Central (https://data.nal.usda.gov/dataset/fooddata-central) and the Agriculture and Food 
System Institutes Crop Composition Database (https://www.cropcomposition.org/). 
13 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.   
  8  Contains Nonbinding Recommendations 
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.14 
 
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.   
 
14  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). 
  9  Contains Nonbinding Recommendations 
 
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).15  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, 
FDAs 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 
 
15 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). 
  10  Contains Nonbinding Recommendations 
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.16 
 
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 
 
16 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. 
  11  Contains Nonbinding Recommendations 
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 FDAs 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 varietyincluding one produced using genome 
editingis 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 questionincluding 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:  
 
  12  Contains Nonbinding Recommendations 
1.  Modifications to endogenous genes that create significant homology to a known 
allergen17 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.18   
 
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 
 
17 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.  
18 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.   
  13  Contains Nonbinding Recommendations 
(e.g., wheatcontaining 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 canola19).    
 
  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 animals 
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: 
 
 
19 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.   
  14  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,20 elevated methionine levels21).   
 
  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 proteins22).   
 
  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 acid23).    
 
  Modifications intended to change the fatty acid profile of the food (e.g., oilseeds with 
increased levels of monounsaturated fatty acids or omega fatty acids24).  
 
  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 
expression25).   
 
 
20 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. 
21 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. 
22 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. 
23 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.    
24 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.  
25 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. 
  15  Contains Nonbinding Recommendations 
  Modifications that elevate antinutrient levels of animal food (e.g., elevated levels of 
tannins, such as in sorghum or clover26). 
 
  Modifications that disrupt the normal digestive physiology when present at high 
levels (e.g., elevated levels of lectin in soybeans,27 modification of fatty acid profile 
to increase long-chain polyunsaturated fatty acids28).  
 
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).29 
  
  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,30 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 
 
26 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). 
27 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). 
28 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). 
29 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.   
30 Lodging is when a plant falls over and does not return to a standing position. 
  16  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 developers 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 
  17  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 developers 
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 foods 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: plantbiotech@fda.hhs.gov.  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 
FDAs website.   
 
H. Early food safety assessment  
 
Separate from premarket consultations or meetings, we recommend that developers consult, 
when relevant, FDAs 2006 guidance on the early food safety assessment of new31 non-
pesticidal32 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 
 
31 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. 
32 This 2006 guidance does not apply to PIPs, which are regulated by EPA. 
  18  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 USDAs 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.  EPAs enforcement of the Federal 
Insecticide, Fungicide, and Rodenticide Act as well as EPAs 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.33  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, 
 
33 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. 
  19  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 
Organization of the United Nations: World Health Organization, Rome, 2003 with 
amendments in 2008.*  
 
3.  Food and Drug Administration. Consultations on Food from New Plant Varieties. 
Accessed at 
https://www.cfsanappsexternal.fda.gov/scripts/fdcc/?set=NewPlantVarietyConsultations 
December 6, 2023.* 
 
4.  Glenn, K. C., Also, B., Bell, E., Goley, M., Jenkinson, J., Liu, B., Martin, C., Parrott, W., 
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 
Characteristics while Minimizing Unintended Changes.  Crop Sciences, 57:2906, 2017. 
 
5.  Graham, N., Patil, G. B., Bubeck, D. M., Dobert, R. C., Glenn, K. C., Gutsche, A. T., Kumar, 
S., Lindbo, J. A., Maas, L., May, G. D., Vega-Sanchez, M. E., Stupar, R. M., & Morrell, P. 
L. Plant Genome Editing and the Relevance of Off-Target Changes.  Plant Physiology, 
183(4): 14531471, 2020. 
 
6.  Hellanas, 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., Burstmayr, H., Stoger, E. Targeted modification of plant genomes for precision 
crop breeding.  Biotechnology Journal, 12: 1600173, 2017. 
 
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 
  20  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 cows 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, 
334: 688-692, 1996. 
 
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 
Cucurbitacin Compounds Occurring in California and Alabama.  Journal of Food 
Protection, 47: 270-271, 1984. 
 
20. Schnell, J., Steele, M., Bean, J., Neuspiel, M., Girard, C., Dormann, N., Pearson, C., Savoie, 
A., Bourbonniere, L. Macdonald, P. A comparative analysis of insertional effects in 
genetically engineered plants: considerations for pre-market assessments.  Transgenic 
Research, 24: 117, 2015. 
 
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): 
192-201, 2022. 
 
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 
  21  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, 
3: 17107, 2017. 
 
26. Zitnak A., Johnston, G. R. Glycoalkaloid content of B5141-6 potatoes.  American Potato 
Journal, 47: 256-260, 1970. 
 
   
  22