• Decrease font size
  • Return font size to normal
  • Increase font size
U.S. Department of Health and Human Services

Food

  • Print
  • Share
  • E-mail

Statement of Policy - Foods Derived from New Plant Varieties

Biotechnology Guidance Documents

 

Guidance to Industry for Foods Derived from New Plant Varieties


FDA Federal Register
Volume 57 - 1992
Friday, May 29, 1992
NOTICES
 



Food for human consumption and animal drugs, feeds, and related products: 
Foods derived from new plant varieties; policy statement, 22984

Vol. 57 No. 104 Friday, May 29, 1992 p 22984 DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 92N-0139]

Statement of Policy: Foods Derived From New Plant Varieties

Agency: Food and Drug Administration, HHS.

Action: Notice.

 

------------------------------------------------------------
Summary: The Food and Drug Administration (FDA) is issuing a 
policy statement on foods derived from new plant varieties, 
including plants developed by recombinant deoxyribonucleic acid 
(DNA) techniques. This policy statement is a clarification of 
FDA's interpretation of the Federal Food, Drug, and Cosmetic 
Act (the act), with respect to new technologies to produce foods, 
and reflects FDA's current judgment based on new plant varieties 
now under development in agricultural research. This action 
is being taken to ensure that relevant scientific, safety, and 
regulatory issues are resolved prior to the introduction of 
such products into the marketplace.

Dates: Written comments by August 27, 1992.

Addresses: Submit written comments to the Dockets Management 
Branch (HFA-305), Food and Drug Administration, rm. 1-23, 12420 
Parklawn Dr., Rockville, MD 20857.

For further information contact: Regarding Human Food Issues: 
James H. Maryanski, Center for Food Safety and Applied Nutrition 
(HFF-300), Food and Drug Administration, 200 C St. SW., Washington, 
DC 20204, 202-485-3617. Regarding Animal Feed Issues: William 
D. Price, Center for Veterinary Medicine (HFV-221), Food and 
Drug Administration, 7500 Standish Pl., Rockville, MD 20855, 
301-295-8724.

Supplementary information:

 

Table of Contents

I. Background and Overview of Policy
II. Responsibility for Food Safety
III. Scope of this Document
IV. Scientific Issues Relevant to Public Health

  A. Unexpected Effects

  B. Known Toxicants

  C. Nutrients
  D. New Substances

  E. Allergenicity

  F. Antibiotic Resistance Selectable Markers

  G. Plants Developed to Make Specialty Nonfood Substances

  H. Issues Specific to Animal Feeds
V. Regulatory Status of Foods Derived from New Plant Varieties

  A. The Statutory Framework for New Foods and Food Ingredients

  B. The Application of Section 402(a)(1) of the Act

  C. The Application of Section 409 of the Act
VI. Labeling
VII. Guidance to Industry for Foods Derived from New Plant Varieties

  A. Introduction

  B. Flow Charts

  C. Effects of Processing

  D. The Host Plant

  E. The Donor(s)

  1. Donor plants

  2. Fragments of donor genetic material

  F. Substances Introduced into the Host Plant from the Donor(s)

  1. Proteins

  2. Carbohydrates

  3. Fats and oils

  G. Toxicology

  H. Other Information

  1. Nucleic acids

  2. Metabolic considerations 

  3. Stability

  I. Future Workshop on Scientific Issues
VIII. Environmental Considerations: Applicability of NEPA 
IX. Coordination with EPA: Pesticide Considerations
X. Environmental Impact
XI. Comments 
XII. References

 

I. Background and Overview of Policy 

   New methods of genetically modifying plants are being used 
to develop new varieties that will be sources of foods. These 
methods, including recombinant DNA techniques and cell fusion 
techniques, enable developers to make genetic modifications 
in plants, including some modifications that would not be possible 
with traditional plant breeding methods. This policy discusses 
the safety and regulatory status of foods derived from new plant 
varieties, including plants developed by the newer methods of 
genetic modification. 
   FDA has received numerous inquiries from industry, government 
agencies, academia, and the public requesting clarification 
of the regulatory status of foods, such as fruits, vegetables, 
grains and their byproducts, derived from new plant varieties 
developed using recombinant DNA techniques. The questions that 
FDA has received center on issues such as whether the agency 
will conduct premarket review of these new foods, whether such 
foods introduced into interstate commerce would be challenged 
by FDA on legal grounds, which new plant varieties might come 
under the jurisdiction of FDA, what scientific information may 
be necessary to satisfy FDA that such foods are safe and comply 
with the law, whether petitions would be required by the agency, 
and whether special labeling would be required. 
   Representatives of the food biotechnology industry have expressed 
to FDA the need for strong but appropriate oversight by Federal 
agencies to ensure public confidence in foods produced by the 
new techniques. FDA has received several specific comments and 
suggestions from the industry and from the public concerning 
Federal oversight of foods developed through new methods of 
genetically modifying plants (Refs. 1 through 4). The agency 
has considered these and other documents, including scientific 
research papers, in developing this notice, and is setting forth 
this policy statement to clarify its interpretation of the act 
with respect to human foods and animal feeds{1} derived from 
new plant varieties,{2} including but not limited to plants 
developed by new methods of genetic modification.{3}
      ³{1} "Food" means (1) Articles used for food or drink 
      ³for man or other animals, (2) chewing gum, and (3) articles 
      ³used for components of any such article (section 201(f) 
      ³of the act (21 U.S.C. 321(f))). "Food" includes human 
      ³food, substances migrating to food from food-contact 
      ³articles, pet food, and animal feed (21 CFR 170.3(m)). 
      ³"Animal feed" means "an article which is intended for 
      ³use for food for animals or other than man and which 
      ³is intended for use as a substantial source of nutrients 
      ³in the diet of the animal, and is not limited to a mixture 
      ³intended to be the sole ration of the animal" (section 
      ³201(x) of the act (21 U.S.C. 321(x)). 
      ³{2} "Variety" is used here as a general term to describe 
      ³subgroups (whether varieties or cultivars) of plants 
      ³within a species developed for desirable traits. 
      ³{3} "Genetic modification" means the alteration of the 
      ³genotype of a plant using any technique, new or traditional. 
      ³"Modification" is used in a broad context to mean the 
      ³alteration in the composition of food that results from 
      ³adding, deleting, or changing hereditary traits, irrespective 
      ³of the method. Modifications may be minor, such as a 
      ³single mutation that affects one gene, or major alterations 
      ³of genetic material that affect many genes. Most, if 
      ³not all, cultivated food crops have been genetically 
      ³modified. 
   Under this policy, foods, such as fruits, vegetables, grains, 
and their byproducts, derived from plant varieties developed 
by the new methods of genetic modification are regulated within 
the existing framework of the act, FDA's implementing regulations, 
and current practice, utilizing an approach identical in principle 
to that applied to foods developed by traditional plant breeding. 
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). 
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, 
rather than the fact that the new methods are used. 
   The safety of a food is regulated primarily under FDA's postmarket 
authority of section 402(a)(1) of the act (21 U.S.C. 342(a)(1)). 
Unintended occurrences of unsafe levels of toxicants in food 
are regulated under this section. Substances that are expected 
to become components of food as result of genetic modification 
of a plant and whose composition is such or has been altered 
such that the substance is not generally recognized as safe 
(GRAS) or otherwise exempt are subject to regulation as "food 
additives" under section 409 of the act (21 U.S.C. 348). Under 
the act, substances that are food additives may be used in food 
only in accordance with an authorizing regulation. 
   In most cases, the substances expected to become components 
of food as a result of genetic modification of a plant will 
be the same as or substantially similar to substances commonly 
found in food, such as proteins, fats and oils, and carbohydrates. 
As discussed in more detail in section V.C., FDA has determined 
that such substances should be subject to regulation under section 
409 of the act in those cases when the objective characteristics 
of the substance raise questions of safety sufficient to warrant 
formal premarket review and approval by FDA. The objective characteristics 
that will trigger regulation of substances as food additives 
are described in the guidance section of this notice (section 
VII.). 
   The guidance section also describes scientific considerations 
that are important in evaluating the safety and nutritional 
value of foods for consumption by humans or animals, regardless 
of whether the food is regulated under section 402(a)(1) or 
section 409 of the act. The guidance section outlines a "decision 
tree" approach to safety assessment of foods derived from new 
plant varieties that FDA believes is compatible with current 
practice among scientists knowledgeable in this area. The guidance 
section also identifies certain scientific questions that may 
raise sufficient safety concern to warrant consultation with 
FDA.
   Finally, this notice addresses FDA's responsibility under 
the National Environmental Policy Act (NEPA) and the food labeling 
provisions of the act as such provisions affect labeling of 
foods derived from new plant varieties.
   This policy statement reflects FDA's current judgment based 
on the new plant varieties now under development in agricultural 
research. FDA invites comments on this document. Because scientific 
developments in this field are occurring rapidly, FDA will refine 
its policy, if circumstances warrant, in a future Federal Register 
notice. Additionally, FDA plans to announce in a future Federal 
Register notice a workshop to discuss specific scientific issues. 
FDA invites comment on topics that might be addressed at such 
a workshop.

II. Responsibility for Food Safety

   FDA is the primary Federal agency responsible for ensuring 
the safety of commerical food and food additives, except meat 
and poultry products. FDA works closely on food safety matters 
with the U.S. Department of Agriculture (USDA), which regulates 
meat and poultry products, and with the U.S. Environmental Protection 
Agency (EPA), which regulates pesticides and sets tolerances 
for pesticide residues in food. FDA's authority is under the 
act, the Public Health Service Act, and FDA's implementing regulations 
codified in title 21 of the CFR. The act gives FDA broad authority 
to initiate legal action against a food that is adulterated 
or misbranded within the meaning of the act.
   Producers of new foods have an obligation under the act to 
ensure that the foods they offer consumers are safe and in compliance 
with applicable legal requirements. Because in some cases the 
regulatory jurisdiction of a new food product including those 
produced using innovative methods may not be clear, producers 
can informally consult with FDA prior to marketing new foods 
to ensure that the safety and regulatory status of a new food 
is properly resolved.
   Elsewhere in this issue of the Federal Register, FDA announces 
the filing of the first request by a producer for consultation 
with FDA concerning a new plant variety developed by recombinant 
DNA techniques. The request submitted by Calgene, Inc., (Calgene) 
concerns the FLAVR SAVR(TM) tomato, a new variety claimed to 
exhibit improved fruit ripening and other properties. Because 
Calgene made this request prior to the finalization of this 
policy statement, FDA advised the firm to submit the information 
about the tomato initially as a request for advisory opinion 
under §10.85 (21 CFR 10.85) to permit the agency to consider 
the status of the new variety, and to utilize an evaluation 
process that is open to public comment and permits the agency 
to make its decision known to the public. Future requests for 
FDA consultation should be made consistent with the principles 
outlined in this notice. Thus, FDA does not anticipate that 
future requests of this nature will be filed under §10.85

III. Scope of This Document

   This notice discusses scientific and regulatory considerations 
for foods derived from new plant varieties. This notice does 
not address foods and food ingredients regulated by FDA that 
have been derived from algae, microorganisms, and other nonplant 
organisms, including: (1) Foods produced by fermentation, where 
microorganisms are essential components of the food (e.g., yogurt 
and single cell protein); (2) food ingredients produced by fermentation, 
such as many enzymes, flavors, amino acids, sweeteners, thickeners, 
antioxidants, preservatives, colors, and other substances; (3) 
substances produced by new plant varieties whose purpose is 
to color food, and (4) foods derived from animals that are subject 
to FDA's authority, including seafood. FDA is considering whether 
to address these issues in future Federal Register notices.
   Finally, the principles discussed in this notice do not apply 
to "new drugs" as defined by section 201 (p) of the act (21 
U.S.C. 321(p)), "new animal drugs" as defined by section 201(w) 
of the act (21 U.S.C. 321(w)), or to "pesticide chemicals" as 
defined by section 201(q) of the act. As discussed in section 
IX., EPA is responsible for pesticide chemicals, including those 
produced in plants as a result to genetic modification.

IV. Scientific Issues Relevant to Public Health

   Plant breeding is the science of combining desirable genetic 
traits into a variety that can be used in agriculture. The desired 
traits can be broadly divided into two classes: Those that affect 
agronomic characteristics of the plant, and those that affect 
quality characteristics of the food. Agronomic characteristics 
include those affecting yield; resistance to diseases, insects, 
and herbicides; and ability to thrive under various adverse 
environmental conditions. Quality characteristics include those 
affecting processing, preservation, nutrition, and flavor.
   The genetic modification techniques used to develop new plant 
varieties constitute a continuum. Traditional breeding typically 
consists of hybridization between varieties of the same species 
and screening for progeny with desired characteristics. Such 
hybridizations only can introduce traits found in close relatives. 
Breeders have developed or adopted a number of techniques to 
expand the range of genetic variation available to them. These 
techniques introduce variation either by using mutagenesis to 
alter the genome or by introducing or modifying DNA segments, 
including DNA segments derived from other organisms.
   Mutagenic techniques include both random mutagenesis, resulting 
from treatment with chemical and physical mutagens, and somaclonal 
variation, whereby, with the use of tissue culture techniques, 
plants are regenerated from callus or leaf tissue explants. 
The regenerated plants often have properties not found in the 
progenitor plant, reflecting both preexisting cellular genetic 
differences and tissue-culture induced mutations. The mutations 
range from single gene changes to chromosomal rearrangements. 
Mutagenesis techniques are limited, however, by their inability 
to target a desired trait. Somaclonal variants also frequently 
are unstable or infertile.
   Techniques for gene transfer between plants that belong to 
different species or genera fall under the general heading of 
"wide crosses." These "crosses" have been accomplished using 
hybridization, and protoplast fusion. Traditional wide crosses 
involve hybridization between closely related species or genera, 
frequently requiring the use of special techniques such as embryo 
rescue and chromosome doubling to overcome physical or genetic 
barriers to the production of fertile progeny. They permit the 
transfer of genetic traits that are not present in close relatives 
of the modern plant varieties but are found in more distant 
wild relatives. Traits that confer resistance to a number of 
diseases have been introduced this way.
   All of the techniques described above require extensive back 
crossing with the parent line{4} to eliminate mutations unlinked 
to that responsible for the desired phenotype and undesirable 
traits in extraneous genetic material introduced along with 
that encoding the desired trait.
      ³{4} A line is a group of individuals from a common ancestry. 
      ³It is a more narrowly defined group than a variety. (Breeding 
      ³Field Crops, J.M. Poehlman, Van Nostrand Reinhold, New 
      ³York, 1987.
   Recombinant DNA techniques involve the isolation and subsequent 
introduction of discrete DNA segments containing the gene(s) 
of interest into recipient (host) plants. The DNA segments can 
come from any organism (microbial, animal, or plant). In theory, 
essentially any trait whose gene has been identified can be 
introduced into virtually any plant, and can be introduced without 
extraneous unwanted genetic material. Since these techniques 
are more precise, they increase the potential for safe, better-
characterized, and more predictable foods.
   DNA segments introduced using the new techniques insert semi-
randomly into the chromosome, frequently in tandem multiple 
copies, and sometimes in more than one site on the chromosome. 
Both the number of copies of the gene and its location in the 
chromosome can affect its level of expression, as well as the 
expression of other genes in the plant. To ensure homozygosity 
and to enhance the stability of the line and the ability to 
cross the trait into other lines, the breeder will often perform 
a limited number of back crosses to ensure that the plant line 
has the new trait inserted in only one location in the chromosome.
   Additionally, as with other breeding techniques, the phenotypic 
effects of a new trait may not always be completely predictable 
in the new genetic background of the host. Therefore, it is 
common practice for breeders using recombinant DNA techniques 
to cross the new trait into a number of hosts to find the best 
genetic background for expression of the new trait. Currently, 
for most crops only a few lines or varieties of any species 
are amendable to the use of recombinant DNA techniques. Once 
the desired trait is introduced into a line amenable to the 
technique, it must then be crossed by traditional means to other 
desired lines or varieties.
   Regardless of the particular combination of techniques used, 
the development of a new plant variety typically will require 
many site-years (number of sites x number of years of plant 
testing) of performance trials before introduction into agricultural 
practice. These range from as few as 10 to 20 site-years for 
some plants to 75 to 100 site-years for others (some 5 to 10 
years). The time of evaluation and the size and number of sites 
will vary as necessary to confirm performance; to reveal vulnerabilities 
to pests, diseases, or other production hazards; to evaluate 
stability of the phenotype; to evaluate characteristics of the 
food; to evaluate environmental effects; and to produce the 
required amount of seed before the new plant variety can be 
grown commercially by farmers. In the course of this intensive 
assessment, individual plants exhibiting undesirable traits 
are eliminated.
   Recombinant DNA techniques are used to achieve the same types 
of goals as traditional techniques: The development of new plant 
varieties with enhanced agronomic and quality characteristics. 
Currently, over 30 different agricultural crops developed using 
recombinant DNA techniques are in field trials. Food crops have 
been developed using these techniques to exhibit improved resistance 
to pests and disease and to chemical herbicides. For example, 
a plant's ability to resist insect infestation reportedly has 
been improved by transferring bacterial genetic material that 
encodes proteins toxic to certain insects (e.g., Bacillus thuringiensis 
delta endotoxin). Other plants have been given viral coat-protein 
genes that confer cross-protection to viral pathogens.
   Other new plant varieties have been developed that exhibit 
traits for improved food processing, improved nutritional content, 
or enhanced protection against adverse weather conditions. For 
example, genetic modifications of plant enzymes involved in 
fruit ripening may yield tomatoes with improved ripening characteristics, 
texture, and flavor. Scientists have used recombinant DNA techniques 
to transfer genetic material for the production of seed storage 
protein conferring improvements in nutritional balance of important 
amino acids in the new plant varieties. Scientists have also 
identified genes in certain fish that encode proteins that conferee 
increased resistance to cold. Copies of these genes have been 
introduced into agricultural crops with the goal of producing 
new plant varieties that show improved tolerance to cold weather 
conditions.
   These examples illustrate only a few of the many improved 
agronomic and food processing traits currently being introduced 
into plants using recombinant DNA techniques. Any genetic modification 
technique has the potential to alter the composition of food 
in a manner relevant to food safety, although, based on experience, 
the likelihood of a safety hazard is typically very low. The 
following paragraphs describe some potential changes in composition 
that may require evaluation to assure food safety.

A. Unexpected Effects

   Virtually all breeding techniques have potential to create 
unexpected (including pleiotropic{5} effects. For example, mutations 
unrelated to the desired modification may be induced; undesirable 
traits may be introduced along with the desired traits; newly 
introduced DNA may physically insert into a transcriptionally 
active site on the chromosome, and may thereby inactivate a 
host gene or alter control of its expression; the introduced 
gene product or a metabolic product affected by the genetic 
change may interact with other cellular products to produce 
a deleterious effect. Plant breeders using well established 
practices have successfully identified and eliminated plants 
that exhibit unexpected, adverse traits prior to commercial 
use.
      ³{5} Pleiotropic effects refer to multiple effects resulting 
      ³from a single genetic change.

B. Known Toxicants

   Plants are known to produce naturally a number of toxicants 
and antinutritional factors, such as protease inhibitors, hemolytic 
agents, and neurotoxins, which often serve the plant as natural 
defense compounds against pests or pathogens. For example, most 
cereals contain protease inhibitors, which can diminish the 
nutritive value of proteins. Many legumes contain relatively 
high levels of lectins and cyanogenic glycosides. Lectins, if 
not destroyed by cooking or removed by soaking, can cause severe 
nausea, vomiting, and diarrhea. Cyanogenic glycosides can be 
hydrolyzed by specific enzymes in the plant to release cyanide 
if food from the plant is improperly prepared. The levels of 
cyanogenic glycosides in cassava and some legumes can lead to 
death or chronic neurological disease if these foods are eaten 
uncooked. Cruciferae contain glucosinolates which may impair 
thyroid function. Squash and cucumber contain cucurbiticin, 
an acute toxicant. Chickpeas contain lathyrogens, which are 
neurotoxins.
   Many of these toxicants are present in today's foods at levels 
that do not cause acuate toxicity. Others, such as in cassava 
and some legumes, are high enough to cause severe illness or 
death if the foods are not properly prepared. FDA seek to assure 
that new plant varieties do not have significantly higher levels 
of toxicants than present in other edible varieties of the same 
species.
   Plants, like other organisms, have metabolic pathways that 
no longer function due to mutations that occurred during evolution. 
Products or intermediates of some such pathways may include 
toxicants. In rare cases, such silent pathways may be activated 
by mutations, chromosomal rearrangements, or new regulatory 
regions introduced during breeding, and toxicants hitherto not 
associated with a plant species may thereby be produced. Similarly, 
toxicants ordinarily produced at low levels in a plant may be 
produced at high levels in a new variety as a result of such 
occurrences. The likelihood of activation of quiescent pathways 
or increased expression from active pathways is considered extremely 
low in food plants with a long history of use that have never 
exhibited production of unknown or unexpected toxins, since 
the genetic changes that can lead to such events occur during 
growth and are induced with traditional breeding manipulations. 
In the few cases where toxicants have been raised to unsafe 
levels in a commercial plant variety, the toxicants were known 
to occur in significant levels in one of the parent species. 
Except in rare cases, plant breeders using well established 
practices have successfully identified and eliminated plants 
that express unacceptably high levels of toxicants prior to 
commercial use. 

C. Nutrients 

   Another unintended consequence of genetic modification of 
the plant may be a significant alteration in levels of important 
nutrients. In addition, changes in bioavailability of a nutrient 
due to changes in form of the nutrient or the presence of increased 
levels of other constituents that affect absorption or metabolism 
of nutrients must be considered for potential nutritional impact. 

D. New Substances 

   Because plant breeders using the new techniques are able 
to introduce essentially any trait or substance whose molecular 
genetic identity is known into virtually any plant, it is possible 
to introduce a protein that differs significantly in structure 
or function, or to modify a carbohydrate, fat or oil, such that 
it differs significantly in composition from such substances 
currently found in food. 

E. Allergenicity 

   All food allergens are proteins. However, only a small fraction 
of the thousands of proteins in the diet have been found to 
be food allergens. FDA's principal concern regarding allergencity 
is that proteins transferred from one food source to another, 
as is possible with recombinant DNA and protoplast fusion techniques, 
might confer on food from the host plant the allergenic properties 
of food from the donor plant. Thus, for example, the introduction 
of a gene that encodes a peanut allergen into corn might make 
that variety of corn newly allergenic to people ordinarily allergic 
to peanuts. 
   Examples of foods that commonly cause an allergenic response 
are milk, eggs, fish, crustacea, molluscs, tree nuts, wheat, 
and legumes (particularly peanuts and soybeans). The sensitive 
population is ordinarily able to identify and avoid the offending 
food. However, if the allergen were moved into a variety of 
a plant species that never before produced that allergen, the 
susceptible population would not know to avoid food from that 
variety. 
   In some foods that commonly cause an allergic response, the 
particular protein(s) responsible for allergenicity is known, 
and therefore the producer may know whether the transferred 
protein is the allergen. However, in other cases, the protein 
responsible for a food's allergenicity is not known, and FDA 
considers it prudent practice for the producer initially to 
assume that the transferred protein is the allergen. Appropriate 
in vitro or in vivo allergenicity testing may reveal whether 
food from the new variety elicits an allergenic response in 
the potentially sensitive population (i.e., people sensitive 
to the food in which the protein is ordinarily found). Producers 
of such foods should discuss allergenicity testing protocol 
requirements with the agency. Labeling of foods newly containing 
a known or suspect allergen may be needed to inform consumers 
of such potential. 
   A separate issue is whether any new protein in food has the 
potential to be allergenic to a segment of the population. At 
this time, FDA is unaware of any practical method of predict 
or assess the potential for new proteins in food to induce allergenicity 
and requests comments on this issue. 

F. Antibiotic Resistance Selectable Markers 

   In gene transfer experiments, only a small percentage of 
the recipient plant cells will actually take up the introduced 
genes, and many desirable traits (i.e., those that specify the 
intended technical effect) are not easy to detect before the 
plant has fully developed. Scientists, therefore, enhance their 
ability to isolate plant cells that have taken up and stably 
incorporated the desired genes by physically linking the desired 
gene to a selectable marker gene, such as a gene that specifies 
the production of a substance that inactivates antibiotics. 
   The kanamycin resistance gene is one of the most widely used 
selectable marker genes. The kanamycin resistance gene specifies 
the information for the production of the enzyme, aminoglycoside 
3'-phosphotransferase II. The common name for this enzyme is 
kanamycin (or neomycin) phosphotransferase II. The kanamycin 
phosphotransferase II enzyme modifies aminoglycoside antibiotics, 
including kanamycin, neomycin, and geneticin (G418), chemically 
inactivating the antibiotic and rendering the cells that produce 
the kanamycin resistance gene product refractory or resistant 
to the antibiotic. Plant cells that have received and stably 
express the kanamycin resistance gene survive and replicate 
on laboratory media in the presence of the antibiotic, kanamycin. 
Plant cells that did not take up and express the introduced 
kanamycin resistance gene will be killed by the antibiotic. 
By linking the selectable marker gene to another gene that specifies 
a desired trait, scientists can identify and select plants that 
have taken up and express the desired genes. 
   The kanamycin resistance gene has been used as a selectable 
marker in more than 30 crops to develop varieties that exhibit 
improved nutritional and processing properties, resistance to 
pests and diseases, tolerance to chemical herbicides, and other 
agronomic properties. Once the desired plant variety has been 
selected, the kanamycin resistance gene serves no further useful 
purpose, although it continues to produce the kanamycin phosphotransferase 
II enzyme in the plant tissues. Thus, while the kanamycin resistance 
gene is a research tool that is important for developing new 
plant varieties through the current recombinant DNA techniques 
of gene transfer, both the kanamycin resistance gene and its 
product, the kanamycin phosphotransferase II enzyme protein, 
are expected to be present in foods derived from such plants, 
unless removed through recently developed techniques (Ref. 5). 
   Selectable marker genes that produce enzymes that inactivate 
clinically useful antibiotics theoretically may reduce the therapeutic 
efficacy of the antibiotic when taken orally if the enzyme in 
the food inactives the antibiotic. FDA believes that it will 
be important to evaluate such concerns with respect to commercial 
use of antibiotic resistance marker genes in food, especially 
those that will be widely used. FDA is now evaluating this and 
other issues with respect to the use of the kanamycin resistance 
marker in food. (See 56 FR 20004, May 1, 1991.)

G. Plants Developed to Make Specialty Nonfood Substances

   New genetic modification techniques may develop plants that 
produce nonfood chemicals, such as polymers and pharmaceuticals. 
In many cases, the plant will not subsequently be used for food. 
In such cases, the developer must ensure that food-use varieties 
of the crop do not cross with or become mixed with the nonfood-
use varieties. This is not a new issue for breeders and growers. 
For example, some varieties of rapeseed oil are grown for industrial 
oil use, and have high levels of toxicants, such as erucic acid 
and glucosinylates, while other varieties are grown for food 
use and have low levels of these substances. Similarly, potatoes 
grown for industrial uses can have higher levels of solanine 
than those grown for retail food use. The producer of the oil 
or potato must ensure that the edible plant variety is not adulterated 
within the meaning of the act. Developers of crops designed 
to produce specialty nonfood substances have a comparable obligation. 
   If plants (or materials derived from plants) used to make 
nonfood chemicals are also intended to be used for food, producers 
should consult with FDA to determine whether the nonfood chemical 
would be a food additive requiring an authorizing regulation 
prior to marketing for food use.

H. Issues Specific to Animal Feeds

   Unlike a food in the human diet, an animal feed derived from 
a single plant may constitute a significant portion of the animal 
diet. For instance, 50 to 75 percent of the diet of most domestic 
animals consists of field corn. 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.
   Further, animals consume plants, plant parts, and plant byproducts 
that are not consumed by humans. For example, animals consume 
whole cottonseed meal, whereas humans consume only cotton seed 
oil. Gossypol, a plant toxicant, is concentrated in the cotton 
seed meal during the production of cotton seed oil. Because 
plant byproducts represent an important feed source for animals, 
it is important to determine if significant concentrations of 
toxicants or other harmful plant constituents are present in 
new plant varieties.
   Nutrient composition and availability of nutrients in feed 
are important safety considerations for animal health. For example, 
if a genetic modification in soybeans caused an increase in 
phytin content, the soybean feed may need to be supplemented 
with phosphorous to avoid problems of animal health.

V. Regulatory Status of Foods Derived From New Plant Varieties

A. The Statutory Framework for New Foods and Food Ingredients

   The United States today has a food supply that is as safe 
as any in the world. Most foods derived from plants predate 
the establishment of national food laws, and the safety of these 
foods has been accepted based on extensive use and experience 
over many years (or even centuries). Foods derived from new 
plant varieties are not routinely subjected to scientific tests 
for safety, although there are exceptions. For example, potatoes 
are generally tested for the glycoalkaloid, solanine. The established 
practices that plant breeders employ in selecting and developing 
new varieties of plants, such as chemical analyses, taste testing, 
and visual analyses, rely primarily on observations of quality, 
wholesomeness, and agronomic characteristics. Historically, 
these practices have proven to be reliable for ensuring food 
safety. The knowledge from this past experience coupled with 
safe practices in plant breeding has contributed to continuous 
improvements in the quality, variety, nutritional value, and 
safety of foods derived from plants modified by a range of traditional 
and increasingly sophisticated techniques (Ref. 1 at xvi). Based 
on this record of safe development of new varieties of plants, 
FDA has not found it necessary to conduct, prior to marketing, 
routine safety reviews of whole foods derived from plants.
   Nevertheless, FDA has ample authority under the act's food 
safety provisions to regulate and ensure the safety of foods 
derived from new plant varieties, including plants developed 
by new techniques. This includes authority to require, where 
necessary, a premarket safety review by FDA prior to marketing 
of the food. Under section 402(a)(1) of the act, a food is deemed 
adulterated and thus unlawful if it bears or contains an added 
poisonous or deleterious substance that may render the food 
injurious to health or a naturally occurring substance that 
is ordinarily injurious. Section 402(a)(1) of the act imposes 
a legal duty on those who introduce food into the market place, 
including food derived from new crop varieties, to ensure that 
the food satisfies the applicable safety standard. Foods that 
are adulterated under section 402(a)(1) of the act are subject 
to the full range of enforcement measures under the act, including 
seizure, injunction, and criminal prosecution of those who fail 
to meet their statutory duty.
   FDA has relied almost exclusively on section 402(a)(1) of 
the act to ensure the safety of whole foods. Toxins that occur 
naturally in food and that render the food ordinarily injurious 
to health (such as poisons in certain mushrooms), and thus adulterated, 
rarely required FDA regulatory action because such cases are 
typically well known and carefully avoided by food producers.
   FDA regards any substance that is not an inherent constituent 
of food or whose level in food has been increased by human intervention 
to be "added" within the meaning of section 402(a)(1) of the 
act. See United States v. Anderson Seafoods, Inc., 622 F. 2d 
157 (5th Cir. 1980). Added substances are subject to the more 
stringent "may render [the food] injurious" safety standard. 
Under this standard, the food is adulterated if, by virtue of 
the presence of the added substance, there is a "reasonable 
possibility" that consumption of the food will be injurious 
to health. United States v. Lexington Mill & Elevator Co., 232 
U.S. 399 (1914). The "may render injurious" standard would apply 
to a naturally occurring toxin in food if the level of the toxin 
in a new plant variety were increased through traditional plant 
breeding or some other human intervention. Section 402(a)(1) 
of the act would have been the legal basis under which FDA could 
have blocked marketing in the 1970's of a new variety of potato 
that had been found during its development to contain elevated 
and potentially harmful levels of solanine as a result of a 
cross with an inedible wild potato.
   Section 402(a)(1) of the act is most frequently used by FDA 
to regulate the presence in food of unavoidable environmental 
contaminants such as lead, mercury, dioxin, and aflatoxin. FDA 
regulary establishes action levels and takes enforcement action 
to prevent the sale of foods that contain unacceptable levels 
of such unintended and undesired contaminants.
   Section 402(a)(1) of the act was signed into law in 1938 
and has its origins in a similar provision in the Federal Food 
and Drugs Act of 1906. Until 1958, this authority was the principal 
tool relied upon by FDA to regulate the safety of food and food 
ingredients. In 1958, in response to public concern about the 
increased use of chemicals in foods and food processing and 
with the support of the food industry, Congress enacted the 
Food Additives Amendment (the amendment) to the act. Among other 
provisions, the amendment established a premarket approval requirement 
for "food additives." The basic thrust of the amendment was 
to require that, before a new chemical additive (such as a preservative, 
antioxidant, emulsifier, or artificial flavor) could be used 
in food processing, its producer must demonstrate the safety 
of the additive to FDA. Congress recognized under this new scheme 
that the safety of an additive could not be established with 
absolute certainty or under all conditions of use. Congress 
thus provided for a science-based safety standard that requires 
producers of food additives to demonstrate to a reasonable certainty 
that no harm will result from the intended use of the additive. 
See 21 CFR 170.3(i). If FDA finds an additive to be safe, based 
ordinarily on data submitted by the producer to the agency in 
a food additive petition, the agency promulgates a regulation 
specifying the conditions under which the additive may be safely 
used. Food additives that are not the subject of such a regulation 
are deemed unsafe as a matter of law, and the foods containing 
them are adulterated under section 402(a)(2)(C) of the act (21 
U.S.C. 342(a)(2)(C)) and are thus unlawful.
   In enacting the amendment, Congress recognized that many 
substances intentionally added to food do not require a formal 
premarket review by FDA to assure their safety, either because 
their safety had been established by a long history of use in 
food or because the nature of the substance and the information 
generally available to scientists about the substance are such 
that the substance simply does not raise a safety concern worthy 
of premarket review by FDA. Congress thus adopted a two-step 
definition of "food additive." The first step broadly includes 
any substance the intended use of which results in its becoming 
a component of food. The second step, however, excludes from 
the definition of food additive substances that are GRAS. It 
is on the basis of the GRAS exception of the "food additive" 
definition that many ingredients derived from natural sources 
(such as salt, pepper, vinegar, vegetable oil, and thousands 
of spices and natural flavors), as well as a host of chemical 
additives (including some sweeteners, preservatives, and artificial 
flavors), are able to be lawfully marketed today without having 
been formally reviewed by FDA and without being the subject 
of a food additive regulation. The judgment of Congress was 
that subjecting every intentional additive to FDA premarket 
review was not necessary to protect public health and would 
impose an insurmountable burden on FDA and the food industry.
   Congress' approach to defining food additives means, however, 
that companies developing new ingredients, new versions of established 
ingredients, or new processes for producing a food or food ingredient 
must make a judgment about whether the resulting food substance 
is a food additive requiring premarket approval by FDA. In many 
cases, the answer is obvious, such as when the ingredient is 
a man made chemical having no widely recognized history of safe 
use in food. Such an ingredient must be approved prior to its 
use by the issuance of a food additive regulation, based on 
information submitted to FDA in a food additive petition.
   In other cases, the answer is less obvious, such as when 
an established ingredient derived from nature is modified in 
some minor way or produced by a new process. In such cases, 
the manufacturer must determine whether the resulting ingredient 
still falls within the scope of any existing food additive regulation 
applicable to the original ingredient or whether the ingredient 
is exempt from regulation as a food additive because it is GRAS. 
The GRAS status of some substances is recognized in FDA's regulations 
(21 CFR parts 182, 184, 186, 582, and 584), but FDA has not 
attempted to include all GRAS substances in its regulations.
   FDA has traditionally encouraged producers of new food ingredients 
to consult with FDA when there is a question about an ingredient's 
regulatory status, and firms routinely do so, even though such 
consultation is not legally required. If the producer begins 
to market the ingredient based on the producer's independent 
determination that the substance is GRAS and FDA subsequently 
concludes the substance is not GRAS, the agency can and will 
take enforcement action to stop distribution of the ingredient 
and foods containing it on the ground that such foods are or 
contain an unlawful food additive.
   FDA considers the existing statutory authority under sections 
402(a)(1) and 409 of the act, and the practical regulatory regime 
that flows from it, to be fully 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. The existing tools provide this assurance 
because they impose a clear legal duty on producers to assure 
the safety of foods they offer to consumers; this legal duty 
is backed up by strong enforcement powers; and FDA has authority 
to require premarket review and approval in cases where such 
review is required to protect public health.
   In the Federal Register of June 26, 1986 (51 FR 23302) (the 
June 1986 notice), FDA, in conjunction with the Office of Science 
and Technology Policy in the Executive Office of the President, 
described FDA's current food safety authorities and stated the 
agency's intention to regulate foods produced by new methods, 
such as recombinant DNA techniques, within the existing statutory 
and regulatory framework. This notice reaffirms that intention. 
The following paragraphs explain briefly how the current framework 
will apply specifically to foods derived from new plant varieties, 
including plants developed by recombinant DNA techniques.

B. The Application of Section 402(a)(1) of the Act

   Section 402(a)(1) of the act will continue to be FDA's primary 
legal tool for regulating the safety of whole foods, including 
foods derived from plants genetically modified by the new techniques. 
Section 402(a)(1) of the act will be applied to any substance 
that occurs unexpectedly in the food at a level that may be 
injurious to health. This includes a naturally occurring toxicant 
whose level is unintentionally increased by the genetic modification, 
as well as an unexpected toxicant that first appears in the 
food as a result of pleiotropic effects. Such substances are 
regarded by FDA as added substances whose presence adulterates 
the food if present at a level that "may render" the food injurious 
to health.
   It is the responsibility of the producer of a new food to 
evaluate the safety of the food and assure that the safety requirement 
of section 402(a)(1) of the act is met. In section VII., FDA 
provides guidance to the industry regarding prudent, scientific 
approaches to evaluating the safety of foods derived from new 
plant varieties, including the safety of the added substances 
that are subject to section 402(a)(1) of the act. FDA encourages 
informal consultation between producers and FDA scientists to 
ensure that safety concerns are resolved. However, producers 
remain legally responsible for satisfying section 402(a)(1) 
of the act, and they will continue to be held accountable by 
FDA through application of the agency's enforcement powers.

C. The Application of Section 409 of the Act

   When Congress enacted the amendment in 1958, it did not explicitly 
address the possible application of the food additive approval 
process to foods derived from new plant varieties. As previously 
discussed, such foods have historically been regulated successfully 
under section 402(a)(1) of the act. The new methods of genetic 
modification have focused attention, however, on the possibility 
that intended changes in the composition of food resulting from 
genetic modification might be of a nature sufficient as a legal 
and public health matter to trigger regulation of a component 
of the food under section 409 of the act.
   As discussed above, the food additive definition broadly 
encompasses any substance that has an intended use in food, 
unless the substance is GRAS. It was on this basis that the 
June 1986 notice indicated that, in some cases, whole foods 
derived from new plant varieties, including plants developed 
by new genetic modification techniques, might fall within the 
scope of FDA's food additive authority. Indeed, FDA's regulations 
have long recognized that it might be appropriate in some circumstances 
to review the GRAS (and implicitly food additive) status of 
foods or substances of natural biological origin that have a 
history of safe use but which subsequently have had "significant 
alteration by breeding and selection." (See 21 CFR 170.30(f).) 
As already discussed, however, FDA has rarely had occasion to 
review the GRAS status of foods derived from new plant varieties 
because these foods have been widely recognized and accepted 
as safe.
   FDA has reviewed its position on the applicability of the 
food additive definition and section 409 of the act to foods 
derived from new plant varieties in light of the intended changes 
in the composition of foods that might result from the newer 
techniques of genetic modification. The statutory definition 
of "food additive" makes clear that it is the intended or expected 
introduction of a substance into food that makes the substance 
potentially subject to food additive regulation. Thus, in the 
case of foods derived from new plant varieties, it is the transferred 
genetic material and the intended expression product or products 
that could be subject to food additive regulation, if such material 
or expression products are not GRAS.
   In regulating foods and their byproducts derived from new 
plant varieties, FDA intends to use its food additive authority 
to the extent necessary to protect public health. Specifically, 
consistent with the statutory definition of "food additive" 
and the overall design of FDA's current food safety regulatory 
program, FDA will use section 409 of the act to require food 
additive petitions in cases where safety questions exist sufficient 
to warrant formal premarket review by FDA to ensure public health 
protection.
   With respect to transferred genetic material (nucleic acids), 
generally FDA does not anticipate that transferred genetic material 
would itself be subject to food additive regulation. Nucleic 
acids are present in the cells of every living organism, including 
every plant and animal used for food by humans or animals, and 
do not raise a safety concern as a component of food. In regulatory 
terms, such material is presumed to be GRAS. Although the guidance 
provided in section VII. calls for a good understanding of the 
identity of the genetic material being transferred through genetic 
modification techniques, FDA does not expect that there will 
be any serious question about the GRAS status of transferred 
genetic material.
   FDA expects that the intended expression product or products 
present in foods derived from new plant varieties will typically 
be proteins or substances produced by the action of protein 
enzymes, such as carbohydrates, and fats and oils. When the 
substance present in the food is one that is already present 
at generally comparable or greater levels in currently consumed 
foods, there is unlikely to be a safety question sufficient 
to call into question the presumed GRAS status of such naturally 
occurring substances and thus warrant formal premarket review 
and approval by FDA. Likewise, minor variations in molecular 
structure that do not affect safety would not ordinarily affect 
the GRAS status of the substances and, thus, would not ordinarily 
require regulation of the substance as a food additive.
   It is possible, however, that the intended expression product 
in a food could be a protein, carbohydrate, fat or oil, or other 
substance that differs significantly in structure, function, 
or composition from substances found currently in food. Such 
substances may not be GRAS and may require regulation as a food 
additive. For example, if a food derived from a new plant variety 
contains a novel protein sweetener as a result of the genetic 
modification of the plant, that sweetener would likely require 
submission of a food additive petition and approval by FDA prior 
to marketing. FDA invites comments on substances, in addition 
to proteins, carbohydrates, and fats and oils, that in the future 
may be introduced into foods by genetic modification.
   Section VII. of this notice provides guidance to producers 
of new foods for conducting safety evaluations. This guidance 
is intended to assist producers in evaluating the safety of 
the food that they market, regardless of whether the food requires 
premarket approval by FDA. This guidance also includes criteria 
and analytical steps that producers can follow in determining 
whether their product is a candidate for food additive regulation 
and whether consultation with FDA should be pursued to determine 
the regulatory status of the product. Ultimately, it is the 
food producer who is responsible for assuring safety.
   FDA has long regarded it to be a prudent practice for producers 
of foods using new technologies to work cooperatively with the 
agency to ensure that the new products are safe and comply with 
applicable legal requirements. It has been the general practice 
of the food industry to seek informal consultation and cooperation, 
and this practice should continue with respect to foods produced 
using the newer techniques of genetic modification.

VI. Labeling

   FDA has received several inquiries concerning labeling requirements 
for foods derived from new plant varieties developed by recombinant 
DNA techniques. Section 403(i) of the act (21 U.S.C. 343(i)) 
requires that a producer of a food product describe the product 
by its common or usual name or in the absence thereof, an appropriately 
descriptive term (21 U.S.C. part 101.3) and reveal all facts 
that are material in light of representations made or suggested 
by labeling or with respect to consequences which may result 
from use (21 U.S.C. 343(a); 21 U.S.C. 321(n)). Thus, consumers 
must be informed, by appropriate labeling, if a food derived 
from a new plant variety differs from its traditional counterpart 
such that the common or usual name no longer applies to the 
new food, or if a safety or usage issue exists to which consumers 
must be alerted.
   For example, if a tomato has had a peanut protein introduced 
into it and there is insufficient information to demonstrate 
that the introduced protein could not cause an allergic reaction 
in a susceptible population, a label declaration would be required 
to alert consumers who are allergic to peanuts so they could 
avoid that tomato, even if its basic taste and texture remained 
unchanged. Such information would be a material fact whose omission 
may make the label of the tomato misleading under section 403(a) 
of the act (21 U.S.C. 343(a)).
   FDA has also been asked whether foods developed using techniques 
such as recombinant DNA techniques would be required to bear 
special labeling to reveal that fact to consumers. To date, 
FDA has not considered the methods used in the development of 
a new plant variety (such as hybridization, chemical or radiation-
induced mutagenesis, protoplast fusion, embryo rescue, somaclonal 
variation, or any other method) to be material information within 
the meaning of section 201(n) of the act (21 U.S.C. 321(n)). 
As discussed above, FDA believes that the new techniques are 
extensions at the molecular level of traditional methods and 
will be used to achieve the same goals as pursued with traditional 
plant breeding. The agency is not aware of any information showing 
that foods derived by these new methods differ from other foods 
in any meaningful or uniform way, or that, as a class, foods 
developed by the new techniques present any different or greater 
safety concern than foods developed by traditional plant breeding. 
For this reason, the agency does not believe that the method 
of development of a new plant variety (including the use of 
new techniques including recombinant DNA techniques) is normally 
material information within the meaning of 21 U.S.C. 321(n) 
and would not usually be required to be disclosed in labeling 
for the food.
   The guidance section (section VII.) of this notice discusses 
certain circumstances where questions may arise about the proper 
labeling of foods derived from new plant varieties. FDA requests 
comments on the labeling of foods derived from new plant varieties, 
including plants developed with recombinant DNA techniques.

 

VII. Guidance to Industry for Foods Derived From New Plant Varieties

A. Introduction

   This guidance section describes many of the scientific considerations 
for evaluating the safety and nutritional aspects of food from 
new plant varieties derived by traditional methods (such as 
hybridization or mutagenesis), tissue culture methods (such 
as somaclonal variation and protoplast fusion), and recombinant 
DNA methods. Although some of the safety considerations are 
specific to individual technologies, many safety considerations 
are similar regardless of the technology used. This guidance 
section does not attempt to delineate acceptable practices for 
each specific technology. FDA expects plant breeders to adhere 
to currently accepted scientific standards of practice within 
each technology. This guidance section is based on existing 
practices followed by the traditional plant breeders to assess 
the safety and nutritional value of new plant varieties and 
is not intended to alter these long-established practices, or 
to create new regulatory obligations for them. 
   This guidance section describes food safety and nutritional 
concerns, rather than performance characteristics for which 
the new plant varieties may have been developed. However, this 
guidance section cannot identify all safety and nutritional 
questions that could arise in a given situation and, while comprehensive, 
should not be viewed as exhaustive. In some cases, additional 
factors may need to be considered, while in other situations, 
some of the factors may not apply. Therefore, this guidance 
section also describes situations in which producers should 
consult with FDA on scientific issues, the design of appropriate 
test protocols, requirements for labeling, and whether a food 
additive petition may be required.
   Genetic modifications of plants can have unintended or unexpected 
effects on the phenotype of the plant, such as poor growth or 
reduced tolerance to conditions of environmental stress, that 
are readily apparent and can be effectively managed by appropriate 
selection procedures. However, effects such as an alteration 
in the concentration of important nutrients, increases in the 
level of natural toxicants, or the transfer of allergens from 
one species to another may not be readily detected without specific 
test procedures. FDA believes that a scientific basis should 
exist to establish that new plant varieties do not exhibit unacceptable 
effects with respect to toxicants, nutritional value, or allergens. 
In cases where the host plant has little or no history of safe 
use, the assessment of new plant varieties should include evidence 
that unknown toxicants are not present in the new plant variety 
at levels that would be injurious to health.
   In addition, by using recombinant DNA techniques, plant breeders 
are now capable theoretically of introducing essentially any 
trait (and thus substance) whose molecular genetic identity 
is known into virtually any plant due to the increased power 
and precision of recombinant DNA techniques. This guidance section, 
however, discusses only proteins, carbohydrates, and fats and 
oils, in the belief that these are the principal substances 
that are currently being intentionally modified or introduced 
into new plant varieties. Using the new techniques, it is possible 
to introduce a gene that encodes a protein that differs significantly 
in structure or function, or to modify a carbohydrate, or fat 
or oil, such that it differs significantly in composition from 
such substances currently found in food. FDA believes that plant 
breeders must carefully evaluate the potential for adverse effects 
that could result from the presence of these substances in new 
plant varieties.
   Theoretically, genetic modifications have the potential to 
activate cryptic pathways synthesizing unknown or unexpected 
toxicants, or to increase expression from active pathways that 
ordinarily produce low or undetectable levels of toxicants. 
However, this potential has been effectively managed in the 
past by sound agricultural practices. The agency believes that 
the use of host plants with a history of safe use, coupled with 
a continuation of sound agricultural practice, will minimize 
the potential for adverse public health consequences that may 
arise from increased levels of unknown or unexpected toxicants.
   This guidance section provides a basis for determining whether 
new plant varieties are as safe and nutritious as their parental 
varieties. The assessment scheme focuses on characteristics 
of the new plant variety, based on characteristics of the host 
and donor species, the nature of the genetic change, the identity 
and function of newly introduced substances, and unexpected 
or unintended effects that accompany the genetic change. The 
assessment focuses on the following considerations:
   1. Toxicants known to be characteristic of the host and donor 
species;
   2. The potential that food allergens will be transferred 
from one food source to another;
   3. The concentration and bioavailability of important nutrients 
for which a food crop is ordinarily consumed;
   4. The safety and nutritional value of newly introduced proteins; 
and
   5. The identity, composition and nutritional value of modified 
carbohydrates, or fats and oils.
   The scientific concepts described in this guidance section 
are consistent with the concepts of substantial equivalence 
of new foods discussed in a document under development by the 
Group of National Experts on Safety in Biotechnology of the 
Organization for Economic Cooperation and Development (OECD). 
This guidance section is also consistent with the principles 
for food safety assessment discussed in the Report of a Joint 
Food and Agriculture Organization/World Health Organization 
Consultation (Ref. 6).

B. Flow Charts

   The flow charts presented in sections VII.D. through VII.F. 
(Figures 2 through 6) outline a series of questions related 
to the safety and nutritional value of foods derived from the 
new plant variety, and are intended to provide general guidance 
to breeders and developers. FDA intends that these flow charts 
be used in conjunction with other information and practices 
that breeders and developers rely on to develop new plant varieties. 
These reflect the current state of scientific information and 
are not intended as regulatory requirements. As new information 
is developed, FDA anticipates that the flow charts may require 
modification.
   The summary flow chart (Figure 1) presented in this section 
is a synopsis of FDA's safety assessment process. It describes, 
in a general way, the assessment for unexpected or unintended 
effects that may arise as a result of the specific characteristics 
that are associated with the host plant and donor(s), as well 
as the assessment of the expected or intended effects. Because 
Figure 1 is a summary, it should not be relied upon for a safety 
assessment. The boxes labeled Figure 2, Figure 3, Figure 4, 
and Figures 5 and 6, respectively, refer to more specific flow 
charts that describe, in appropriate detail, the safety assessment 
from the perspective of the host, donor, and new substances 
that are introduced into the new plant variety.
   Sections VII.D. through VII.F. address the scientific considerations 
pertaining to the host plant, donor(s), and new substances in 
more detail. Each section describes information that relates 
to the safety assessment, presents a flow chart that summarizes 
the safety assessment, discusses each of the questions in that 
flow chart, and describes the endpoints that are reached in 
that flow chart.
   There are three endpoints in the flow charts in this notice: 
(1) No concerns, (2) new variety not acceptable, and (3) consult 
FDA. The notes to each individual flow chart discuss the interpretation 
of these endpoints in relation to that particular flow chart. 
In general, the interpretation of "no concerns" or "new variety 
not acceptable" is similar for each flow chart. The endpoint 
"consult FDA" means that producers may need to consult FDA on 
regulatory questions, such as whether a food additive petition 
or special labeling is needed, or on technical questions, such 
as appropriate testing protocols or specific scientific issues.




>>>>  See the accompanying hardcopy volume for non-machine-readable
data that appears at this point. (Figure 1. Safety Assessment of
New Varieties:  Summary)  <<<<





C. Effects of Processing

   Processing (e.g., cooking) may affect the safety of a substance. 
This is particularly important in the safety assessment of proteins 
transferred from one food source to another. For example, lectins, 
which are inactivated by cooking, would raise a safety concern 
if transferred from kidney beans, which are eaten cooked, to 
tomatoes, which may be eaten raw. The effects of any potential 
differences in food processing between the donor and the new 
plant variety should be carefully considered at each stage in 
the safety assessment.

D. The Host Plant

   A premise basic to this guidance section is that a long history 
of safe use of the host species in food provides much information 
regarding the potential of new plant varieties to produce toxicants 
and antinutrients (substances that adversely affect the nutritional 
quality of food). In assessing the potential of the host plant 
to contribute unexpected harmful substances, producers should 
consider attributes of the host plant and its progenitors such 
as the following:
   1. Taxonomy.
   a. Variety name.
   b. Known phenotypes and relevant genotypes.
   2. Other species or varieties that have previously contributed 
genetic information to the host.
   3. History of safe use.
   a. Extent of previous experience.
   b. The part of the plant used as food.
   c. The presence and identity of potentially harmful constituents 
such as toxicants and antinutrients.
   d. Typical methods of processing and the impact of this processing 
on the reduction or enhancement of effects from potentially 
harmful constituents.
   4. The identity and level of nutrients for which the food 
is consumed.

Figure 2

   The numbers above each box in the flow chart refer to accompanying 
notes that immediately follow the flow chart.




>>>>  See the accompanying hardcopy volume for non-machine-readable
flow chart that appears at this point. <<<<





Notes to Figure 2

   1-Does the host species have a history of safe use?
   This guidance section is primarily designed for the development 
of new varieties of currently consumed food plants whose safety 
has been established by a history of use. If exotic species 
are used as hosts, testing may be needed to assure the safety 
and wholesomeness of the food. 
   2-Do characteristics of the host species, related species, 
or progenitor lines warrant analytical or toxicological tests?
   It is not possible to establish a complete list of all toxicants 
that should be considered for each plant species. In general, 
the toxicants that are of highest concern in any particular 
species are those that have been documented to cause harm in 
normal or animal diets, or that have been found at unsafe levels 
in some lines or varieties of that species or related species. 
   In many cases, characteristic properties (such as a bitter 
taste associated with alkaloids) are known to accompany elevated 
levels of specific natural toxicants. If such characteristic 
provide an assurance that these toxicants have not been elevated 
to unsafe levels, analytical or toxicological tests may not 
be necessary. 
   3-Do test results provide evidence that toxicant levels in 
the new plant variety do not present a safety concern?
   If a host plant or related species is known to contain toxicants 
whose presence must be assessed, analytical tests may be appropriate 
to establish that the toxicant levels are in a safe range. There 
is, however, a wide variation in the level of natural toxicants 
within and between varieties of a species, due to differences 
in genetic makeup and in environmental conditions during growth, 
harvest, and storage. Due to this natural variation, analytical 
tests, if necessary, should be performed using as a control 
the parental variety that has been grown, harvested, and stored 
under the same conditions as the new plant variety.
   In some cases, analytical methods alone may not be available, 
practical, or sufficient for all toxicants whose levels are 
needed to be assessed. In such situations, comparative toxicological 
tests on the new and parental plant varieties may provide assurance 
that the new variety is safe. FDA encourages producers of new 
plant varieties to consult informally with the agency on testing 
protocols for whole foods when appropriate. 
   4-Is the concentration and bioavailability of important nutrients 
in the new variety within the range ordinarily seen in the host 
species?
   If the native levels of important nutrients for which a food 
is widely consumed are not within the range ordinarily seen 
in the host species, appropriate labeling may be required. In 
addition, changes in bioavailability of a nutrient due to changes 
in form of the nutrient or the presence of increased levels 
of other constituents that affect absorption or metabolism of 
nutrients must be considered for potential nutritional impact. 
   5-Endpoints in Figure 2. 
   5a-No concerns. 
   When this endpoint is reached, safety and nutritional concerns 
relative to the host plant will generally have been satisfied. 
   5b-New variety not acceptable. 
   This endpoint is reached when test results indicate that 
food derived from the new plant variety may be unsafe-e.g., 
if it contains unacceptable levels of toxicants. 
   5c-Consult FDA. 
   Producers should consult informally with FDA when the concentration 
or bioavailability of important nutrients is not within the 
range ordinarily seen in the host species. FDA will work with 
the producers on a case-by-case basis to address requirements 
such as labeling, or other issues relating to nutritional concerns. 

E. The Donor(s)

   In some cases, the donor will not have a history of safe 
use in food. For example, the donor may be a wild species that 
is related to the host plant, or may be a microorganism with 
no history of use in food. The potential of the donor(s) to 
contribute undesirable characteristics to the new plant variety 
should be assessed. In assessing the potential of the donor 
to contribute unexpected harmful substances, producers should 
consider attributes of the donor plant, or of fragments of genetic 
material from one or multiple donors, to the extent that such 
information is available (see Figure 3). 

1. Donor Plants 

   Attributes of the donor plant and its progenitors, such as 
the following, should be considered: 
   1. Taxonomy. 
   a. Variety name.
   b. Known phenotypes and relevant genotypes. 
   2. Other species or varieties that have previously contributed 
genetic information to the donor plant. 
   3. History of use (as applicable). 
   a. The part of the plant used as food. 
   b. The presence and identity of potentially harmful constituents 
such as toxicants, antinutrients, and allergens. 
   c. Typical methods of processing and the impact of this processing 
on the reduction or enhancement of effects from potentially 
harmful constituents. 

2. Fragments of Donor Genetic Material 

   Attributes of each donor, and its progenitors when appropriate, 
such as the following, should be considered: 
   1. Taxonomy. 
   2. Other species or varieties that have previously contributed 
genetic information to the donor(s). 
   3. History of use (as applicable).
   a. The part of the donor(s) used as food. 
   b. The presence and identity of potentially harmful constituents, 
such as toxicants, antinutrients, and allergens. 
   c. Typical methods of processing and the impact of this processing 
on the reduction or enhancement of effects from potentially 
harmful constituents. 
   d. The association of the transferred genetic material with 
harmful constituents. 
   4. Additional information consistent with currently accepted 
scientific practices, such as: 
   a. History and derivation of molecular constructs, such as 
passage through microbial hosts. 
   b. Known activities of any introduced regulatory sequences, 
such as environmental, developmental and tissue-specific effects 
on promoter activity. 
   c. The presence of extraneous open reading frames, and the 
potential for transcription and expression of these additional 
open reading frames. 

Figure 3

   The numbers above each box in the flow chart refer to accompanying 
notes that immediately follow the flow chart. 




>>>>  See the accompanying hardcopy volume for non-machine-readable
flow chart that appears at this point. <<<<





Notes to Figure 3 

   6-Is food from the donor commonly allergenic? If yes, can 
it be demonstrated that the allergenic determinant has not been 
transferred to the new variety of host plant? 
   Some examples of foods that commonly cause an allergenic 
response are milk, eggs, fish, crustacea, molluscs, tree nuts, 
wheat, and legumes (particularly peanuts and soybeans). Allergens 
from these common sources may be knowingly or unknowingly transferred 
from a donor to a new variety of host plant. Knowledge of the 
identity of the allergenic determinant of the donor, coupled 
with appropriate knowledge of the genetic fragment that has 
been transferred from the donor to the new plant variety, may 
provide sufficient evidence that the allergenic determinant 
has not been transferred to the new variety of the host plant. 
   7-Do characteristics of the donor species, related species, 
or progenitor lines warrant analytical or toxicological tests? 
   It is possible that a toxicant present in the donor may be 
transferred to the host, e.g., during hybridization of a cultivated 
variety with a wild, poisonous relative. However, it is also 
possible to use a toxic donor safely. For example, a gene coding 
for an enzyme that is not toxic and does not yield toxic products 
may be isolated from pathogenic bacteria and safely transferred 
to a plant. 
   The potential that toxicants known to exist in the donor, 
related species, or progenitor lines will be present in the 
new plant variety should be addressed as described previously 
for the host plant (section VII.D.). Unless there is sufficient 
evidence that the toxicant has not been transferred to the new 
variety of host plant, such transfer should be assumed, and 
analytical and/or toxicological tests may be warranted. 
   8-Do test results provide evidence that toxicant levels in 
the new variety do not present a safety concern? 
   When the presence of donor-associated toxicants must be assessed, 
analytical or toxicological studies may provide assurance that 
the new variety is safe as described previously for the host 
species (section VII.D.). FDA encourages producers of new plant 
varieties to consult with the agency on testing protocols. 
   9-Endpoints in Figure 3. 
   9a-No concerns. 
   When this endpoint is reached, safety concerns relative to 
the donor will generally have been satisfied. 
   9b-New variety not acceptable. 
   This endpoint is reached when test results indicate that 
food derived from the new plant variety may be unsafe, e.g., 
if it contains unacceptable levels of toxicants. 
   9c-Consult FDA. 
   Appropriately designed tests may provide evidence that the 
suspected allergen in the donor was not transferred to the new 
plant variety, or is not allergenic in the new variety. Producers 
should consult informally with FDA on protocols that are designed 
to assess allergenicity. FDA will work with the producer on 
a case-by-case basis to address requirements such as labeling. 

F. Substances Introduced Into the Host Plant From the Donor(s) 

   Safety assessment should address the specific risks associated 
with the new substances introduced from the donor(s) to a degree 
that is consistent with currently accepted scientific practices. 

1. Proteins 

   Depending upon the circumstances, safety assessment of an 
introduced protein should be based on: 
   1. Presence and level in the food product. 
   2. Origin. 
   3. Known or suspected allergenicity. 
   4. Evidence of consumption in other foods at similar levels 
and under similar conditions of processing (e.g., eaten cooked 
or uncooked). 
   5. Effects of processing (e.g., cooking). 
   6. Biological function. 
   7. Known or potential toxicity. 
   8. Chemical differences and similarities to edible proteins. 
   9. The presence of host-specific posttranslational modifications. 

Figure 4 

   The numbers above each box in the flow chart refer to accompanying 
notes that immediately follow the flow chart. 




>>>>  See the accompanying hardcopy volume for non-machine-readable
flow chart that appears at this point. <<<<





Notes to Figure 4 

   10-Is the newly introduced protein present in food derived 
from the plant? 
   For example, an enzyme introduced to alter the fatty acid 
composition of an oil may be removed from the oil as a result 
of processing. Alternatively, an enzyme introduced to confer 
antibiotic resistance for use as a selectable marker may be 
present in food products. 
   11-If an introduced protein is derived from a food source, 
the question of allergenicity must be addressed in the same 
fashion as was discussed from the perspective of the donor as 
a whole. 
   12-Is the introduced protein that is derived from a food 
source, or is substantially similar to an edible protein, reported 
to be toxic? 
   For example, some lectins are toxic unless inactivated by 
cooking. If a protein whose safety is dependent on processing 
such as cooking has been transferred from a species that is 
commonly cooked before consumption to a species that may be 
eaten raw, safety questions may arise. 
   13-If the intake of an introduced protein that is derived 
from a food source, or that is substantially similar to an edible 
protein, is not generally comparable to the intake of the same 
or similar protein in the donor or other food, the biological 
function of the protein should be assessed. 
   14-The biological function of the introduced protein should 
be assessed if either of the following occur: 
   a. The introduced protein is not derived from a food source, 
or is not substantially similar to an edible protein;{6}
      ³{6} The issue of potential allergenicity of any new protein 
      ³(as opposed to the allergenicity of a protein derived 
      ³from a known source of allergens) is frequently raised. 
      ³FDA recognizes that routine procedures for testing foods 
      ³derived from new plant varieties for the presence of 
      ³unknown allergens are not currently available. If the 
      ³donor has no history of use in food, the issue of allergenicity 
      ³cannot be addressed at this time. Comparison of gene 
      ³sequences to data banks of known allergens may become 
      ³increasingly useful as the information on such proteins 
      ³expands. FDA invites comments on methods that may be 
      ³available to address the issue of allergenicity of new 
      ³proteins in foods. 
   b. The intake of the introduced protein in the new variety 
is not comparable to the intake of the same or similar protein 
in the donor or other food. 
   15-Does the biological function of the introduced protein 
raise any safety concerns, or is the introduced protein reported 
to be toxic?
   In general, proteins that function as enzymes do not raise 
concern{7} Exceptions include enzymes that produce substances 
that are not ordinarily digested and metabolized by vertebrates, 
or that produce toxic substances (e.g., the enzymes that convert 
cyanogenic glycosides to cyanide). 
      ³{7} Pariza and Foster (Ref. 7) note that very few toxic 
      ³agents have enzymatic properties. Exceptions include 
      ³diphtheria toxin and certain enzymes in the venom of 
      ³poisonous snakes. 
   Other functions that could raise concern include any reported 
toxicity, such as known toxic activity toward vertebrates, known 
toxic activity toward nonvertebrates when the absence of toxic 
activity to vertebrates is not established, and unusual properties 
that indicate that the protein is significantly different from 
other proteins found in the diet. If the function of the protein 
is not known, see note 17d. 
   16-Is the introduced protein likely to be a macroconstituent 
in the human or animal diet?
   From a nutritional standpoint, the amount and quality of 
total protein in the diet, rather than of any particular protein, 
is of greatest significance. However, while most individual 
proteins (e.g., enzymes) that might be introduced into food 
derived from plants will be present at relatively low concentrations, 
some proteins (e.g., seed storage proteins){8} may become macroconstituents 
of the plant-derived food. Other proteins (e.g., enzymes used 
as selectable marker genes) may be introduced into many plants 
and therefore be consumed at a substantial level. Dietary exposure 
to such proteins should be considered. 
      ³{8} The nutritional content of seed storage proteins 
      ³from some crops is particularly important in the case 
      ³of animal feed, where one crop may furnish a substantial 
      ³portion of the diet. 
   17-Endpoints in Figure 4. 
   17a-No concerns. 
   When this endpoint is reached, safety concerns relative to 
intentionally introduced proteins will generally have been satisfied. 
   17b-Consult FDA: Allergens. 
   Producers should consult informally with FDA on protocols 
that are designed to assess allergenicity. FDA will work with 
the producer on a case-by-case basis to address requirements 
such as labeling. 
   17c-Consult FDA: Toxicity. 
   Producers should consult informally with FDA when a protein 
is reported to be toxic or when the safety of an introduced 
protein is dependent on processing such as cooking. FDA will 
determine on a case-by-case basis whether it will review the 
food additive status of these proteins, or whether the proteins 
are unacceptable in the new plant variety. 
   17d-Consult FDA: Function and toxicity. 
   Producers should consult informally with FDA on scientific 
issues and design of appropriate test protocols when the function 
of the protein raises concern or is not known, or the protein 
is reported to be toxic. FDA will determine on a case-by-case 
basis whether it will review the food additive status of these 
proteins. 
   17e-Consult FDA: Macroconstituents in the diet. 
   Producers should consult informally with FDA when a protein 
is expected to become a macroconstituent of the diet, whether 
as a result of its presence in high levels in one food or as 
a result of its use in many foods. FDA will determine on a case-
by-case basis whether it will review the food additive status 
of these proteins. 

2. Carbohydrates 

   Safety assessment of a new or modified carbohydrate should 
be based on the nature of the carbohydrate or modification. 

Figure 5 

   The numbers above each box in the flow chart refer to accompanying 
notes that immediately follow the flow chart. 




>>>>  See the accompanying hardcopy volume for non-machine-readable
flow chart that appears at this point. <<<<





Notes to Figure 5

   18-Have any structural features or functional groups been 
introduced into the carbohydrate that do not normally occur 
in food carbohydrates?
   For example, developments that affect carbohydrates will 
frequently be modifications of food starches, presumably affecting 
the content of amylose and amylopectin, as well as the branching 
of amylopectin. Such modified starches are likely to be functionally 
and physiologically equivalent to starches commonly found in 
food and thus would not suggest any specific safety concerns. 
However, if functional groups or structural features that normally 
do not occur in food carbohydrates are introduced, such modifications 
should be evaluated with respect to any safety concerns that 
may arise.
   19-Have there been any alterations that could affect digestibility 
or nutritional qualities in a carbohydrate that is likely to 
be a macroconstituent in the diet?
   If a vegetable or a fruit is modified to produce high levels 
of an indigestible carbohydrate that normally occurs at very 
low levels, or to convert a normally digestible carbohydrate 
to an indigestible form, nutritional questions may arise.
   20-Endpoints in Figure 5.
   20a-No concerns.
   When this endpoint is reached, safety and nutritional concerns 
relative to intentional modifications of food carbohydrates 
will generally have been satisfied.
   20b-Consult FDA.
   Producers may consult informally with FDA on scientific issues. 
FDA will determine on a case-by-case basis whether it will review 
the food additive status of these carbohydrates, and will work 
with the sponsor on a case-by-case basis to address requirements 
such as labeling.

3. Fats and Oils

   Safety assessment of a new or modified fat or oil should 
be based on its composition and the presence of any unusual 
components at levels that would cause safety concern.

Figure 6

   The numbers above each box in the flow chart refer to accompanying 
notes that immediately follow the flow chart.




>>>>  See the accompanying hardcopy volume for non-machine-readable
flow chart that appears at this point. <<<<





Notes to Figure 6

   21-Has there been an intentional alteration in the identity, 
structure, or composition of fats or oils that are likely to 
be a macroconstituent in the diet?
   Some alterations in the composition or structure of fats 
and oils, such as an alteration in the ratio of saturated to 
unsaturated fatty acids, may have significant nutritional consequences, 
or result in marked changes in digestibility. Other changes 
may produce a fat or oil that has been altered such that it 
is no longer representative of fats and oils from the host species.
   22-Are any unusual or toxic fatty acids produced in the new 
variety?
   For example, safety questions may arise as a result of the 
presence of fatty acids with chain length greater than C-22, 
fatty acids with cyclic substituents, fatty acids with functional 
groups not normally present in dietary fats and oils, and fatty 
acids of known toxicity (e.g., erucic acid).
   23-Endpoints in Figure 6.
   23a-No concerns.
   When this endpoint is reached, safety and nutritional concerns 
relative to intentional modifications of fats and oils will 
generally have been satisfied.
   23b-Consult FDA.
   Producers may consult informally with FDA on scientific issues. 
FDA will determine on a case-by-case basis whether it will review 
the food additive status of these fats or oils, and will work 
with the sponsor on a case-by-case basis to address requirements 
such as labeling.

G. Toxicology

   Feeding studies or other toxicological tests may be warranted 
when the characteristics of the plant or the nature of the modification 
raise safety concerns that cannot be resolved by analytical 
methods. FDA recognizes that feeding studies on whole foods 
have limited sensitivity because of the inability to administer 
exaggerated doses. Because of the difficulty of designing meaningful 
studies, FDA encourages companies to consult informally with 
the agency about test protocols.

H. Other Information

   The information described below is not directly addressed 
in the flow charts but should be considered during the development 
of new plant varieties.

1. Nucleic Acids

   Introduced nucleic acids, in and of themselves, do not raise 
safety concerns. Thus, for example, the introduction of a gene 
encoding an anti-sense ribonucleic acid (RNA) would not raise 
concerns about either the gene or the anti-sense RNA. Any safety 
considerations would focus on the intended effects of the anti-
sense RNA. Hence, continuing the example, if the anti-sense 
RNA were used to suppress an enzyme, then just as for any other 
method intended to suppress an enzyme, such as deletion or nonsense 
mutations, the metabolic effects on the host plant of such enzyme 
suppression should be considered at the conceptual stage of 
development and monitored, when appropriate and feasible.

2. Metabolic Considerations

   The effects of an intentional alteration of a biochemical 
pathway should be considered at the conceptual stage of development, 
and monitored when appropriate and feasible. For example, are 
there any toxic effects of a metabolic imbalance with respect 
to enzyme substrate depletion and product accumulation? Are 
any auxiliary pathways likely to be affected?

3. Stability

   The genetic stability of the new plant variety and the inheritance 
of the introduced genetic material as a single Mendelian trait 
are important safety considerations. A safety assessment of 
food derived from early generations of the new variety may not 
be valid if the new genetic material is expressed at substantially 
different levels in subsequent generations. Factors that favor 
stability include a minimum number of copies of the introduced 
genetic material, and insertion at a single site.

I. Future Workshop on Scientific Issues

   FDA recognizes the desirability of establishing consensus 
within the industry, the scientific community, and the public 
on the agency's scientific assessment approach to food safety 
presented in this guidance section. For this reason, FDA plans 
to announce, in a future Federal Register notice, a workshop 
to discuss specific scientific issues. The notice announcing 
the workshop will include a description of the scientific issues 
to be discussed. FDA invites comment on topics that might be 
addressed at such a workshop.

VIII. Environmental Consideration: Applicability of NEPA

   NEPA requires FDA to consider in its decisionmaking the environmental 
impact of its major Federal actions that significantly affect 
the quality of the human environment. The promulgation of a 
food additive regulation is an agency action that ordinarily 
triggers the NEPA requirement for development of an environmental 
assessment (21 CFR 25.22(a)(10)) and, if the agency does not 
make a finding of no significant environmental impact, an environmental 
impact statement is prepared (21 CFR 25.21(b)).
   The Council on Environmental Quality (CEQ) regulations (40 
CFR 1500 through 1508) provide that in complying with NEPA, 
an agency should avoid unnecessary duplication and should tier 
its NEPA statements with those of other agencies to eliminate 
repetitive discussions of the same issues and to focus on the 
actual issues ripe for decision at each level of environmental 
review (40 CFR 1502.20 and 1508.28).
   Other agencies, particularly USDA and EPA, may prepare NEPA 
and other environmental documentation before products are presented 
to FDA for a decision. FDA intends to rely on such documentation 
to the maximum extent possible.
   Under regulations administered by the Animal and Plant Health 
Inspection Service (APHIS) in USDA (7 CFR part 340), the majority 
of plants developed by recombinant DNA techniques that are being 
commercially developed have been considered "regulated articles." 
The action that results in a permit for introduction of a regulated 
article into the environment is subject to NEPA review. At some 
stage of research and development of a regulated article, an 
interested party will request from APHIS a determination of 
the article's regulatory status. APHIS has informed FDA that 
when APHIS receives a petition or other request it intends to 
consult with other agencies. This should enable FDA to identify 
the type of data that would be useful if any subsequent environmental 
review is to be prepared for actions under FDA jurisdiction.
   EPA has authority, under the Federal Insecticide, Fungicide, 
and Rodenticide Act (FIFRA) (7 U.S.C. 136 et seq.), to regulate 
all pesticides, no matter how they are made or their mode of 
action. Under the act, EPA has authority to regulate pesticide 
residues in foods. Any relevant review that EPA conducts under 
FIFRA, the act, or any other of its statutes, involving an assessment 
of potential effects on human health and the environment will 
be available to FDA.
   FDA intends to work closely with USDA and EPA to minimize 
duplication of environmental reviews. The agency will, to the 
extent possible, invoke the tiering provisions in the CEQ regulations 
and, in FDA's environmental assessments, rely on APHIS NEPA 
reviews and other such documents, as well as relevant environmental 
documents considered by EPA. Further, FDA will provide informal 
guidance on environmental issues to assist individuals who are 
preparing food additive petitions to meet FDA's requirements 
for environmental assessments.
   FDA does not consider that the activities it may undertake 
with respect to foods from new plant varieties other than promulgation 
of food additive regulations, such as consultation with producers 
on safety issues and providing advice on the regulatory status 
of foods from new plant varieties, will constitute agency action 
under NEPA.

IX. Coordination With EPA: Pesticide Considerations

   Questions have been raised concerning whether FDA or EPA 
would have jurisdiction when plants are modified to express 
pesticidal substances. FDA and EPA are agreed that substances 
that are pesticides as defined by FIFRA (7 U.S.C. section 136(u)), 
are subject to EPA's regulatory authority. The agencies also 
agree that FDA's authority under the act extends to any nonpesticide 
substance that may be introduced into a new plant variety and 
that is expected to become a component of food.
   EPA and FDA are aware that there may be cases in which the 
jurisdictional responsibility for a substance is not clear. 
Because pesticides, as defined by FIFRA, are subject to EPA's 
jurisdiction, the agencies encourage producers who have such 
questions to contact EPA. FDA and EPA intend to consult closely 
on such jurisdictional questions, as well as on scientific matters 
where consultation will be helpful in resolving safety questions.
   The agencies are also aware that, in some circumstances, 
evaluation of a particular substance introduced into a plant 
may require the expertise of both EPA and FDA. Both agencies 
agree that EPA will address under its regulatory jurisdiction 
the food safety issues associated with the pesticide, including 
marker genes used to confirm the presence of the pesticidal 
gene. Any food safety questions beyond those associated with 
the pesticide, such as those raised by unexpected or unintended 
compositional changes, are under FDA's jurisdiction and should 
be addressed under the policy set forth elsewhere in this notice.
   Based upon the agencies' current knowledge, examples of substances 
that fall under FDA's authority include: (1) Substances intended 
to alter the nutritional composition of the food (e.g., amino 
acids or carbohydrates); (2) substances intended to enhance 
the plant's resistance to chemical herbicides (e.g., bromoxynil, 
glyphosate, and sulfonylurea); and (3) substances intended to 
alter the flavor or the texture of the food.
   Similarly, based upon the agencies' current knowledge of 
new plant varieties being developed using the new technologies 
of gene transfer, EPA is in the process of evaluating how or 
if it will exert its oversight for the following examples subject 
to its jurisdiction under FIFRA and therefore not under FDA's 
jurisdiction: (1) Substances that are intended to kill insects 
(e.g., Bacillus thuringiensis delta-endotoxin);
   (2) Substances intended to protect plants from viral, fungal, 
or bacterial infection (e.g., cecropin); and (3) substances 
that are plant regulators and thus "pesticides" under FIFRA.

X. Environmental Impact

   The agency has determined under 21 CFR 25.24(a)(8) that this 
action is of a type that does not individually or cumulatively 
have a significant effect on the human environment. Therefore, 
neither an environmental assessment nor an environmental impact 
statement is required. 
   This action is intended to provide guidance to developers 
by describing the scientific considerations for the safe development 
of foods derived from new plant varieties. 

XI. Comments

   Interested persons may, on or before August 27, 1992, submit 
to the Dockets Management Branch (address above) written comments 
regarding this notice. Two copies of any comments are to be 
submitted, except that individuals may submit one copy. Comments 
are to be identified with the docket number found in brackets 
in the heading of this document. Received comments may be seen 
in the office above between 9 a.m. and 4 p.m., Monday through 
Friday. 

XII. References

   The following references have been placed on display in the 
Dockets Management Branch (address above) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through 
Friday. 

   1. Anonymous, "Biotechnologies and Food: Assuring the Safety 
of Foods Produced by Genetic Modification," International Food 
Biotechnology Council, Regulatory Toxicology and Pharmacology, 
Vol. 12, No. 3, Part 2 of 2 Parts, New York, December 1990. 
   2. Letter, Hopkins, D. D., R. J. Goldburg, and S. A. Hirsch 
to Dr. David Kessler, September 30, 1991, and enclosure, "A 
Mutable Feast: Assuring Food Safety in the Era of Genetic Engineering." 
   3. Letter, Richard D. Godown to James H. Maryanski, January 
3, 1992; Letter, W. Douglas Crabb to Fred R. Shank, January 
24, 1992. 
   4. Comments to Docket No. 90A-0416, Federal Register, May 
1, 1991 (56 FR 20004). 
   5. Dale, E. C. and D. W. Ow, "Gene Transfer with Subsequent 
Removal of the Selection Gene from the Host Genome," Proceedings 
of the National Academy of Sciences USA, 88:10558-10562, 1991. 
   6. Anonymous, "Strategies for Assessing the Safety of Foods 
Produced by Biotechnology," World Health Organization, Geneva, 
1991. 
   7. Pariza, M. W. and E. M. Foster, "Determining the Safety 
of Enzymes Used in Food Processing," Journal of Food Protection, 
46:453-468, 1983. 

   Dated: April 2, 1992.

David A. Kessler,
Commissioner of Food and Drugs.

[FR Doc. 92-12660 Filed 5-26-92; 3:57 pm]
BILLING CODE 4160-01-M