Federal Regulation of Substances Generally Recognized As Safe (GRAS) and the Use of Carbon Monoxide in Packaging for Meat and Fish

Federal Regulation of Substances Generally
Recognized As Safe (GRAS) and the Use of
Carbon Monoxide in Packaging for Meat and Fish
Updated September 25, 2008
Vanessa K. Burrows
Legislative Attorney
American Law Division
Cynthia Brougher
Legislative Attorney
American Law Division

Federal Regulation of Substances
Generally Recognized As Safe (GRAS) and the Use
of Carbon Monoxide in Packaging for Meat and Fish
Summary
The use of carbon monoxide (CO) in the packaging of meat and fish has
generated considerable debate. The presence of CO results in the meat turning a
bright red color that lasts longer than the color in untreated meat. Additionally, fish
treated with CO gain a fresher appearance and a red tint. The meat industry,
consumer groups, scientists, and policy makers disagree as to whether the use of CO
in meat and fish packaging should be regulated by the Food and Drug Administration
(FDA) and the United States Department of Agriculture (USDA), through labeling
or otherwise, and whether CO should be a substance Generally Recognized As Safe
(GRAS) under current and proposed FDA rules.
Two bills have been introduced in the 110th Congress regarding the use of
carbon monoxide in meat, poultry products, and seafood: H.R. 3115 and H.R. 3610.
The discussion draft of the Food and Drug Administration Globalization Act of 2008,
issued by Representatives Dingell, Pallone, and Stupak, similarly addresses the issue.
The bills and the discussion draft propose to amend section 201 of the Federal Food,
Drug, and Cosmetic Act (FFDCA). Under the proposals, if CO is used to treat meat,
poultry, or seafood that is intended for human consumption, and if the conditions of
that use would affect the color of the products, CO must be treated as a color additive
under FFDCA, unless the product’s label includes a statement that is prominently and
conspicuously placed to notify the consumer of the use of CO and to warn the
consumer of proper factors to judge the safety of the product. The bills and the
discussion draft would allow the Secretary of Health and Human Services (HHS) to
establish alternative labeling requirements five years after the effective date of the
labeling requirement, if the Secretary finds that the labeling requirement is no longer
necessary to prevent consumer deception. The discussion draft contains an additional
provision related to GRAS determinations that would require the Secretary to
publish, in the Federal Register, notice of receipt of a request for a substance to be
determined by the Secretary to be GRAS. The Secretary would then have 90 days
after publication of the notice to determine whether the substance is GRAS; the
Secretary’s determination would also be published in the Federal Register. Other
bills also address GRAS substances: H.R. 2633, H.R. 3290, H.R. 3580, H.R. 6635,
and S. 1342.
This report provides an overview of the FDA’s regulation of GRAS substances,
which are exempt from the premarket approval process for food additives. The report
next discusses the FDA’s 1997 proposed rule, which would create a notification
procedure for GRAS substances through which manufacturers can notify the FDA
of their “determination that a particular use of a substance is GRAS.” The FDA has
been using this GRAS notification procedure since the publication of the proposed
rule on an “interim policy” basis. The roles of the USDA and FDA are also
discussed, including the 2000 Memorandum of Understanding regarding review of
substances used in the production of meat and poultry products. Finally, the report
examines GRAS notices regarding intended uses of carbon monoxide.

Contents
In troduction ..................................................1
Legal Regulation of Food Additives and GRAS Substances.............3
The FDA’s 1997 Proposed Rule................................7
Statistics on FDA GRAS Notices................................10
The Role of USDA in Food Additive Safety Determinations...........11
Dual Process of Review for Meat and Poultry Products...........12
FSIS Review of Substances in Meat or Poultry Products..........13
GRAS Substances........................................14
GRAS Notices Regarding Intended Uses of Carbon Monoxide.........15^th
Proposed Legislation in the 110 Congress.........................17

Federal Regulation of Substances
Generally Recognized As Safe (GRAS) and
the Use of Carbon Monoxide in Packaging
for Meat and Fish
Introduction
The use of carbon monoxide (CO) in the packaging of meat and fish has
generated considerable debate. Carbon monoxide, in combination with nitrogen and
carbon dioxide, is used in a packaging process for fresh meat called Modified¹
Atmosphere Packaging (MAP). In the MAP process, the meat is placed in a
container with an “impermeable film similar to a vacuum package but ... the air [is
evacuated] from the package and replac[ed] ... with a specified mixture of gases that
provides for better control of product properties.”² The presence of CO results in the
meat turning a bright red color that lasts longer than the color in untreated meat.
Additionally, fish treated with CO (for example, as part of a gas mixture called³⁴
“tasteless smoke”) gain a fresher appearance and a red tint. Conflicting studies have
shown that consumers rely primarily on the appearance, including the red color of⁵
meat or fish, when choosing which package to purchase, and alternatively, that

¹ Agency Response Letter GRAS Notice No. GRN 000083 from Alan M. Rulis, Director,
Office of Food Additive Safety, Center for Food Safety and Applied Nutrition, FDA, to Eric
Greenberg, Ungaretti and Harris (on behalf of Pactiv Corp.) (Feb. 12, 2002),
[http://www.cfsan.fda.gov/~rdb/opa-g083.html], [hereinafter GRAS Notice No. 83].
² To Review Technologies in the Meat Industries: Hearing before the H. Comm. on
Agriculture, 110th Cong. 2 (2007) (statement of Joe Sebranek, Dep’t of Animal Science and
Dep’t of Food Science, Iowa State Univ.), [http://agriculture.house.gov/testimony/110/
h71030/Sebranek.doc].
³ Agency Response Letter GRAS Notice No. GRN 000015 from Janice F. Oliver, Deputy
Director, Center for Food Safety and Applied Nutrition, FDA, to Martin J. Hahn, Hogan &
Hartson LLP (on behalf of Hawaii International Seafood, Inc.) (Mar. 10, 2000),
[http://www.cfsan.fda.gov/~rdb/opa-g015.html], [hereinafter GRAS Notice No. 15].
⁴ Harold McGee, The Red-Meat Miracle, and Other Tales from the Butcher Case, N.Y.
Times, Dining, 4 (Apr. 4, 2007).
⁵ Press Release, Consumer Federation of America, Most Consumers Are Concerned About
Practice of Adding Carbon Monoxide to Meat, New Survey Finds (Sept. 25, 2006),
[ h t t p : / / www.consumer f e d.or g/ pdf s/ CO_Meat_Consumer_Press_Release_9.25.06.pdf ] .
(“Sixty-three percent (63%) agreed with the statement that ‘the freshness of meat is directly
related to the color of the meat.’”).

consumers rely mostly on “sell by” dates.⁶ The meat industry, consumer groups,
scientists, and policy makers disagree as to whether the use of CO in meat and fish
packaging should be regulated by the Food and Drug Administration (FDA) and the
United States Department of Agriculture (USDA), through labeling or otherwise, and
whether CO should be a substance Generally Recognized As Safe (GRAS) under
current and proposed FDA rules.
The meat industry, some scientists, and other supporters argue that MAP
reduces shrinkage of the meat, allows for a longer shelf life, “keep[s] meat fresh,
protect[s] meat, [and] prevent[s] cross-contamination” because MAP packages are
tamper resistant and leak-proof.⁷ One scientist believes that MAP offers “better
flavor, greater tenderness, and suppression of bacterial growth.”⁸ Supporters of MAP
also assert that such products are more sustainable, less wasteful, and more flexible
in terms of distribution because more packages can be transported per truck.⁹
Additionally, they note that consumers prefer the bright red color of meat achieved
in MAP.¹⁰ Finally, MAP system supporters dispute the scientific basis for claims that
the use of carbon monoxide is misleading or dangerous and declare the consumers
use “sell by” dates when determining the freshness of many products.¹¹
Opponents allege that the use of CO misleads consumers into thinking meat and
fish are fresher than they are; that certain populations, such as those with a reduced
sense of smell, will be at increased risk if they consume spoiled meat or fish that still
appears fresh due to the use of CO; that consumers may eat undercooked meat
because meat packed in MAP systems may brown faster when cooked than untreated
meat; that “sell by” dates are not adequate to assist consumers in determining
freshness; that consumers will be exposed to CO; that such MAP products are
misbranded and adulterated under the Federal Food, Drug, and Cosmetic Act; and
that the FDA is violating its own regulations on CO.¹² Another concern of consumer
groups and some scientists is that CO provides a cover for spoiled or “temperature
abused” meat and fish, meaning that the use of CO conceals visual cues of
decomposition caused in part by exposure to changes in temperature or storage or

⁶ To Review Technologies in the Meat Industries: Hearing before the H. Comm. on
Agriculture, 110th Cong. 11, 21 (2007) (statement of Phil Minerich, Vice President,
Research and Development, Hormel Foods Corp.), [http://agriculture.house.gov/testimony/
110/h71030/Minerich.pdf] (A 2005 Food Marketing Institute study cited by Minerich in his
testimony concluded that “81% of consumers rely on sell by dates.”).
⁷ GRAS Notice No. 83, supra note 1; Minerich, supra note 6, at 6.
⁸ Sebranek, supra note 2, at 3.
⁹ Minerich, supra note 6, at 17; GRAS Notice No. 83, supra note 1.
¹⁰ See Minerich, supra note 6, at 30 (quoting Dr. Gary Acuff, Professor of Microbiology,
Texas A&M University in a May 26, 2006, letter to the editor of Meating Place magazine);
Sebranek, supra note 2, at 1.
¹¹ Sebranek, supra note 2, at 1; Minerich, supra note 6, at 25.
¹² Citizen Petition from Donald R. Berdahl, Executive Vice President, Kalsec, Inc., to Laura
M. Tarantino, Director, Office of Food Safety, Center for Food Safety and Applied
Nutrition, FDA (Nov. 20, 2006), [http://www.co-meat.com/Kalsec_November_2006_
filing.PDF] at 5-6, 8; Sebranek, supra note 2, at 2-3; McGee, supra note 4.

transport at improper temperatures. Fish, such as tuna, may develop toxic levels of
scombrotoxin (histamine) through time and/or temperature abuse, which can make
consumers ill.¹³ Opponents of the use of CO on meat and fish note that the European
Union, Canada, Singapore, and Japan have prohibited or decided not to recognize or
approve CO for use in fresh meat or fresh fish packaging.¹⁴ Additionally, certain
grocery store chains — including Giant, Safeway, Kroeger, and Publix — either do
not sell or have announced that they will no longer sell MAP products.¹⁵ Others have
taken different steps. At a March hearing, a Target Corporation executive testified
that its primary meat supplier had received approval from FSIS to add a label to its
packaging that would state: “Color is not an accurate indicator of freshness. Refer
to Use or Freeze By [date].”¹⁶
Legal Regulation of Food Additives and GRAS Substances
Both the FDA and USDA play a role in food safety and the types of substances
that can be added to food. This section will focus on the FDA’s regulation of food
additives and GRAS substances, which the agency is responsible for under the
Federal Food, Drug, and Cosmetic Act (FFDCA) and parts of Title 21, Code of
Federal Regulations. FFDCA § 201(s) defines a food additive as:
any substance the intended use of which results or may reasonably be expected
to result, directly or indirectly, in its becoming a component or otherwise
affecting the characteristics of any food (including any substance intended for
use in producing, manufacturing, packing, processing, preparing, treating,
packaging, transporting, or holding food; and including any source of radiation¹⁷
intended for such use)....
The latter half of the above definition includes “food contact substances,” which the
FFDCA defines as “any substance intended for use as a component of materials used
in manufacturing, packing, packaging, transporting, or holding food if such use is not¹⁸

intended to have any technical effect in such food.”
¹³ Center for Food Safety and Applied Nutrition, FDA, Fish and Fisheries Products Hazards
and Controls Guidance, ch. 7, (June 2001), [http://www.cfsan.fda.gov/~comm/haccp4g.
html].
¹⁴ Carbon Monoxide in Fresh Meat, Selected Countries Prohibiting Carbon Monoxide (CO)
Gas in Fresh Meat and Fresh Fish Packaging, [http://www.co-meat.com/countries.html].
¹⁵ Julie Schmidt, Carbon Monoxide Keeps Meat Red Longer; Is that Good?, USA Today,
Oct. 30, 2007.
¹⁶ Regulatory Failure: Must America Live with Unsafe Food? Hearing before the H. Comm.
on Energy and Commerce, Subcomm. on Oversight and Investigations, 110th Cong. (Mar.
12, 2008) (statement of Danielle Lachman, Divisional Merchandise Manager, Target
Corporation), [http://energycommerce.house.gov/cmte_mtgs/110-oi-hrg.031208.Lachman-
Testimony.pdf].
¹⁷ FFDCA § 201(s); 21 U.S.C. § 321(s).
¹⁸ FFDCA § 409(h)(6); 21 U.S.C. § 348(h)(6).

The definition of food additive excludes certain classes of substances:
(1) pesticide chemical residues in or on a raw agricultural commodity or processed
food, (2) pesticide chemicals, (3) color additives, (4) substances used in accordance
with their sanction or approval under FDA and USDA laws prior to 1958, (5) new
animal drugs, (6) dietary ingredients in dietary supplements, and (7) substances
GRAS under the conditions of the substances’ intended use. These seven categories
of substances are exemptions to FFDCA § 201(s) and do not have to obtain FDA
approval as food additives before they can enter the market.¹⁹ If a food additive does
not meet one of the exemptions under the FFDCA, a rule must be in place that details
the circumstances under which the food additive can be safely used.²⁰
GRAS substances must be “generally recognized, among experts qualified by
scientific training and experience to evaluate [their] safety.”²¹ FDA regulations
recognize the difficulty of establishing the harmlessness of a substance and therefore
define safety as “a reasonable certainty in the minds of competent scientists that the
substance is not harmful under the intended conditions of use.”²² The person seeking
GRAS status for a substance has the burden of proving the substance is GRAS under
conditions of the substances’ use.²³ A determination that a substance has GRAS
status is not limited to FDA scientists. Experts may base their view of a general
recognition of safety on either (1) scientific procedures or (2) common use of a
substance in food prior to January 1, 1958.
The first type of GRAS substances is those that have “been adequately shown
through scientific procedures ... to be safe under the conditions of [their] intended
use.”²⁴ Scientific procedures include published and unpublished human, animal,
analytical, and other scientific studies that are “appropriate to establish the safety of
a substance.”²⁵ A GRAS determination based on scientific procedures “require[s] the
same quantity and quality of scientific evidence as is required to obtain approval of
a food additive regulation for the ingredient.”²⁶ The GRAS determination must
“ordinarily” be based on published studies, but can be corroborated by unpublished
studies and other information.²⁷ FDA regulations do not require a unanimous opinion
from the scientific community that a substance is GRAS under the conditions of its
intended use; rather, the person seeking GRAS status “must show that there is a

¹⁹ FFDCA § 409; 21 U.S.C. § 348.
²⁰ FFDCA § 409(a)(2); 21 U.S.C. § 348(a)(2).
²¹ FFDCA § 201(s); 21 U.S.C. § 321(s).
²² 21 C.F.R. § 170.3(I). This reasonable certainty of no harm standard applies to food
additives, color additives, and food contact substances, in addition to GRAS substances.
²³ See Substances Generally Recognized as Safe, 62 Fed. Reg. 18937, 18939 (proposed Apr.

17, 1997).

²⁴ FFDCA § 201(s); 21 U.S.C. § 321(s).
²⁵ 21 C.F.R. § 170.3(h).
²⁶ 21 C.F.R. § 170.30(b).
²⁷ 21 C.F.R. § 170.30(b).

consensus of expert opinion regarding the safety of the use of the substance.”²⁸
However, “a severe conflict among experts regarding the safety of the use of a
substance, precludes a finding” that a substance is GRAS.²⁹
The second type of GRAS substances is those that were “used in food prior to
January 1, 1958, [and shown] through either scientific procedures or experience
based on common use in food[] to be safe under the conditions of [their] intended
use.”³⁰ FDA regulations define the phrase “common use in food” as “a substantial
history of consumption of a substance for food use by a significant number of
consumers.”³¹ In this instance, a GRAS determination ordinarily turns on “generally
available data and information.”³² These substances are known as prior-sanctioned
substances. They can include substances used in food where the use prior to January
1, 1958, “occurred exclusively or primarily outside of the United States if the
information about the experience establishes that the use of the substance is safe.”³³
Published information regarding substances used outside the United States must be
corroborated.³⁴
The FDA lists some GRAS substances in 21 C.F.R. Part 182. However, this list
of GRAS substances is not exhaustive as “[i]t is impracticable to list all substances
that are [GRAS] for their intended use.”³⁵ The list of GRAS substances in 21 C.F.R.
Part 182 includes spices, essential oils, natural extracts, synthetic flavoring
substances, substances that migrate from dry food packaging and paper products,
multipurpose substances, anticaking agents, chemical preservatives, emulsifying
agents, stabilizers, sequestrants, and nutrients.³⁶
The FDA Commissioner can affirm the GRAS status of a substance based on
a petition from a manufacturer or others or on his or her own initiative.³⁷ Substances
affirmed as GRAS, listed in 21 C.F.R. Part 184, differ from the GRAS substances
listed in Part 182 because their GRAS status has been sustained through a notice-and-

²⁸ Substances Generally Recognized as Safe, 62 Fed. Reg. 18937, 18939 (proposed Apr. 17,

1997).

²⁹ Id.
³⁰ FFDCA § 201(s); 21 U.S.C. § 321(s).
³¹ 21 C.F.R. § 170.3(f).
³² 21 C.F.R. § 170.30(c)(1).
³³ 21 C.F.R. § 170.30(c)(2).
³⁴ 21 C.F.R. § 170.30(c)(2).
³⁵ 21 C.F.R. § 182.1(a).
³⁶ See 21 C.F.R. § 170.3 (providing definitions of several of the above terms). Sequestrants
are “[s]ubstances which combine with polyvalent metal ions to form a soluble metal
complex, to improve the quality and stability of products.” 21 C.F.R. § 170.3(o)(26).
³⁷ 21 C.F.R. § 170.35(a). “The rulemaking process in § 170.35(c) whereby manufacturers
may petition FDA to affirm that a substance is GRAS under certain conditions of use was
designed as a voluntary administrative process whose purpose was to provide a mechanism
for official recognition of lawfully made GRAS determinations.” 62 Fed. Reg. 18941.

comment rulemaking. The concept of affirming the GRAS status of substances
began in 1969, when questions arose about whether cyclamate salts, a substance that
had been considered GRAS, were safe because “they were implicated in the
formation of bladder tumors in rats.”³⁸
The affirmation of GRAS status occurs through the notice and comment
rulemaking process, in which the Commissioner publishes a notice of the substance
proposed to be affirmed as GRAS in the Federal Register, allows 60 days for
comments, evaluates the comments (and the petition, if one was filed), and either
(1) publishes a notice in the Federal Register affirming the substance is GRAS if
there is “convincing evidence” or (2) “concludes that there is a lack of convincing
evidence that the substance is GRAS and that it should be considered a food
additive” subject to premarket approval by the FDA under FFDCA § 409.³⁹ If the
agency affirms that the use of a substance is GRAS, the substance is added to a list
in the Code of Federal Regulations as a substance affirmed as GRAS “for the
purposes and under the conditions prescribed,”⁴⁰ allowing for the possibility that use
of a substance under a condition other than the one specified in the regulation may
not be GRAS.⁴¹ The FDA has reviewed the direct food substances on the list in Part
184 and determined that they are GRAS “for the purposes and under the conditions
prescribed.”⁴² These ingredients are also GRAS as indirect food ingredients, also

³⁸ Substances Generally Recognized as Safe, 62 Fed. Reg. 18937, 18939 (proposed Apr. 17,
1997). The FDA Commissioner “conclude[d] that cyclamates c[ould] no longer be regarded
as generally recognized as safe for use in food” and amended the Code of Federal
Regulations to delete such substances from the GRAS list. 34 Fed. Reg. 17063 (Oct. 21,

1969).

³⁹ 21 C.F.R. § 170.35.
⁴⁰ 21 C.F.R. § 170.35(b), (c); Substances Generally Recognized as Safe, 21 C.F.R. Part 182;
Direct food substances affirmed as generally recognized as safe, 21 C.F.R. Part 184; Indirect
food substances affirmed as generally recognized as safe, 21 C.F.R. Part 186.
⁴¹ 21 C.F.R. § 184.1(b)(1); 21 C.F.R. § 170.30(I). In such a case, a manufacturer or other
person must “independently establish that that use is GRAS or shall use the ingredient in
accordance with a food additive regulation.” 21 C.F.R. § 184.1(b)(1); see also 21 C.F.R.
§ 170.30(I).
⁴² 21 C.F.R. § 184.1(a). Presently, the FDA is evaluating a Citizen’s Petition with regard
to the affirmed GRAS status of diacetyl, “a primary component of butter flavoring in a
number of foods, including microwave popcorn,” that has been linked to brochiolitis
obliterans, “a rare, sometimes fatal respiratory disease.” E-mail from FDA Office of
Legislation, Feb. 8, 2008 (on file with author); Andrew Schneider, Flavoring Additive Puts
Professional Cooks at Risk, Seattle Post-Intelligencer, (Dec. 21, 2007), [http://seattlepi.
nwsource.com/national/344277_diacetyl21.html]. While 21 C.F.R. § 184.1278 does not
place any limits on the use of diacetyl, and the FDA has stated it is “not aware of any
evidence that consumption of diacetyl (as opposed to inhalation) is unsafe,” the FDA would
have the power to prescribe limits under 21 C.F.R. § 184 on the purposes and conditions for
which diacetyl could be used — for example, not as a component of flavoring for
microwave popcorn or butter substitutes that release a potentially harmful vapor from
diacetyl when heated. Schneider, supra.

known as food contact substances, within certain limitations.⁴³ Part 186 of Title 21,
Code of Federal Regulations, lists the indirect food substances/food contact
substances affirmed as GRAS, such as wrappers, containers, and other food-contact
surfaces.⁴⁴
If the Commissioner reviews a food ingredient and finds that it is a GRAS
substance, under 21 C.F.R. § 184.1, the final rule approving the GRAS substance for
the purposes and under the conditions prescribed may contain limits on the
application and use of the substance. First, the regulation identifies the
characteristics of the ingredient in such a way that it can be differentiated from other
versions of the ingredient that the FDA has not affirmed as GRAS.⁴⁵ Second, the
substance affirmed as GRAS “must be used in accordance with current good
manufacturing practices.”⁴⁶ Third, a FDA regulation affirming GRAS status “when
the safety of an ingredient has been evaluated on the basis of limited conditions of
use” will specify the limited conditions of use. Use of the ingredient under a
condition other than the one specified in the regulation may not be GRAS.⁴⁷ In such
a case, the manufacturer must “independently establish that that use is GRAS or shall
use the ingredient in accordance with a food additive regulation.”⁴⁸ Fourth, the
substance affirmed as GRAS for the purposes and conditions prescribed cannot be
used “in a manner that may lead to deception of the consumer” or FFDCA
violations.⁴⁹ Finally, ingredients listed as GRAS cannot be combined, in order to
achieve the same technological effect in a food, at levels greater than were permitted
for a single ingredient.⁵⁰
The FDA’s 1997 Proposed Rule
The procedure outlined in a FDA proposed rule from 1997 would eliminate the
notice and comment rulemaking process described above for substances affirmed as
GRAS.⁵¹ The proposed rule would also end the GRAS petition process and create
a new GRAS notification procedure.⁵² Although the notice and comment rulemaking

⁴³ Id.
⁴⁴ 21 C.F.R. § 186.1(b).
⁴⁵ 21 C.F.R. § 184.1(a).
⁴⁶ 21 C.F.R. § 184.1(b).
⁴⁷ 21 C.F.R. § 184.1(b)(1).
⁴⁸ 21 C.F.R. § 184.1(b)(1).
⁴⁹ 21 C.F.R. § 184.1(c).
⁵⁰ 21 C.F.R. § 184.1(d).
⁵¹ Substances Generally Recognized as Safe, 62 Fed. Reg. 18937, 18939 (proposed Apr. 17,
1997); see also Agency Information Collection Activities; Proposed Collection; Comment
request; Notice of a Claim for Generally Recognized as Safe Exemption Based on a
Generally Recognized as Safe Determination, 70 Fed. Reg. 73009 (Dec. 8, 2005).
⁵² The FDA’s notification procedure outlined in the 1997 proposed rule is not unique. The
Food and Drug Administration Modernization Act of 1997 (FDAMA) created a notification
(continued...)

process for GRAS substances is still in effect in the FDA regulations, the FDA has
effectively been using the GRAS notification procedure outlined in the proposed rule
since 1998 without issuing a final rule. Since the FDA has not issued a final rule, it
is important to note that the FDA’s procedure set forth in the 1997 proposed rule is
only guidance and not law. The agency has also issued guidance for industry in the
form of frequently asked questions about GRAS that includes a discussion of the
GRAS notification program.⁵³ More than 250 GRAS notifications have been
submitted under the procedure outlined in the 1997 proposed rule. The FDA has
issued one of the three responses described below for most of these notices, and both
a numerical and alphabetical list of notices received and agency responses can be
found on the FDA’s website.⁵⁴
Under the notification procedure in the proposed rule, industry submits a GRAS
notification to the FDA that states the company’s view that the substance is GRAS.
These notifications identify the notifier and describe the substance that is the subject
of the notice, the applicable conditions of use, and the basis for the GRAS
determination, including a summary of supporting information “that forms the basis
for an exemption from a statutory requirement.”⁵⁵ The notifier “explicitly accepts
responsibility for the GRAS determination,” unlike the protocol in the current
regulations, in which such responsibility falls on the agency because an interested
person has petitioned the FDA to affirm a use of a substance as GRAS or the FDA
itself has affirmed a substance’s use as GRAS.⁵⁶
Rather than requiring that the FDA affirm that a substance is GRAS through a
notice-and-comment rulemaking, the 1997 proposed rule provides that the FDA does
not make a finding that a substance in a GRAS notification made under the proposed
rule process actually is a GRAS substance. Instead, the agency states that (1) it has
“no questions” about the notifier’s conclusion that a substance is GRAS, (2) the
notice does not provide a basis for a GRAS status determination, or (3) the notifier
has stopped the GRAS notification process.⁵⁷ If the agency’s review of a GRAS
notification does not furnish appropriate information to find a basis for a GRAS

⁵² (...continued)
procedure for food contact substances, and developers of genetically engineered crops need
to obtain authorization from USDA’s Animal and Plant Health Inspection Service through
either a permit or notification process.
⁵³ Center for Food Safety and Applied Nutrition, FDA, Guidance for Industry: Frequently
Asked Questions About GRAS (Dec. 2004), [http://www.cfsan.fda.gov/~dms/grasguid.
html].
⁵⁴ Center for Food Safety and Applied Nutrition, FDA, Numerical Listing of GRAS Notices
(October 2007), [http://www.cfsan.fda.gov/~rdb/opa-gras.html]; Center for Food Safety and
Applied Nutrition, FDA, Alphabetical Listing of GRAS Notices (Oct. 2007), [http://www.
cfsan.fda.gov/~rdb/opagr as1.html ].
⁵⁵ 62 Fed. Reg. 18947. “[T]he notifier must consent to grant the FDA access to the data and
information that are the basis of the GRAS determination,” and the agency has stated that
it “intends to conduct random audits of [this] data and information.” Id.
⁵⁶ 62 Fed. Reg. 18946.
⁵⁷ Substances Generally Recognized as Safe, 62 Fed. Reg. 18937 (proposed Apr. 17, 1997).

determination, it will issue such a response, potentially in light of the following
reasons to question the use of the substance:
FDA may question the GRAS status of use of a substance if the information
provided in a notice: (1) Does not adequately establish technical evidence of
safety; (2) is not generally available; (3) does not convince the agency that there
is the requisite expert consensus about the safety of the substance for its intended
use; or (4) is so poorly presented that the basis for the GRAS determination is not
clear. FDA also may be aware of information that is not included in the notice
but raises important public health issues that lead the agency to question GRAS⁵⁸
status of use of the substance.
The FDA notes that notifiers “receive as a benefit a response that documents the
agency’s awareness of the [GRAS] determination” by the notifier.⁵⁹
If, as in the majority of the FDA’s responses to GRAS notification submissions,
the FDA has no questions about the notification, this determination does not mean
that the FDA has approved the substance in the notification as GRAS.⁶⁰ In other
words, none of the uses of the substances reviewed by the FDA through a GRAS
notification are deemed to actually be GRAS by the FDA.⁶¹ Moreover, in contrast
to the FDA’s GRAS affirmation regulations, which allow the FDA to place potential
limits on the use of a GRAS substance, the GRAS notification procedures in the
FDA’s proposed rule do not appear to allow this, as the FDA only responds in one
of three ways noted above. Nonetheless, an FDA response of “no questions” could
give a substance an imprimatur of safety from the federal government. Such a
response may also give manufacturers confidence that the substance is acceptable,
and they would be able to tell their suppliers and others of the FDA’s response to the
notification. Additionally, an FDA response of “no questions” may convey to
manufacturers a feeling of less uncertainty and less potential liability about using
such a GRAS substance that has been through the GRAS notification process, as the
agency may not be as likely to seize a substance or find a product adulterated or
misbranded if the FDA itself has said it has “no questions.”⁶²
As mentioned above, the agency has yet to issue a final rule on the notification
procedure; however, the FDA has “invite[d] interested persons” to submit such
notifications as described in the proposed rule on an “interim policy” basis until the

⁵⁸ 62 Fed. Reg. 18950.
⁵⁹ 62 Fed. Reg. 18947.
⁶⁰ 62 Fed. Reg. 18951.
⁶¹ The use of the term ‘review’ here does not mean that the agency will necessarily “conduct
its own detailed evaluation” of, for example, raw data of toxicological studies or data used
to support the notifier’s GRAS determination. 62 Fed. Reg. 18948-49.
⁶² See Community Nutrition Institute v. Young, 818 F.2d 943, 949 n.10 (D.C. Cir. 1987)
(characterizing, in a case where the FDA set levels above which it could take action on
adulterated corn, the U.S. Supreme Court’s description of action levels as “agency
assurance”: “In setting an action level, the FDA essentially assures food producers that it
ordinarily will not enforce the general adulteration provisions of the Act against
them.”)(internal citations omitted).

publication of the final rule.⁶³ The agency has accepted more than 250 notification
submissions under the proposed rule procedures.⁶⁴ In its proposal, the FDA has
stated that it “will determine whether its experience in administering such notices
suggests modifications to the proposed procedure.”⁶⁵ The agency’s description and
adoption of the new GRAS notification process (as delineated in the proposed rule)
on an interim policy basis may be characterized as the equivalent of a guidance
document.⁶⁶
Statistics on FDA GRAS Notices
The chart below provides the number of FDA response letters in each of the
three categories discussed above, as well as a fourth category for the number of
GRAS notices that are awaiting a response from the FDA, and the percent of the total
number of letters issued by the FDA under its procedure in the 1997 proposed rule.
One GRAS notification, GRN No. 13, was counted twice — once in the “FDA has
no questions” category and once in the “Notice does not provide a basis for a GRAS
determination” category — because the FDA had no questions for three botanical
substances in the notice (Chrysanthemum, Licorice, and Jellywort) but the FDA
stated that the notice did not provide a basis for a GRAS determination for six other
substances (Honeysuckle; Lophatherum; Mulberry leaf; Frangipani; Selfheal;
Sophora flower bud).
The FDA’s response to GRAS notifications that were initially submitted, but
then were either withdrawn or determined not to provide a basis for a GRAS
determination, were only included for the resubmitted notices for the same
substances. For example, Hawaii International Seafood, Inc. initially submitted its
GRAS notification for tasteless smoke as GRAS Notice No. 5, but then at the

⁶³ 62 Fed. Reg. 18954-55.
⁶⁴ The FDA’s acceptance of GRAS notifications since the publication of the 1997 proposed
rule could be seen as an “experiment[] while the rulemaking is in progress” that could
bolster the need for a subsequent notice-and-comment period before the agency publishes
a final rule. J^EFFREYS.L^UBBERS, AG^UI^{DE TO}F^EDERALA^GENCYR^ULEM^AKI^NG 292-93 (4th
ed. 2006). Agencies frequently publish requests for additional rounds of notice-and-
comment during the rulemaking process. The FDA’s NPRM on GRAS substances asked
for the submission of written comments by July 16, 1997. 62 Fed. Reg. 18938.
⁶⁵ 62 Fed. Reg. 18954.
⁶⁶ If the interim policy procedures are considered to be a guidance document, which is a type
of general statement of policy under the Administrative Procedure Act (APA), 5 U.S.C.
§ 553(b), then the FDA arguably would not need to complete the rulemaking because the
notice and comment provisions of the APA would not apply. SeeL^UBBERS, supra note 64,
at 94. Thus the agency would not appear to be violating the APA if the guidance document
procedures are prospective and voluntary and if the interim policy preserves the FDA’s
discretion. Moreover, the GRAS affirmation regulations are still law and may still be used
by interested persons. However, completing the rulemaking may clarify agency policy.
Additionally, although the APA does not impose a limit on the time between an agency’s
publication of a proposed rule and its issuance of a final rule, the 1997 proposed rule may
be considered to be stale, and a new rulemaking may be necessary. 5 U.S.C. § 555(b);
L^UBBERS, supra note 64, at 293, n. 82, 357-58.

company’s request, the FDA ceased to evaluate the notice. Hawaii International
Seafood, Inc. then resubmitted its GRAS notification for tasteless smoke as GRAS
Notice No. 15, and the FDA had no questions. Only the FDA’s response to the
resubmitted notification is included on the chart below. There were 18 instances of
GRAS notifications being resubmitted, which explains the difference in the chart’s
total number of notices (238) and the number of GRAS notifications listed on the
FDA website (256).
Categories At notifier’s
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The Role of USDA in Food Additive Safety Determinations
Under the current legislative and regulatory schemes, the FDA shares
responsibility for some food safety issues with the United States Department of
Agriculture (USDA). While the FDA is responsible for safety of the vast majority
of food categories, the USDA is specifically authorized to regulate the safety and
wholesomeness of meat and poultry products that are intended for use as human⁶⁸
food. Under this authority, the USDA, and consequently the Food Safety and
Inspection Service (FSIS),⁶⁹ is required to provide a mark of inspection on meat and

⁶⁷ See, e.g., Agency Response Letter GRAS Notice No. GRN 000156 from Laura M.
Tarantino, Director, Office of Food Additive Safety, Center for Food Safety and Applied
Nutrition, FDA, to George Burdock, Burdock Group (on behalf of LycoRed Natural
Products Industries, Ltd.), Feb. 7, 2005, [http://www.cfsan.fda.gov/~rdb/opa-g156.html].
⁶⁸ This authority is provided for by the Federal Meat Inspection Act (21 U.S.C. § 601 et seq.)
and the Poultry Products Inspection Act (21 U.S.C. § 451 et seq.), respectively.
⁶⁹ The Secretary of the USDA delegates this authority to FSIS under 9 C.F.R. § 300.2.

poultry products.⁷⁰ The mark of inspection reflects a determination that the product
is not adulterated⁷¹ or misbranded.⁷²
Dual Process of Review for Meat and Poultry Products. There is a
two-step process for approving the use of additive substances in meat and poultry
products: (1) FDA determines the safety of substances and prescribes safe conditions
of use, and (2) FSIS determines whether new substances or new applications of
substances are suitable for use in meat and poultry products.⁷³ In other words, FDA
makes determinations based on the safety of the substance itself, while FSIS
approves the substance’s application to the meat or poultry product.
In 2000, the roles of FDA and FSIS in this joint review process of substances
used in meat and poultry products were laid out in a Memorandum of Understanding
(MOU).⁷⁴ The MOU provides for standard operating procedures regarding
submissions to FDA or FSIS that, for example, petition for the approval of food and
color additives intended for use in meat or poultry products, as well as GRAS
notifications “regarding the use of a substance in the production of meat or poultry
products.”⁷⁵ The MOU generally instructs the agency that receives a request for
review of a substance used in meat or poultry products to seek review by the other
agency regarding the substance as well. For example, when FSIS receives a request
for an acceptability determination regarding the application of a substance in the
production of meat or poultry products, it confirms the status of the substance’s⁷⁶
safety with FDA. Conversely, if FDA receives a request for a suitability
determination regarding the use of a substance in meat or poultry products, the⁷⁷

request must be transferred to FSIS.
⁷⁰ See 21 U.S.C. § 606; 21 U.S.C. § 457.
⁷¹ A product can be considered “adulterated” if it “bears or contains any poisonous or
deleterious substance which may render it injurious to health;” contains any additives
considered unsafe; “consists in whole or in part of any filthy, putrid, or decomposed
substance or is for any other reason unsound, unhealthful, unwholesome, or otherwise unfit
for human food;” or “has been prepared, packed, or held under insanitary conditions.” See

21 U.S.C. § 601(m).

⁷² A product can be considered “misbranded” if its label is false or misleading; contains an
inaccurate description of the product; does not identify its manufacturer, packer or
distributor and an accurate statement of quantity of the contents; or does not contain other
information that may be required by the act. See 21 U.S.C. § 601(n).
⁷³ See 9 C.F.R. § 424.21.
⁷⁴ Memorandum of Understanding Between the Food Safety and Inspection Service United
States Department of Agriculture and the Food and Drug Administration United States
Department of Health and Human Services Regarding the Listing or Approval of Food
Ingredients and Sources of Radiation Used in the Production of Meat and Poultry Products,
[ h t t p : / / www.f s i s .us da .gov/ Re gul a t i ons _&_Pol i c i e s / La be l i n g_ FDA_M OU/ i nde x.a s p ] .
⁷⁵ Id.
⁷⁶ Standard Operating Procedures D, [http://www.fsis.usda.gov/Regulations_&_Policies/
Labeling_FDA_MOU/index.asp].
⁷⁷ Standard Operating Procedures E, [http://www.fsis.usda.gov/Regulations_&_Policies/

The MOU provides that when FDA receives a GRAS Notice regarding the use
of a substance in the production of meat or poultry products, FDA and FSIS proceed
jointly, as they would regarding requests for approval of a food or color additive
intended for use in the production of meat or poultry products. FDA informs and
consults with FSIS, and FSIS provides written comments to FDA within 60 days.
FDA’s response to the notifier includes information regarding the notifier’s
responsibilities under the Federal Meat Inspection Act and Poultry Products
Inspection Act and “may include concerns about the suitability of the use of the
substance in the production of meat or poultry products and, when applicable, any
restrictions or conditions of use in the production of meat or poultry products that
FSIS recommends in writing.”⁷⁸
FSIS Review of Substances in Meat or Poultry Products. Under the
dual review process, if FDA approves a substance, such as a food or color additive,
or lists the substance as GRAS for use in food, the substance is not automatically
acceptable for use in meat and poultry products. If FDA’s approval of a food or color
additive, or if the FDA’s GRAS listing does not specifically mention meat or poultry
products, FSIS needs an affirmative written statement from FDA that it did consider
the substance’s use in meat or poultry or that it has no objections with regard to
safety when the substance is used in meat or poultry.⁷⁹ FSIS then needs to determine⁸⁰
suitability and whether rulemaking is required. Whether a substance is suitable
depends on “the effectiveness of the substance in performing the intended technical
purpose of use, at the lowest level necessary, and the assurance that the conditions
of use will not result in an adulterated product or one that misleads customers.”⁸¹
To satisfy the requirement of suitability, FSIS needs certain data as evidence that⁸²
the substance or use of the substance is suitable for its intended technical purposes.
The data must show the effectiveness of the substance in achieving the intended⁸³
purpose of its use. The data must show that the use is at the lowest level necessary

⁷⁷ (...continued)
Labeling_FDA_MOU/index.asp].
⁷⁸ Standard Operating Procedures C, [http://www.fsis.usda.gov/Regulations_&_Policies/
Labeling_FDA_MOU/index.asp].
⁷⁹ Safe and Suitable Ingredients Used in the Production of Meat and Poultry Products, FSIS
Directive 7120.1, December 17, 2002, part V, [http://www.fsis.usda.gov/OPPDE/rdad/
FSISDirectives/7120.1.pdf].
⁸⁰ Id.
⁸¹ Guidance on the Procedures for Joint Food Safety and Inspection Service and Food and
Drug Administration Approval of Ingredients and Sources of Radiation Used in the
Production of Meat and Poultry Products, [http://www.fsis.usda.gov/OPPDE/rdad/FRPubs/

00-022N/ApprovalofIngr edients.htm] .

⁸² See Guidance on the Procedures for Joint FSIS and FDA Approval of Ingredients and
Sources of Radiation Used in the Production of Meat and Poultry Products,
[ h t t p : / / www.f s i s .usda.gov/ OPPDE/ r dad/ FRPubs/ 00-022N/ Appr oval of In gr edi e nt s.ht m] .
⁸³ Id.

to achieve the intended effect under the proposed conditions of use.⁸⁴ The data must
show that the use cannot result in adulteration or misbranding.⁸⁵ FSIS regulations
currently prohibit the use of substances that conceal damage or inferiority or make
a product appear better or of greater value than it is.⁸⁶ The regulations also provide
that substances that are intended to be used to impart color in any meat or poultry
product cannot be used unless approved as a color additive (under FDA regulations)
or approved by FSIS regulations.⁸⁷ This data must be provided for each separate
product in which the use of the substance is intended.⁸⁸ Based on the merits of these
data, FSIS can permit the use of the substance or the new use of a substance under
the proposed conditions of use and in conformance with standards and labeling
requirements.
With respect to whether rulemaking is required, if FDA has found or confirmed
the safety of the substance, FSIS regulations are not amended.⁸⁹ If rulemaking is not
required, FSIS notifies the requestor in writing of its determination in what is known
as an acceptability determination.⁹⁰ If the use of the substance is prohibited or
limited or if the substance is not normally found in the product, FSIS regulations may
be necessary.⁹¹ If rulemaking is required, the substance is added to the current list of
approved substances after the formal rulemaking process is completed.⁹² Because not
all approved substances are listed in the published regulations under this process,
FSIS maintains a directive system of all approved substances that are accepted as safe
and suitable by FSIS on its website.⁹³
GRAS Substances. As discussed above, a determination that a substance is
GRAS may be made by the FDA, through the affirmation of the GRAS status of a
substance, or by industry (including via a GRAS notification), based on scientific

⁸⁴ Id.
⁸⁵ Id.
⁸⁶ See 9 C.F.R. § 424.23.
⁸⁷ See 9 C.F.R. § 424.21(b)(3).
⁸⁸ FSIS has accepted data that has not been specifically applied to all categories if the data
can be easily extrapolated to all species. See GRAS Notice No. 83, supra note 1.
⁸⁹ Id.
⁹⁰ Safe and Suitable Ingredients Used in the Production of Meat and Poultry Products, FSIS
Directive 7120.1, December 17, 2002, part V, [http://www.fsis.usda.gov/OPPDE/rdad/
FSISDirectives/7120.1.pdf].
⁹¹ Id.
⁹² Specific substances that FSIS has approved by regulation are listed in 9 C.F.R.
§ 424.21(c).
⁹³ Safe and Suitable Ingredients Used in the Production of Meat and Poultry Products, FSIS
Directive 7120.1, Dec. 17, 2002, [http://www.fsis.usda.gov/OPPDE/rdad/FSISDirectives/

7120.1.pdf]. An amended version (dated Oct. 23, 2007) can be found at [http://www.fsis.

usda.gov/OPPDE/rdad/FSISDirectives/7120.1Ame nd13.pdf].

procedures or common use of a substance in food prior to January 1, 1958.⁹⁴ FSIS
cannot rely on the industry’s determination of a substance as GRAS because of
statutory requirements requiring USDA inspection of meat and poultry products.⁹⁵
Meat and poultry products are required to have a mark of inspection that “reflects a
determination by FSIS that the food product is not adulterated, and thus that all
substances used to make the product are safe and suitable.”⁹⁶ As a result, “FSIS must
have from FDA, at the very least, a written statement of no objection with regard to
the safety of the use of the substance.”⁹⁷
GRAS Notices Regarding Intended Uses of Carbon Monoxide
Under the process outlined in the FDA’s 1997 proposed rule, manufacturers
have submitted GRAS notifications to the FDA that state their view that carbon
monoxide is a GRAS substance. The FDA has responded that it has “no questions”
about the conclusion that CO is GRAS. The FDA’s responses to the GRAS
notifications informed the industry that it had the continuing responsibility to ensure
the substance’s safety and compliance with other legal and regulatory requirements.
The FDA first determined that it had no questions regarding a GRAS
notification for the use of carbon monoxide in March 2000. The notifier, Hawaii
International Seafood, Inc., stated its determination that the use of “tasteless smoke”
(of which carbon monoxide is a component) on raw seafood is GRAS.⁹⁸ The
company defined its intended use as involving a procedure before the fish is frozen
that would preserve the color, taste, aroma, and texture of raw seafood.⁹⁹ In addition
to determining that it had no questions, the FDA stated that the company’s use of
tasteless smoke constituted a preservative and noted that the fish must be labeled so
that it complies with misbranding provisions of the FFDCA and the FDA’s labeling
regulations.

⁹⁴ Guidance on the Procedures for Joint FSIS and FDA Approval of Ingredients and Sources
of Radiation Used in the Production of Meat and Poultry Products, [http://www.fsis.
usda.gov/OPPDE/rdad/FRPubs/00-022N/ApprovalofIngr edients.htm] .
⁹⁵ See 21 U.S.C. § 601 et seq.; 21 U.S.C. § 451 et seq.
⁹⁶ Guidance on the Procedures for Joint FSIS and FDA Approval of Ingredients and Sources
of Radiation Used in the Production of Meat and Poultry Products, [http://www.fsis.
usda.gov/OPPDE/rdad/FRPubs/00-022N/ApprovalofIngr edients.htm] .
⁹⁷ Id.
⁹⁸ The company first submitted a notification regarding tasteless smoke as a GRAS
substance in 1998, but asked the FDA to cease to evaluate the notice and then resubmitted
the notice in 1999. See GRAS Notice No. 15, supra note 3; Agency Response Letter GRAS
Notice No. GRN 000005 from Linda S. Kahl, Regulatory Policy Branch, Division of
Product Policy, Office of Premarket Approval, Center for Food Safety and Applied
Nutrition, FDA, to Martin J. Hahn, Hogan & Hartson LLP (on behalf of Hawaii
International Seafood, Inc.) (Dec. 11, 1998), [http://www.cfsan.fda.gov/~rdb/opa-g005.
html].
⁹⁹ GRAS Notice No. 15, supra note 3.

The FDA next determined that it had no questions regarding the use of carbon
monoxide as a GRAS substance in meat packaging in a letter to Pactiv Corporation
in February 2002.¹⁰⁰ The agency also stated that it had not made an independent
determination of the GRAS status of the use of CO described in the notification.¹⁰¹
FDA noted the industry’s conclusion that the use of carbon monoxide allows meat
to maintain a desirable red color during storage but once the product was removed
from storage, the color of the meat “deteriorates at a similar rate to that of meat that
has not been exposed to CO.”¹⁰² FSIS concluded that the use of carbon monoxide in
the MAP system as it had been described by Pactiv in its GRAS notification “would
be acceptable for packaging red meat cuts and ground meat.”¹⁰³ FSIS agreed with the
company that “there is no lasting functional effect in the food and there is an
insignificant amount of carbon monoxide present in the finished product under the
proposed conditions of use.”¹⁰⁴ FDA restated that it had no questions regarding the
industry’s determination that carbon monoxide is GRAS in July 2004 and September

2005 in response letters to Precept Foods, LLC, and Tyson Foods, Inc.,

respectively.¹⁰⁵ Currently, two additional GRAS notifications regarding carbon
monoxide are pending.¹⁰⁶
Although notifiers seeking a response from the FDA on GRAS notices for CO
have submitted notices describing other conditions of use of CO, it appears possible

¹⁰⁰ See GRAS Notice No. 83, supra note 1.
¹⁰¹ See GRAS Notice No. 83, supra note 1.
¹⁰² GRAS Notice No. 83, supra note 1.
¹⁰³ GRAS Notice No. 83, supra note 1. FDA response letters include FSIS conclusions on
the substance. Although FSIS did not approve the use of carbon monoxide based on the
original information provided, it did ultimately approve the use after receiving additional
data. See Letters from Robert C. Post, Director, Labeling and Consumer Protection Staff,
FSIS, to Lane Highbarger, Office of Food Additive Safety, FDA (Apr. 28, 2004 and June

2, 2004).

¹⁰⁴ See GRAS Notice No. 83, supra note 1.
¹⁰⁵ See Agency Response Letter GRAS Notice No. GRN 000143 from Laura M. Tarantino,
Director, Office of Food Additive Safety, Center for Food Safety and Applied Nutrition,
FDA, to Gary J. Kushner and Anne M. Boeckman, Hogan and Hartson (on behalf of Precept
Foods, LLC) (July 29, 2004), [http://www.cfsan.fda.gov/~rdb/opa-g143.html], [hereinafter
GRAS Notice No. 143]; Agency Response Letter GRAS Notice No. GRN 000167, from
Laura M. Tarantino, Director, Office of Food Additive Safety, Center for Food Safety and
Applied Nutrition, FDA, to Mark L. Itzkoff, Olsson, Frank and Weeda, PC (on behalf of
Tyson Foods, Inc.), [http://www.cfsan.fda.gov/~rdb/opa-g167.html], [hereinafter GRAS
Notice No. 167]. The FDA ceased to evaluate another GRAS notification regarding carbon
monoxide, GRAS Notice No. 167, at the request of the notifier, Freezing Machines, Inc.
Agency Response Letter GRAS Notice No. GRN 000166 from Antonia Mattia, Director,
Division of Biotech and GRAS Notice Review, Office of Food Additive Safety, Center for
Food Safety and Applied Nutrition, FDA, to Mark L. Itzkoff, Olsson, Frank and Weeda, PC
(on behalf of Freezing Machines, Inc.) (Oct. 12, 2005), [http://www.cfsan.fda.gov/~rdb/opa-
g166.html].
¹⁰⁶ See listings for GRAS Notifications 188 and 194. Center for Food Safety and Applied
Nutrition, FDA, Numerical Listing of GRAS Notices (Oct. 2007), [http://www.cfsan.fda.
gov/ ~rdb/opa-gras.html ].

that a manufacturer could potentially rely on a FDA response that the agency “has no
questions” to use a GRAS substance in a manner other than the use described in the
GRAS notice for which the FDA had no questions. For example, two of the CO
GRAS notices, 83 and 143, discuss a level of CO that is 0.4 percent in a MAP
system. Conceivably, a company could interpret the agency’s lack of questions
regarding the 0.4 CO level and use a CO level of 0.45 percent in a MAP system.
However, if the FDA made a determination that the use of 0.45 percent CO, or even
0.4 percent CO, violated the FFDCA, the agency could attempt to seek criminal and
civil penalties for violations such as adulteration and misbranding. The FFDCA also
provides the FDA with other enforcement mechanisms such as seizure and
injunctions.
Proposed Legislation in the 110^th Congress
Two bills have been introduced in the House of Representatives regarding the
use of carbon monoxide in meat and poultry products: H.R. 3115 (the Carbon
Monoxide Treated Meat, Poultry, and Seafood Safe Handling, Labeling, and
Consumer Protection Act) and H.R. 3610 (the Food and Drug Import Safety Act of
2007). Additionally, the discussion draft of the Food and Drug Administration
Globalization Act of 2008, issued by Representatives Dingell, Pallone, and Stupak,
similarly addresses the issue. Other bills also address GRAS substances: H.R. 2633,
H.R. 3290, H.R. 3580, H.R. 6635, and S. 1342.
H.R. 3115, H.R. 3610, and the discussion draft propose to amend FFDCA
§ 201.¹⁰⁷ Under the proposals, if carbon monoxide is used to treat meat, poultry or
seafood that is intended for human consumption and if the conditions of that use
would affect the color of the products, carbon monoxide must be treated as a color
additive under FFDCA,¹⁰⁸ unless the product’s label includes a statement that is
“prominently and conspicuously” placed to notify the consumer of the use of carbon
monoxide and to warn the consumer of proper factors to judge the safety of the
product.¹⁰⁹ The bills and the discussion draft would allow the Secretary of Health and
Human Services (HHS) to establish alternative labeling requirements five years after
the effective date of the labeling requirement, if the Secretary finds that the labeling
requirement is no longer necessary to prevent consumer deception.

¹⁰⁷ H.R. 3115, 110^th Cong. § 3 (2007); H.R. 3610, 110^th Cong. § 14 (2007).
¹⁰⁸ See H.R. 3115 § 3(a); H.R. 3610 § 14(a).
¹⁰⁹ The statement provided by the bills reads as follows: “SAFETY NOTICE: Carbon
monoxide has been used to preserve the color of this product. Do not rely on color or the
‘use or freeze by’ date alone to judge the freshness or safety of the product. Discard any
product with an unpleasant odor, slime, or a bulging package.” H.R. 3115 § 3(a); H.R. 3610
§ 14(a).
The statement provided by the discussion draft would remove the last sentence and
slightly alter the wording as follows: “CONSUMER NOTICE: Carbon monoxide has
been used to preserve the color of this product. Do not rely on color or the ‘use or freeze
by’ date alone to judge the freshness of the product.” Discussion Draft, § 132.

The discussion draft contains an additional provision related to GRAS
determinations that would require the Secretary to publish, in the Federal Register,
notice of receipt of a request for a substance to be determined by the Secretary to be
GRAS. The Secretary would then have 90 days after publication of the notice to
determine whether the substance is GRAS; the Secretary’s determination would also
be published in the Federal Register. It is unclear if the discussion draft is referring
to a petition for affirmation of GRAS status under 21 C.F.R. § 170.35 as the “request
for a substance to be determined by the Secretary to be a GRAS substance,” or an
alternate situation. (See page 5 in the PDF version of this report.) If the FDA
Commissioner receives a petition to affirm the GRAS status of a substance “that
directly or indirectly become[s] [a] component[] of food,” the Commissioner must
publish a notice of the filing of the petition in the Federal Register within 30 days
after the date of filing of the petition.¹¹⁰ There is a 60-day comment period after the
notice of filing in the current regulations.¹¹¹ The current regulations state that the
FDA Commissioner will publish an order listing the substance as GRAS if the
petition and all available information “provide[s] convincing evidence that the
substance is GRAS.”¹¹² Alternatively, if the Commissioner “concludes that there is
a lack of convincing evidence that the substance is GRAS and that it should be
considered a food additive subject to” FFDCA § 409, the Commissioner must publish
a notice of this determination in the Federal Register.¹¹³

¹¹⁰ 21 C.F.R. § 170.35(c)(2).
¹¹¹ 21 C.F.R. § 170.35(c)(4).
¹¹² 21 C.F.R. § 170.35(c)(5).
¹¹³ 21 C.F.R. § 170.35(c)(4)-(6).