Order Code RL34247
Federal Regulation of Substances Generally
Recognized As Safe (GRAS) and the Use of
Carbon Monoxide in Packaging for Meat and Fish
November 9, 2007
Vanessa K. Burrows
Legislative Attorney
American Law Division
Cynthia Brougher
Legislative Attorney
American Law Division

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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 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). Both
bills 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.
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.

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Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Legal Regulation of Food Additives and GRAS Substances . . . . . . . . . . . . . 3
The FDA’s 1997 Proposed Rule
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Statistics on FDA GRAS Notices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
The Role of USDA in Food Additive Safety Determinations . . . . . . . . . . . . 9
Dual Process of Review for Meat and Poultry Products . . . . . . . . . . . . 9
FSIS Review of Substances in Meat or Poultry Products . . . . . . . . . . 10
Approval of GRAS Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
GRAS Notices Regarding Intended Uses of Carbon Monoxide . . . . . . . . . 12
Proposed Legislation in the 110th Congress . . . . . . . . . . . . . . . . . . . . . . . . . 14

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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 Modified
Atmosphere Packaging (MAP).1 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 called
“tasteless smoke”)3 gain a fresher appearance and a red tint.4 Conflicting studies have
shown that consumers rely primarily on the appearance, including the red color of
meat or fish, when choosing which package to purchase,5 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.) (February 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.) (March 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 (April 4, 2007).
5 Press Release, Consumer Federation of America, Most Consumers Are Concerned About
Practice of Adding Carbon Monoxide to Meat, New Survey Finds (September 25, 2006),
[http://www.consumerfed.org/pdfs/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.’”).

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CRS-2
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 (November 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.

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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
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. The FDA regulates food additives and GRAS substances
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 radiation
intended for such use)....16
The later 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 not
intended to have any technical effect in such food.” 17 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.18
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,
October 30, 2007.
16 FFDCA § 201(s); 21 U.S.C. § 321(s).
17 FFDCA § 409(h)(6); 21 U.S.C. § 348(h)(6).
18 FFDCA § 409; 21 U.S.C. § 348.

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GRAS substances must be “generally recognized, among experts qualified by
scientific training and experience to evaluate [their] safety.”19 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.”20 The person seeking
GRAS status for a substance has the burden of proving the substance is GRAS under
conditions of the substances’ use.21 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.”22 Scientific procedures include published and unpublished human, animal,
analytical, and other scientific studies that are “appropriate to establish the safety of
a substance.”23 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.”24 The GRAS determination must
“ordinarily” be based on published studies, but can be corroborated by unpublished
studies and other information.25 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
consensus of expert opinion regarding the safety of the use of the substance.”26
However, “a severe conflict among experts regarding the safety of the use of a
substance, precludes a finding” that a substance is GRAS.27
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.”28 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
19 FFDCA § 201(s); 21 U.S.C. § 321(s).
20 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.
21 See Substances Generally Recognized as Safe, 62 FR 18937, 18939 (proposed April 17,
1997).
22 FFDCA § 201(s); 21 U.S.C. § 321(s).
23 21 C.F.R. § 170.3(h).
24 21 C.F.R. § 170.30(b).
25 21 C.F.R. § 170.30(b).
26 Substances Generally Recognized as Safe, 62 FR 18937, 18939 (proposed April 17,
1997).
27 Id.
28 FFDCA § 201(s); 21 U.S.C. § 321(s).

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CRS-5
consumers.”29 In this instance, a GRAS determination ordinarily turns on “generally
available data and information.”30 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.”31
Published information regarding substances used outside the United States must be
corroborated.32
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.”33 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.34
The FDA Commissioner can affirm the GRAS status of a substance based on
a petition or on his or her own initiative.35 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 affirmed. 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.”36
The affirmation of GRAS status occurs through the notice and comment
rulemaking process, in which the Commissioner publishes a notice of the proposed
GRAS substance in the Federal Register, allows 60 days for comments, evaluates the
comments, and either (1) publishes a final rule in the Federal Register or
(2) concludes that the substance is not GRAS and “that it should be considered a food
additive” subject to premarket approval under FFDCA § 409.37 The FDA has
reviewed the direct food substances on the list in Part 184 and determined that they
29 21 C.F.R. § 170.3(f).
30 21 C.F.R. § 170.30(c)(1).
31 21 C.F.R. § 170.30(c)(2).
32 21 C.F.R. § 170.30(c)(2).
33 21 C.F.R. § 182.1(a).
34 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).
35 21 C.F.R. § 170.35(a).
36 Substances Generally Recognized as Safe, 62 FR 18937, 18939 (proposed April 17,
1997).
37 21 C.F.R. § 170.35.

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are GRAS “for the purposes and under the conditions prescribed.”38 These
ingredients are also GRAS as indirect food ingredients, also known as food contact
substances, within certain limitations.39 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.40

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.41 Second, the substance affirmed
as GRAS “must be used in accordance with current good manufacturing practices.”42
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.43 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.”44 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.45 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.46
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.47 The proposed rule would also end the GRAS petition process and create
a new GRAS notification procedure.48 Although the notice and comment rulemaking
38 21 C.F.R. § 184.1(a).
39 Id.
40 21 C.F.R. § 186.1(b).
41 21 C.F.R. § 184.1(a).
42 21 C.F.R. § 184.1(b).
43 21 C.F.R. § 184.1(b)(1).
44 21 C.F.R. § 184.1(b)(1).
45 21 C.F.R. § 184.1(c).
46 21 C.F.R. § 184.1(d).
47 Substances Generally Recognized as Safe, 62 FR 18937, 18939 (proposed April 17,
1997).
48 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...)

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CRS-7
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 ever 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.49 Over 230 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.50
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 describe the substance that is the subject of the notice, the
applicable conditions of use, and the basis for the GRAS determination, including
supporting information. 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. Rather, the agency states that (1) it has “no questions” about the
company’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.51 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. In other words, none of the substances reviewed by the FDA
in the GRAS notification process are approved by the FDA. In contrast to the GRAS
affirmation regulations in 21 C.F.R. § 184.1(b)(1) that describe the potential limits
on the use of a GRAS substance, the GRAS notification procedures in the FDA’s
proposed rule do not appear to impose limits on the conditions of use, as the FDA
only responds in one of these three ways.
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
48 (...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.
49 Center for Food Safety and Applied Nutrition, FDA, Guidance for Industry: Frequently
Asked Questions About GRAS (December 2004), [http://www.cfsan.fda.gov/~dms/
grasguid.html].
50 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 (October 2007),
[http://www.cfsan.fda.gov/~rdb/opagras1.html].
51 Substances Generally Recognized as Safe, 62 FR 18937 (proposed April 17, 1997).

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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 to not 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
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 16 instances of
GRAS notifications being resubmitted, which explains the difference in the chart’s
total number of notices (218) and the number of GRAS notifications listed on the
FDA website (234).
Categories of
At notifier’s
Notice does not
FDA
FDA
request, FDA
provide a basis
Responses or
has no
ceased to
Pending
Total
for a GRAS
Response is
questionsa
evaluate the
determination
Pendinga
notice
Number of
FDA Letters
171
11
18
18
218
in Each
Categorya
Percentage
of Total
78.44
5.05
8.26
8.26
100.01b
Lettersc
a. The categories of FDA letters and the number of FDA letters in each category were obtained from
the FDA Center for Food Safety and Applied Nutrition’s Numerical Listing of GRAS Notices
for October 2007. [http://www.cfsan.fda.gov/~rdb/opa-gras.html].
b. This category includes notices in which the FDA had no questions but stated that some uses of a
GRAS substance may require a color additive listing.52
c. Percentages were calculated by CRS and rounded to two decimal points.
52 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.), February 7, 2005, [http://www.cfsan.fda.gov/~rdb/opa-g156.
html].

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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 human
food.53 Under this authority, the USDA, and consequently the Food Safety and
Inspection Service (FSIS),54 is required to provide a mark of inspection on meat and
poultry products.55 The mark of inspection reflects a determination that the product
is not adulterated56 or misbranded.57
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.58 In other words, FDA
approves the substances 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).59 The MOU provides for standard operating procedures to provide
consistency in the processing of relevant submissions of substances for approval.60
The MOU generally instructs the agency that receives a request for review of a
53 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.
54 The Secretary of the USDA delegates this authority to FSIS under 9 C.F.R. § 300.2.
55 See 21 U.S.C. § 606; 21 U.S.C. § 457.
56 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).
57 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).
58 See 9 C.F.R. § 424.21.
59 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,
available at [http://www.cfsan.fda.gov/~dms/opa-fsis.html].
60 Id.

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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’s safety with
FDA.61 Conversely, if FDA receives a request for a suitability determination
regarding the use of a substance in meat or poultry products, the request must be
transferred to FSIS.62
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 other requests for approval of a substance 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.”63
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 substance
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.64 FSIS then needs to determine suitability and whether
rulemaking is required.65 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.”66
61 Standard Operating Procedures D, available at [http://www.cfsan.fda.gov/~dms/opa-
fsis.html].
62 Standard Operating Procedures E, available at [http://www.cfsan.fda.gov/~dms/opa-
fsis.html]
63 Standard Operating Procedures C, available at [http://www.cfsan.fda.gov/~dms/opa-
fsis.html].
64 Safe and Suitable Ingredients Used in the Production of Meat and Poultry Products, FSIS
Directive 7120.1, December 17, 2002, part V, available at [http://www.fsis.usda.gov/
OPPDE/rdad/FSISDirectives/7120.1.pdf].
65 Id.
66 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, available at [http://www.fsis.usda.gov/OPPDE/
rdad/FRPubs/00-022N/ApprovalofIngredients.htm].

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To satisfy the requirement of suitability, FSIS needs certain data as evidence that
the substance or use of the substance is suitable for its intended technical purposes.67
The data must show the effectiveness of the substance in achieving the intended
purpose of its use.68 The data must show that the use is at the lowest level necessary
to achieve the intended effect under the proposed conditions of use.69 The data must
show that the use cannot result in adulteration or misbranding.70 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.71 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.72 This data must be provided for each separate
product in which the use of the substance is intended.73 Based on the merits of these
data, FSIS can permit 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.74 If rulemaking is not
required, FSIS notifies the requestor in writing of its determination in what is known
as an acceptability determination.75 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.76 If rulemaking is required, the substance is added to the current list of
approved substances after the formal rulemaking process is completed.77 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.78
67 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, available at
[http://www.fsis.usda.gov/OPPDE/rdad/FRPubs/00-022N/ApprovalofIngredients.htm].
68 Id.
69 Id.
70 Id.
71 See 9 C.F.R. § 424.23.
72 See 9 C.F.R. § 424.21(b)(3).
73 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.
74 Id.
75 Safe and Suitable Ingredients Used in the Production of Meat and Poultry Products, FSIS
Directive 7120.1, December 17, 2002, part V, available at [http://www.fsis.usda.gov/
OPPDE/rdad/FSISDirectives/7120.1.pdf].
76 Id.
77 Specific substances that FSIS has approved by regulation are listed in 9 C.F.R. §
424.21(c).
78 Safe and Suitable Ingredients Used in the Production of Meat and Poultry Products, FSIS
(continued...)

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Approval of GRAS Substances. As discussed above, the FDA uses three
methods to adopt substances as GRAS: listing the substance in its regulations, relying
on industry self-determination of the substance, or making the substance the subject
of a GRAS Notice.79 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.80 Meat and poultry products are required to have a mark of
inspection that reflects a determination that the product has not been adulterated and
therefore all substances used in the product are safe and suitable. As a result, FSIS
must have at the very least a written statement of no objection from the FDA with
regard to the safety of the use of the substance.81
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 the company’s 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.82 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.83 In addition
to determining that it had no questions, the FDA stated that the company’s use of
78 (...continued)
Directive 7120.1, December 17, 2002, available at [http://www.fsis.usda.gov/OPPDE/
rdad/FSISDirectives/7120.1.pdf]. An amended version (dated October 23, 2007) can be
found at [http://www.fsis.usda.gov/OPPDE/rdad/FSISDirectives/7120.1Amend13.pdf].
79 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, available at
[http://www.fsis.usda.gov/OPPDE/rdad/FRPubs/00-022N/ApprovalofIngredients.htm].
80 See 21 U.S.C. § 601 et seq.; 21 U.S.C. § 451 et seq.
81 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, available at
[http://www.fsis.usda.gov/OPPDE/rdad/FRPubs/00-022N/ApprovalofIngredients.htm].
82 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.) (December 11, 1998), [http://www.cfsan.fda.gov/~rdb/opa-
g005.html].
83 GRAS Notice No. 15, supra note 3.

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CRS-13
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.
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 2002.84 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.85
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.”86 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.”87 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.”88 FDA reaffirmed the status of carbon monoxide as
GRAS in July 2004 and September 2005 in response letters to Precept Foods, LLC,
and Tyson Foods, Inc., respectively.89 Currently, two additional GRAS notifications
regarding carbon monoxide are pending.90
84 See GRAS Notice No. 83, supra note 1.
85 See GRAS Notice No. 83, supra note 1.
86 GRAS Notice No. 83, supra note 1.
87 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 (April 28, 2004 and June
2, 2004).
88 See GRAS Notice No. 83, supra note 1.
89 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.) (October 12, 2005), [http://www.cfsan.fda.gov/
~rdb/opa-g166.html].
90 See listings for GRAS Notifications 188 and 194. Center for Food Safety and Applied
Nutrition, FDA, Numerical Listing of GRAS Notices (October 2007), [http://www.cfsan.fda.
gov/~rdb/opa-gras.html].

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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
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 110th 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).
Both bills propose to amend section 201 of the Federal Food, Drug, and
Cosmetic Act (FFDCA).91 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,92 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.93
91 H.R. 3115, 110th Cong. § 3 (2007); H.R. 3610, 110th Cong. § 14 (2007).
92 See H.R. 3115 § 3(a); H.R. 3610 § 14(a).
93 The statement provided by the bill reads as follows: “Safety Notice: Carbon monoxide has
been used to preserve the color of this product. Do not rely on the 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).

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