[Federal Register Volume 80, Number 116 (Wednesday, June 17, 2015)]
[Notices]
[Pages 34650-34670]
[FR Doc No: 2015-14883]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2013-N-1317]

Final Determination Regarding Partially Hydrogenated Oils

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; declaratory order.

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SUMMARY: Based on the available scientific evidence and the findings of
expert scientific panels, the Food and Drug Administration (FDA or we)
has made a final determination that there is no longer a consensus
among qualified experts that partially hydrogenated oils (PHOs), which
are the primary dietary source of industrially-produced trans fatty
acids (IP-TFA) are generally recognized as safe (GRAS) for any use in
human food. This action responds, in part, to citizen petitions we
received, and we base our determination on available scientific
evidence and the findings of expert scientific panels establishing the
health risks associated with the consumption of trans fat.

DATES: Compliance date: Affected persons must comply no later than June
18, 2018.

FOR FURTHER INFORMATION CONTACT: Mical Honigfort, Center for Food
Safety and Applied Nutrition (HFS-265), Food and Drug Administration,
5100 Paint Branch Pkwy., College Park, MD 20740,<PHONE_NUMBER>, email:
<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
II. Definitions and Scope, and Related Comments With FDA Responses
III. Discussion of Legal Issues, and Related Comments With FDA
Responses
    A. GRAS
    B. Prior Sanctions
    C. Procedural Requirements
IV. Discussion of Scientific Issues, and Related Comments With FDA
Responses
    A. Intake Assessment
    B. Safety
V. Citizen Petitions
VI. Environmental Impact
VII. Economic Analysis
VIII. Compliance Date and Related Comments With FDA Responses
IX. Conclusion and Order
X. References

I. Background

    In accordance with the process set out in Sec.  170.38(b)(1) (21
CFR 170.38(b)(1)), we issued a notice on November 8, 2013 (the November
2013 notice, 78 FR 67169), announcing our tentative determination that,
based on currently available scientific information, PHOs are no longer
GRAS under any condition of use in human food and therefore are food
additives subject to section 409 of the Federal Food, Drug, and
Cosmetic Act (the FD&C Act) (21 U.S.C. 348).
    FDA's evaluation of the GRAS status of PHOs centers on the trans
fatty acid (TFA, also referred to as ``trans fat'') component of these
oils. Although we primarily use the word ``oil'' when discussing PHOs
in this document, partially hydrogenated fats (such as partially
hydrogenated lard), are included within the definition of PHOs
(discussed in section II) and therefore within the scope of this order,
and references to ``oil'' in this document should be read in most cases
to include fats. PHOs are the primary dietary source of industrially-
produced trans fatty acids (Ref. 1). As explained in the tentative
determination (78 FR 67169), all refined edible oils contain some trans
fat as an unintentional byproduct of their manufacturing process;
however, unlike other edible oils, trans fats are an integral component
of PHOs and are purposely produced in these oils to affect the
properties of the oils and the characteristics of the food to which
they are added. In addition, the trans fat content of PHOs is
significantly greater than the amount in other edible oils. Non-
hydrogenated refined oils may contain trans fatty acids as a result of
high-temperature processing, at levels typically below 2 percent (Ref.
2). Low levels (below 2 percent) may also be found in fully
hydrogenated oils (FHOs) due to incomplete hydrogenation (Ref. 3).
Small amounts (typically around 3 percent) may be found in the fat
component of dairy and meat products from ruminant animals (Ref. 4).
    FDA's tentative determination identified the significant human
health risks associated with the consumption of trans fat (78 FR 67169
at 67171). The tentative determination was based on evidence including
results from a number of controlled feeding studies on trans fatty acid
consumption in humans (Refs. 5 and 6), findings from long-term
prospective epidemiological studies (Refs. 5 and 6), and the opinions
of expert panels (Refs. 7, 8, 9, 10, 11, 12, 13, and 14). The latter
included the 2005 recommendation of the Institute of Medicine (IOM) to
limit trans fat consumption as much as possible while consuming a
nutritionally adequate diet, recognizing that trans fat occurs
naturally in meat and dairy products from ruminant animals and that
naturally-occurring trans fat is unavoidable in ordinary, non-vegan
diets without significant dietary adjustments that may introduce
undesirable effects (Ref. 7). In addition, in the tentative
determination FDA cited

a peer reviewed, published estimate of deaths and coronary events that
would be prevented annually in the United States from elimination of
remaining uses of PHOs from the food supply (Ref. 15). Given all this
evidence, we tentatively determined that there is no longer a consensus
among qualified experts that PHOs, the primary dietary source of IP-
TFA, are safe for human consumption, either directly or as ingredients
in other food products.
    PHOs have a long history of use as food ingredients. The two most
common PHOs currently used by the food industry, partially hydrogenated
soybean oil and partially hydrogenated cottonseed oil, are not listed
as GRAS or as approved food additives in FDA's regulations. However,
these and other commonly used PHOs (e.g., partially hydrogenated
coconut oil and partially hydrogenated palm oil) have been considered
GRAS by the food industry based on a history of use prior to 1958. By
contrast, the partially hydrogenated versions of low erucic acid
rapeseed oil (LEAR oil; Sec.  184.1555(c)(2) (21 CFR 184.1555(c)(2))
and menhaden oil (Sec.  184.1472(b) (21 CFR 184.1472(b))) have been
affirmed by regulation as GRAS for use in food. Partially hydrogenated
LEAR oil was affirmed as GRAS for use in food (50 FR 3745 (January 28,
1985)) through scientific procedures. Partially hydrogenated menhaden
oil was affirmed as GRAS for use in food (54 FR 38219 (September 15,
1989)) on the basis that the oil is chemically and biologically
comparable to commonly used partially hydrogenated vegetable oils such
as corn and soybean oils. FDA believes that partially hydrogenated LEAR
and menhaden oils are not currently widely used by the food industry.
We plan to amend these regulations in a future rulemaking.
    In the November 2013 notice, FDA requested additional data and
scientific information related to our tentative determination and, in
particular, requested comment on several questions (78 FR 67169 at
67174). Interested persons were originally given until January 7, 2014,
to comment on the notice. However, in response to several requests, we
extended the comment period to March 8, 2014 (78 FR 79701 (December 31,
2013)).
    We received over 6000 comments in response to the November 2013
notice announcing our tentative determination, including over 4500 form
letters. In addition to submissions from individuals, we received
comments from industry and trade associations, consumer and advocacy
groups, health professional groups, and state/local governments. Most
comments generally supported the tentative determination or supported
aspects of it. FDA also received numerous comments stating that
although they agreed with FDA's efforts to further reduce trans fat in
the food supply, they disagreed with our tentative determination
regarding the GRAS status of PHOs. Of the comments that objected to the
tentative determination, many disagreed with FDA's scientific analysis
and offered alternative approaches to address trans fat in the food
supply. Some comments addressed issues outside the scope of the
tentative determination (such as disruptions to trade, taxation of
foods, and requests for bans on other substances) and were not
considered. We reviewed all comments that were submitted to the docket
before arriving at the decision outlined in this order.
    We have arranged comments and our responses by topic throughout the
remainder of this document. To make it easier to identify the comments
and our responses, the word ``Comment,'' in parentheses, appears before
the comment's description and the word ``Response,'' in parentheses,
appears before FDA's response. Each comment is numbered to help
distinguish between different comments. The number assigned to each
comment is purely for organizational purposes and does not signify the
comment's value or importance.
    The major provisions of this order are:
     PHOs are not GRAS for any use in human food.
     Any interested party may seek food additive approval for
one or more specific uses of PHOs with data demonstrating a reasonable
certainty of no harm of the proposed use(s).
     For the purposes of this declaratory order, FDA is
defining PHOs as those fats and oils that have been hydrogenated, but
not to complete or near complete saturation, and with an iodine value
(IV) greater than 4.
     FDA is establishing a compliance date of June 18, 2018.

II. Definitions and Scope, and Related Comments With FDA Responses

    (Comment 1) Some comments requested that we define PHOs and clearly
delineate them from FHOs. The comments suggested various parameters for
defining these fats and oils, including setting a specification for
trans fat content (e.g., a percentage) or using iodine value (IV; also
interchangeably called iodine number).
    (Response) FDA agrees with the comments that we should define PHOs
to differentiate them from FHOs, which are outside the scope of this
order. When a fat or oil is hydrogenated, the degree of hydrogenation
can be tailored to obtain the desired properties for the application.
FHOs are produced by allowing the hydrogenation process to proceed to
complete or near complete saturation to obtain a more solid fat. In
practice, the reaction does not proceed to 100 percent completion, even
when producing FHOs, and some degree of unsaturation unavoidably
remains in the final fat or oil. Non-hydrogenated refined fats and oils
generally contain trans fatty acids as an unavoidable impurity as a
result of high-temperature processing, at levels typically below 2
percent (Ref. 2). The IV of a fat or oil is not a direct measure of the
TFA content, but is a measure of the degree of unsaturation. Thus, in a
fat or oil that has been hydrogenated, a low degree of unsaturation
(i.e., a low IV number) will correlate to a low level of TFA. FHOs with
an IV of 4 or less generally contain trans fat at levels similar to
non-hydrogenated refined fats and oils (less than 2 percent). By
contrast, when the hydrogenation process is arrested before near
complete saturation, trans fat content is typically higher, and IV is
typically greater than 4.
    Based on data for FHOs that are currently available on the market,
which are indicative of modern hydrogenation technology (Ref. 16), we
define FHOs for the purposes of this order as fats and oils that have
been hydrogenated to complete or near complete saturation, and with an
IV of 4 or less, as determined by a method that is suitable for this
analysis (e.g., ISO 3961 or equivalent). FHOs are outside the scope of
this order. For the purposes of this order, we define PHOs as fats and
oils that have been hydrogenated, but not to complete or near complete
saturation, and with an IV greater than 4 as determined by a method
that is suitable for this analysis (e.g., ISO 3961 or equivalent).
These definitions will ensure that IP-TFA content in the food supply
will be kept to the minimum amount feasible with current technology,
except as otherwise authorized.
    (Comment 2) We received several comments requesting clarification
on the scope of FDA's tentative determination, including whether it
applies only to PHOs used in human food; whether it applies to
ingredients that contain only naturally occurring trans fat, such as
those ingredients derived from ruminant sources; and whether it applies
to conjugated linoleic acid. We also received a citizen petition
(discussed in section V) raising questions related to partially
hydrogenated methyl ester of rosin.

    (Response) FDA wishes to clarify that this order applies only to
PHOs used in human food, not animal feed, and applies to PHOs used as a
food ingredient, which includes those uses sometimes considered
processing aids or food contact substances (e.g., pan-release agents).
By contrast, the use of PHOs as raw materials used to synthesize other
ingredients is outside the scope of this order. We do not have specific
information on the intake of industrially-produced trans fat from this
source. There is no requirement that materials used to make food
ingredients be GRAS themselves; rather, the resultant food ingredient
must be safe for the intended conditions of use. The use of PHOs as raw
materials to make other food ingredients may result in the
incorporation of industrially-produced trans fats into those
ingredients. When ingredients are synthesized using PHOs, and the
ingredient is being used on the basis of a GRAS self-determination,
reevaluation of such a determination may be appropriate in light of the
health effects from the intake of trans fat that underlie our
determination that PHOs do not meet the GRAS standard.
    This order does not apply to ingredients that contain only
naturally occurring trans fat, such as those ingredients derived from
ruminant sources.
    This order does not apply to the use of conjugated linoleic acid
(CLA) as a food ingredient. CLA does not fit the definition of PHO.
CLAs are a class of fatty acid isomers derived from linoleic acid and
do not contain nonconjugated double bonds in a trans configuration nor
are CLAs triglyceride molecules. On the other hand, PHOs are primarily
mixtures of triglycerides, produced by partial hydrogenation and
include at least one nonconjugated double bond(s) in a trans
configuration (Ref. 16). Considering CLA to be distinct from PHOs is
consistent with how FDA has previously defined trans fatty acids for
nutrition labeling purposes, focusing on the presence of nonconjugated
bond(s) in a trans configuration (see Sec.  101.9(c)(2)(ii) (21 CFR
101.9(c)(2)(ii))).
    This order also does not apply to the use of partially hydrogenated
methyl ester of rosin. Partially hydrogenated methyl ester of rosin
does not fit the definition of PHO. Partially hydrogenated methyl ester
of rosin is composed of resin acids that are chemically and
structurally distinct from fatty acids found in PHOs. Resin acids are
terpene-derived aromatic compounds that do not have long chain fatty
acid components with cis/trans double bonds (Ref. 16).

III. Discussion of Legal Issues, and Related Comments With FDA
Responses

A. GRAS

    Section 409 of the FD&C Act provides that a food additive is unsafe
unless it is used in accordance with conditions set forth in that
section. ``Food additive'' is defined by section 201(s) of the FD&C Act
(21 U.S.C. 321(s)) as any substance the intended use of which results
or may reasonably be expected to result in its becoming a component or
otherwise affecting the characteristics of any food, if such substance
is not GRAS or otherwise excluded from the definition. Certain other
substances that may become components of food are also excluded from
the statutory definition of food additive, including pesticide
chemicals and their residues, new animal drugs, color additives, and
dietary ingredients in dietary supplements (section 201(s)(1) through
(6) of the FD&C Act).
    A substance is GRAS if it is generally recognized, among experts
qualified by scientific training and experience to evaluate its safety,
as having been adequately shown through scientific procedures (or, in
the case of a substance used in food prior to January 1, 1958, through
either scientific procedures or experience based on common use in food)
to be safe under the conditions of its intended use (section 201(s) of
the FD&C Act). However, history of use prior to 1958 is not sufficient
to support continued GRAS status if new evidence demonstrates that
there is no longer a consensus that an ingredient is safe. See Sec.
170.30(l) (21 CFR 170.30(l)) (``New information may at any time require
reconsideration of the GRAS status of a food ingredient.'').
    FDA has defined safe as ``a reasonable certainty in the minds of
competent scientists that the substance is not harmful under the
intended conditions of use'' (Sec.  170.3(i) (21 CFR 170.3(i)), and
general recognition of safety must be based only on the views of
qualified experts (21 CFR 170.30(a)). To establish general recognition
of safety, there must be a consensus of expert opinion regarding the
safety of the use of the substance. See, e.g., United States v. Western
Serum Co., Inc., 666 F.2d 335, 338 (9th Cir. 1982) (citing Weinberger
v. Hynson, Westcott & Dunning, 412 U.S. 609, 629-32 (1973)). General
recognition of safety does not require unanimous agreement. See, e.g.,
United States v. Articles of Drug * * * 5,906 boxes, 745 F.2d 105, 119
n. 22 (1st Cir. 1984); United States v. Articles of Food and Drug
(Coli-Trol 80), 518 F.2d 743, 746 (5th Cir. 1975) (``What is required
is not unanimous recognition but general recognition.''); United States
v. Articles of Drug * * * Promise Toothpaste, 624 F. Supp. 776, at 782-
3 (N.D. Ill. 1985) (``There is nothing in the statute to indicate that
Congress intended `generally recognized' in other than its commonly
understood meaning. The adverb, `generally,' is defined, inter alia, to
mean . . . extensively, though not universally'' (internal quotations
omitted)). Conversely, general recognition of safety does not exist if
there is a lack of consensus among qualified experts that the use of a
substance is safe. See, e.g., Coli-Trol 80, 518 F.2d at 746 (no general
recognition of safety where there was ``no recognition of the safety .
. . of these products at all''); Premo Pharmaceutical Laboratories v.
United States, 629 F.2d 795, 803-4 (2nd Cir. 1980) (``genuine dispute
among qualified experts'' precludes finding of general recognition, and
no general recognition existed as a matter of law where there was a
``sharp difference'' of expert opinion); United States v. Article of
Food * * * Coco Rico, 752 F.2d 11, 15 n 6 (1st Cir. 1985) (substance
was not GRAS as a matter of law based on existence of ``genuine dispute
among qualified experts'' regarding safety of use); Promise Toothpaste,
624 F. Supp. at 783 (court could not conclude whether a ``genuine
dispute'' existed without considering the substance of the experts'
opinions, such that a triable issue of fact existed regarding general
recognition). See also United States v. Articles of Drug * * * 5,906
Boxes, 745 F.2d 105, 119 n. 22 (1st Cir. 1984) (noting certain cases in
which lack of general recognition was established as a matter of law
and others in which there was a triable issue of fact regarding general
recognition).
    Importantly, the GRAS status of a specific use of a particular
substance in food may change as knowledge changes. For example, as new
scientific data and information develop about a substance or the
understanding of the consequences of consumption of a substance
evolves, expert opinion regarding the safety of a substance for a
particular use may change such that there is no longer a consensus that
the specific use is safe. The fact that the status of the use of a
substance under section 201(s) of the FD&C Act may evolve over time is
the underlying basis for FDA's regulation at Sec.  170.38, which
provides, in part, that we may, on our own initiative, propose to
determine that a substance is not GRAS. (See generally 37 FR 6207
(March 25, 1972) (proposal of 21 CFR 121.41, the

predecessor of Sec.  170.38); 37 FR 25705 (December 2, 1972) (issuance
of 21 CFR 121.41); 35 FR 18623 (December 8, 1970) (proposal of 21 CFR
121.3, the predecessor of Sec.  170.30); and 36 FR 12093 (June 25,
1971) (issuance of 21 CFR 121.3)). Further, as stated in section I,
history of the safe use of a substance in food prior to 1958 is not
sufficient to support continued GRAS status if new evidence
demonstrates that there is no longer expert consensus that an
ingredient is safe (Sec.  170.30(l)).
    As noted in section III.A, under section 201(s) of the FD&C Act, a
substance that is GRAS for a particular use in food is not a food
additive, and may lawfully be utilized for that use without FDA review
or approval. Currently, a GRAS determination may be made when the
manufacturer or user of a food substance evaluates the safety of the
substance and the views of qualified experts and determines that the
use of the substance is GRAS. This approach is commonly referred to as
``GRAS self-determination'' or ``independent GRAS determination.''
    Other substances that are GRAS may be identified in FDA regulations
in one of two ways. Following the passage of the 1958 Food Additives
Amendment, we established in our regulations a list of food substances
that, when used as indicated, are considered GRAS. We made clear that
this was not a comprehensive list. This list (commonly referred to as
the ``GRAS list'') now appears at 21 CFR part 182. Thereafter, in 1972,
we established the GRAS affirmation process through which we affirmed,
through notice and comment rulemaking, the GRAS status of particular
uses of certain substances in food. Regulations affirming the GRAS
status of certain substances appear at 21 CFR parts 184 and 186. (As a
general matter, we no longer affirm the GRAS status of substances
through notice-and-comment rulemaking. In April 1997, we proposed to
replace the voluntary GRAS affirmation petition process with a
voluntary GRAS notification program, which would not involve rulemaking
(62 FR 18938 (April 17, 1997)). At the time of the proposal, we
initiated a pilot of the GRAS notification program, which continues to
function. A firm may voluntarily submit information on a GRAS self-
determination to FDA for review through the GRAS notification program,
but is not required to do so.)
    FDA received numerous comments on our tentative determination. Many
related to the GRAS standard and what is needed to demonstrate that a
substance is not GRAS. Many comments agreed with our determination that
there is not a consensus among qualified experts that PHOs are safe for
use in human food. However, there were also many comments that
disagreed with FDA's tentative determination and stated that we did not
adequately demonstrate that PHOs are not GRAS.
    (Comment 3) Some comments stated that FDA must show a ``severe
conflict'' among experts about the safety of a substance in order to
determine that PHOs are not GRAS.
    (Response) FDA disagrees that ``severe conflict'' is the relevant
standard. As discussed in section III.A, general recognition of safety
does not exist if there is a lack of consensus among qualified experts
that the use of a substance is safe. We have considered all available
information and determined that there is no longer a consensus among
qualified experts that PHOs are safe for human consumption. To the
extent there is disagreement among qualified experts about the safety
of PHOs for human consumption, this genuine dispute regarding safety
precludes a finding of GRAS.
    (Comment 4) Some comments focused on the idea that it may be
possible to establish a threshold below which PHOs may be safely used
in the food supply. One comment argued that there is no consensus among
experts that PHOs are unsafe below some low threshold level of use.
    (Response) As discussed later in section IV.B.1, FDA does not agree
that such a threshold has been identified based on the available
science. Importantly, even if such a threshold could be identified,
this alone would not meet the requirement of ``general recognition''
for uses below the threshold without there also being consensus among
qualified experts that uses below the threshold are safe. (See United
States v. 7 Cartons, 293 F. Supp. 660, 663 (S.D. Ill. 1968) (``an
inference that safety might be shown by scientific testing and
procedures'' is insufficient as a matter of law to demonstrate general
recognition of safety), affirmed in relevant part, 424 F.2d 1364 (7th
Cir. 1970).) FDA has no basis to conclude that there is any such
consensus. FDA has previously revoked GRAS status under similar
circumstances (51 FR 25021 at 25023, July 9, 1986; revoking GRAS status
of sulfiting agents on fruits and vegetables intended to be served or
sold raw to consumers; explaining that it was not possible to set a
threshold for safe use based on available information). Moreover, we
need not determine that there is a consensus that low level uses are
unsafe to find that PHOs are not GRAS at low levels; we need only
determine that based on available scientific evidence there is not a
consensus among qualified experts that such uses are safe, as we do
here. We acknowledge that scientific knowledge advances and evolves
over time. We encourage submission of scientific evidence as part of
food additive petitions under section 409 of the FD&C Act for one or
more specific uses of PHOs for which industry or other interested
individuals believe that safe conditions of use may be prescribed. We
are establishing a compliance date of June 18, 2018 for this order to
allow time for such petitions and their review.
    (Comment 5) One comment stated that FDA must demonstrate that each
and every PHO, and every use of PHOs, is not safe.
    (Response) FDA disagrees. FDA need not demonstrate that PHOs are
unsafe to determine that they are not GRAS, only that there is a lack
of consensus among qualified experts regarding their safety. In
addition, our consideration of PHOs as a class is justified because the
available, relevant scientific evidence demonstrates an increased risk
of coronary heart disease (CHD) attributable to trans fat (see section
VI.B); PHOs are the primary dietary source of IP-TFA; and there is a
lack of consensus among qualified experts that PHOs are safe for use in
food at any level.
    (Comment 6) Some comments stated that, by determining that the use
of PHOs are not GRAS because they contain a nutrient that increases
risk of CHD, FDA would be calling into question the regulatory status
of other food sources of trans fat.
    (Response) FDA disagrees. As noted in section II, this order does
not apply to ingredients that contain naturally occurring trans fat
(such as those ingredients derived from ruminant sources), fully
hydrogenated oils, or edible oils that contain IP-TFA as an impurity.
FDA has considered the available information and concluded that there
is a lack of consensus among qualified experts that PHOs, as the
primary dietary source of IP-TFA, are safe for use in human food. We
may determine that the use of an artificial substance is not GRAS
without necessarily making the same determination about naturally-
occurring versions of the substance. (See, e.g., 35 FR 7414 (May 13,
1970) (Rescinding letters that had expressed opinions that certain uses
of glycine and its salts are GRAS, and stating that such added
substances are no longer GRAS in human food); 37 FR 6938 (April 6,
1972) (Amino Acids in Food for Human Consumption; Proposed Conditions
of Safe Use in Food and Deletion From GRAS List) (``[T]he mere natural

presence of an amino acid in unprocessed foods in free or combined (as
protein) form does not qualify it as safe for addition in a pure form
as a component of a formulated or processed food''), 38 FR 20036 (July
26, 1973) (Amino Acids in Food for Human Consumption; Conditions of
Safe Use in Food and Deletion From GRAS List); 47 FR 22545 (May 25,
1982) (Cinnamyl Anthranilate; Proposed Prohibition of Use in Human
Food) (acknowledging ``the presence of other cinnamyl and anthranilate
derivatives naturally in food and in natural substances used to flavor
food'' but proposing to prohibit only cinnamyl anthranilate); 50 FR
42929 (October 23, 1985) (Cinnamyl Anthranilate; Prohibition of Use in
Human Food)).
    (Comment 7) One comment stated that Congress, through the Nutrition
Labeling and Education Act of 1990 (NLEA) (Pub. L. 101-535), prescribed
labeling as the sole vehicle for achieving the nutritional policy
objective of shifting dietary patterns to reduce the risk of
multifactorial chronic diseases such as CHD. The comment argued that
FDA's use of its food additive authority with respect to PHOs and their
effect on risk of CHD is not within FDA's legal authority. Some
comments characterized the tentative determination as a new approach or
a change in interpretation, arguing that FDA has not previously
addressed health concerns related to nutrient intake through the FD&C
Act's food additive provisions. In support of the argument that FDA has
changed its interpretation of the applicability of the food additive
provisions of the FD&C Act, one comment cited a statement by FDA in
rulemaking regarding health claims that ``where the only safety issue
is an increased risk of chronic disease from excessive consumption, the
safety provisions of the act would not provide regulatory sanctions
against such components of food, at least if they have not been added
to foods'' (58 FR 2478 at 2490 (January 6, 1993)).
    (Response) FDA disagrees with these comments. FDA may properly
address such health risks using the food additive authorities in the
FD&C Act (sections 201(s), 409, and 402(a)(2)(C) of the FD&C Act). The
broad language of the food additive definition in section 201(s) of the
FD&C Act covers ``any substance'' added to food, including nutrients.
Nothing in the FD&C Act or its legislative history suggests that the
food additive definition should be interpreted in a way that limits its
applicability as the comment suggests. On the contrary, the legislative
history of the Food Additives Amendment of 1958 (Pub. L. 85-929)
emphasizes the broad applicability of sections 201(s), 409, and
402(a)(2)(C) of the FD&C Act, which apply to ``any substances the
ingestion of which reasonable people would expect to produce not just
cancer but any disease or disability'' (S. Rep. No. 2422, at 11 (1958),
as reprinted in Vol. 14, Legislative History of the Food, Drug &
Cosmetic Act and its Amendments, at 923 (1979)). In fact, we have
previously taken action regarding health risks related to nutrients
using these authorities (55 FR 50777 (December 10, 1990) (determining
certain Vitamin K Active Substances not GRAS); and 38 FR 20036 (July
26, 1973) (establishing conditions of safe use for amino acids for
nutritive purposes and deleting them from GRAS list)). We also have
previously applied these authorities to substances presenting increased
health risks related to chronic multifactorial diseases, such as cancer
(50 FR 42929 (October 23, 1985) (prohibiting use of cinnamyl
anthranilate in food); and 34 FR 17063 (October 21, 1969) (prohibiting
use of cyclamates in food)).
    With respect to the comment citing a statement from a final rule on
health claims, FDA does not agree that this statement shows any change
in FDA's position, as it was explicitly limited to situations that did
not meet the food additive definition because the components discussed
``have not been added to foods.'' The statement is consistent with
FDA's current understanding of the law.
    Moreover, FDA disagrees with the argument that FDA must address
health risks related to PHOs through food labeling requirements rather
than through the food additive provisions of the FD&C Act. The NLEA
amended the FD&C Act to provide, among other things, for certain
nutrients and food components to be included in nutrition labeling.
Section 403(q)(2)(A) and (q)(2)(B) (21 U.S.C. 343(q)(2)(A) and
(q)(2)(B)) of the FD&C Act state that the Secretary of Health and Human
Services (the Secretary) (and, by delegation, FDA) can, by regulation,
add or delete nutrients included in the food label or labeling if he or
she finds such action necessary to assist consumers in maintaining
healthy dietary practices. We have used this authority to require
labeling of trans fat content (68 FR 41434 (July 11, 2003); see also
Sec.  101.9(c)(2)(ii) and Sec.  101.36(b)(2)(i)) (21 CFR
101.36(b)(2)(i)). Although we may further address trans fat through
labeling requirements in the future, labeling is not the only method by
which we may address health risks related to trans fats, and more
specifically health risks related to PHOs, the primary dietary source
of IP-TFA. Nothing in the NLEA suggested that its passage limited the
preexisting food additive provisions in the FD&C Act, or that the food
additive provisions did not apply to nutrients and chronic
multifactorial disease under appropriate circumstances. On the
contrary, as the comment noted, the NLEA contained a clause stating
that ``[t]he amendments made by this Act shall not be construed to
alter the authority of the Secretary of Health and Human Services . . .
under the [FD&C Act]'' (NLEA section 9).
    The FD&C Act's nutrition labeling and food additive provisions are
two different kinds of authority, with different standards, and we may
choose among available approaches to a public health problem when the
FD&C Act provides multiple options. See, e.g., Chevron U.S.A. Inc. v.
Natural Resources Defense Council, 467 U.S. 837, 865-6 (1984) (``While
agencies are not directly accountable to the people, the Chief
Executive is, and it is entirely appropriate for this political branch
of the Government to make such policy choices--resolving the competing
interests which Congress itself either inadvertently did not resolve,
or intentionally left to be resolved by the agency charged with the
administration of the statute in light of everyday realities''); United
States v. Mead Corp., 533 U.S. 218, 227 (2001) (``agencies charged with
applying a statute necessarily make all sorts of interpretive
choices''). There is no ``conflict'' between the FD&C Act's nutrition
labeling provisions and food additive provisions as the comment
suggests. It is also worth noting that we have previously determined
that a use of a substance is not GRAS while rejecting a labeling-based
approach to the health risks presented by that use (51 FR 25021 (July
9, 1986) (final rule revoking GRAS status of sulfiting agents on fruits
and vegetables intended to be served or sold raw to consumers); and 50
FR 32830 (August 14, 1985) (proposal to revoke GRAS status of sulfiting
agents on fruits and vegetables intended to be served or sold raw to
consumers)).
    (Comment 8) Some comments stated that the expert panels we cited in
the tentative determination (i.e., the Institute of Medicine/National
Academy of Sciences (IOM/NAS), American Heart Association, American
Dietetic Association, World Health Organization, Dietary Guidelines
Advisory Committee, and the FDA Food Advisory Committee Nutrition
Subcommittee) were not experts qualified by scientific training and
experience to evaluate the safety of substances in food. The comments
also

stated that these expert panels were not convened for the purposes of
evaluating the safety of PHOs and did not make determinations regarding
the GRAS status of PHOs. Therefore, the comments argued that the
conclusions of these panels do not demonstrate a lack of consensus
among qualified experts that PHOs are GRAS.
    (Response) FDA disagrees with these comments. The expert panels we
cited were composed of scientists qualified by relevant training and
experience to review literature on trans fat consumption, because of
their nationally recognized and established expertise in the area of
food and nutrition. For example, the Food and Nutrition Board at IOM/
NAS is a recognized national resource for recommendations on health
issues, and the Dietary Guidelines Advisory Committee members are
nationally recognized experts in nutrition and health. These panels'
evaluations and conclusions raised significant questions about the
safety of trans fat, thus showing that there is no consensus among
qualified scientific experts that PHOs are safe, because PHOs are the
primary dietary source of IP-TFA. The safety information reviewed by
the panels is further discussed in section IV.B.2. We consider that the
conclusions of the panels demonstrate that there is a ``lack of the
proper reputation . . . for safety of the food additive among the
appropriate experts.'' Coli-Trol 80, 518 F.2d at 746. Further, whether
the panels were convened specifically to make a GRAS determination is
irrelevant; the purpose of the panels was to review the available data
on health risks associated with consumption of trans fat. Moreover, the
expert panel conclusions are not the only evidence upon which we rely
for this determination, and conclusions of an expert panel are not
required to establish general recognition of safety or its absence.
    (Comment 9) Several comments stated that the expert panels we cited
considered nutritional science and not safety.
    (Response) FDA disagrees that the panels were not considering
safety data; panels were considering data from controlled trials and
observational studies on trans fat consumption that showed adverse
effects on risk factors (e.g., effects on cholesterol) and increased
risk of CHD (see section IV.B.2 for further discussion on expert panel
reviews). As discussed in more detail in section III.A, FDA regulations
define ``safe'' as ``a reasonable certainty in the minds of competent
scientists that the substance is not harmful under the intended
conditions of use'' (Sec.  170.3(i)), and data showing a potential
relationship between a nutrient (or any other substance added to food)
and disease are safety data. Studies reviewed by expert panels showed
that trans fatty acids cause significant health risks. Such studies are
safety data.
    (Comment 10) One comment stated that FDA should hold the
manufacturer initially introducing the food or ingredient into
interstate commerce responsible for compliance with a determination
that PHOs are not GRAS, and that distributors should not be responsible
for determining whether foods they merely distribute contain PHOs.
    (Response) Although we are mindful of the need to focus our
enforcement efforts, those needs do not change the underlying law or
FDA's legal authority. Food that is adulterated may be subject to
seizure and distributors, manufacturers, and other parties responsible
for such food may be subject to injunction. We recognize that
manufacturers who have previously added PHO to food, rather than other
parties such as distributors who merely receive and sell finished
foods, are the members of the food industry who will be most directly
affected by this order, and we intend to focus our outreach and
enforcement resources accordingly. However, we remind distributors and
other members of the food industry that they have an obligation to
ensure that the food they manufacture, distribute, sell, or otherwise
market complies with the FD&C Act.
    (Comment 11) Some comments requested that FDA take a position
regarding the effect of this order on state and local laws regarding
PHOs.
    (Response) There is no statutory provision in the FD&C Act
providing for express preemption of any state or local law prohibiting
or limiting use of PHOs in food, including state or local legislative
requirements or common law duties. As with any Federal requirement, if
a State or local law requirement makes compliance with both Federal law
and State or local law impossible, or would frustrate Federal
objectives, the State or local requirement would be preempted. See
Wyeth v. Levine, 555 U.S. 555 (2009); Geier v. American Honda Co., 529
U.S. 861 (2000); English v. General Electric Co., 496 U.S. 72, 79
(1990), Florida Lime & Avocado Growers, Inc., 373 U.S. 132, 142-143
(1963); Hines v. Davidowitz, 312 U.S. 52, 67 (1941). We decline to take
a position regarding the potential for implied preemptive effect of
this order on any specific state or local law; as such matters must be
analyzed with respect to the specific relationship between the state or
local law and the federal law. FDA believes, however, that state or
local laws that prohibit or limit use of PHOs in food are not likely to
be in conflict with federal law, or to frustrate federal objectives.

B. Prior Sanctions

    We stated in our tentative determination that we were not aware
that FDA or U.S. Department of Agriculture (USDA) had granted any
explicit approval for any use of PHOs in food prior to the 1958 Food
Additives Amendment to the FD&C Act, and requested comments on whether
there was knowledge of an applicable prior sanction for the use of PHOs
in food (78 FR 67169 at 67174). We received various comments on this
topic. We are not making a determination regarding the existence of any
prior sanctions for uses of PHO in this order. This order is limited to
our determination regarding the GRAS status of PHOs. We intend to
address any claims of prior sanction in a future action.

C. Procedural Requirements

    Under 5 U.S.C. 554(e) (section 5(d) of the Administrative Procedure
Act (APA)), an agency, ``in its sound discretion, may issue a
declaratory order to terminate a controversy or remove uncertainty.''
The APA defines ``order'' as ``the whole or a part of a final
disposition, whether affirmative, negative, injunctive, or declaratory
in form, of an agency in a matter other than rulemaking but including
licensing'' (5 U.S.C. 551(6)). The APA defines ``adjudication'' as
``agency process for the formulation of an order'' (5 U.S.C. 551(7)).
    FDA's regulations, consistent with the APA, define ``order'' to
mean ``the final agency disposition, other than the issuance of a
regulation, in a proceeding concerning any matter . . .'' (Sec.
10.3(a) (21 CFR 10.3(a)). Our regulations also define ``proceeding and
administrative proceeding'' to mean ``any undertaking to issue, amend,
or revoke a regulation or order, or to take or not to take any other
form of administrative action, under the laws administered by the Food
and Drug Administration'' (Sec.  10.3(a)). Moreover, our regulations
establish that the Commissioner may initiate an administrative
proceeding to issue, amend, or revoke an order (21 CFR 10.25(b)).
    FDA's regulations also set forth a process by which we, on our own
initiative or on the petition of an interested person, may determine
that a substance is not GRAS. Specifically, FDA may initiate this
process by issuing

a notice in the Federal Register proposing to determine that a
substance is not GRAS and is a food additive subject to section 409 of
the FD&C Act (Sec.  170.38(b)). The notice must allow a period of 60
days for comment. If, after review of comments, FDA determines that
there is a lack of convincing evidence that a substance is GRAS or is
otherwise exempt from the definition of a food additive in section
201(s) of the FD&C Act, FDA will publish a notice thereof in the
Federal Register (Sec.  170.38(b)(3)). Such a notice ``shall provide
for the use of the additive in food or food contact surfaces as
follows: (1) It may promulgate a food additive regulation governing use
of the additive[;] (2) It may promulgate an interim food additive
regulation governing use of the additive[;] (3) It may require
discontinuation of the use of the additive[;] (4) It may adopt any
combination of the above three approaches for different uses or levels
of use of the additive'' (Sec.  170.38(c)).
    On our own initiative, we began an administrative proceeding to
formulate a 5 U.S.C. 554(e) declaratory order to remove uncertainty
regarding the GRAS status of PHOs. Accordingly, we published a notice
in the Federal Register, consistent with Sec.  170.38(b), communicating
our tentative determination that PHOs are no longer GRAS for any use in
food, and allowed 60 days for comments (78 FR 67169 (November 8,
2013)). We later extended the comment period for an additional 60 days
(78 FR 79701 (December 31, 2013)).
    In the tentative determination, FDA noted that two PHOs had been
affirmed by regulation as GRAS for use in food (78 FR 67169 at 67171;
the partially hydrogenated versions of low erucic acid rapeseed oil
(LEAR oil; Sec.  184.1555(c)(2)) and menhaden oil (Sec.  184.1472(b)).
We also noted that the nature of some of the products for which there
are standards of identity is such that PHOs historically have been used
in their manufacture in conformance with those standards (78 FR 67169
at 67171). However, we also noted that no food standard of identity
requires the use of PHOs and, therefore, industry's ability to comply
with any standard would not be prevented by a change in the regulatory
status of PHOs. As discussed in section III.B, two standards of
identity explicitly mention PHOs in allowing partially hydrogenated
vegetable oil as an optional ingredient; the standards of identity for
peanut butter (Sec.  164.150 (21 CFR 164.150)) and canned tuna (Sec.
161.190 (21 CFR 161.190)). Because these standards do not require the
use of PHOs, industry's ability to comply with them would not be
prevented by a change in the regulatory status of PHOs. In addition,
our labeling regulations explicitly address ingredient designations for
PHOs (Sec.  101.4(b)(14) (21 CFR 101.4(b)(14))).
    This final determination is a 5 U.S.C. 554(e) declaratory order
regarding the status of PHOs. Consistent with Sec.  170.38(b)(3), we
have reviewed the comments received and determined that there is a lack
of convincing evidence that PHOs are GRAS. Thus, consistent with Sec.
170.38(c)(3), we are publishing a notice thereof in the Federal
Register that requires discontinuation of the use of these additives.
Moreover, we are providing advance notice of our intention to undertake
rulemaking with respect to the uses of PHOs explicitly permitted for
use by regulation and other conforming changes.
    (Comment 12) Some comments argued that FDA must determine the GRAS
status of PHOs through notice-and-comment rulemaking.
    (Response) FDA agrees that we must conduct rulemaking to revise
Sec. Sec.  184.1555(c)(2) and 184.1472(b), which explicitly permit the
use of partially hydrogenated LEAR oil and partially hydrogenated
menhaden oil, respectively. FDA will also consider taking further
action to revise regulations regarding the standards of identity for
peanut butter (Sec.  164.150(c)) and canned tuna (Sec.
161.190(a)(6)(viii)), the regulation regarding ingredient designations
for PHOs (Sec.  101.4(b)(14)), and nutrition labeling regulations
regarding trans fats (Sec. Sec.  101.9(c)(2)(ii) and 101.36(b)(2)(i)).
We note that although trans fat does occur naturally in some product
groups such as dairy foods, it is only likely to be present at levels
at or above 0.5 g per serving in products containing PHOs.
    We do not agree that we must determine the GRAS status of PHOs
generally via rulemaking. FDA may properly make such a determination in
an order, as we have chosen to do here. This is not the first time FDA
has issued a declaratory order when determining that a substance is not
GRAS and is a food additive. See 55 FR 50777, 50778 (Declaratory Order
regarding Vitamin K Active Substances in Animal Food, issued under 21
CFR 570.38, the regulation for animal food that parallels Sec.  170.38
for human food).
    We have authority to administer the statutory provisions of the
FD&C Act that are most relevant to this determination, namely, are
sections 201(s), 402(a)(2)(C), and 409 of the FD&C Act. Section 201(s)
of the FD&C Act defines a food additive, in part, as a substance that
is not GRAS, and section 402(a)(2)(C) of the FD&C Act establishes that
food bearing or containing a food additive that is unsafe within the
meaning of section 409 of the FD&C Act is adulterated. Section 409 of
the FD&C Act establishes that a food additive is unsafe for the
purposes of section 402(a)(2)(C) of the FD&C Act (and therefore
adulterated) unless certain criteria are met, such as conformance with
a regulation prescribing the conditions under which the additive may be
safely used. Section 409 of the FD&C Act also sets forth a process by
which we administer the review of food additive petitions and may
establish regulations prescribing conditions of safe use for such
additives. Thus, we have explicit statutory authority to review,
approve, and deny food additive petitions.
    Because it is necessary to determine whether the use of a substance
is GRAS as part of identifying it as a food additive, it is implicit in
this statutory structure that we also have the authority to determine
whether the use of a substance is, or is not, GRAS. The statute does
not explicitly provide the procedure we must use to make such
determinations. Thus, we may choose to use either rulemaking or
adjudication. ``The choice between rule-making or declaratory order is
primarily one for the agency regardless of whether the decision may
affect policy and have general prospective application.'' (See Viacom
v. FCC, 672 F.2d 1034, 1042 (2nd Cir. 1982). See also SEC v. Chenery,
332 U.S. 194, 203 (1947); NLRB v. Wyman-Gordon Co., 394 U.S. 759
(1969); NLRB v. Bell Aerospace Co., 416 U.S. 267, 294 (1974); Almy v.
Sebelius, 679 F.3d 297, 303 (4th Cir. 2012); City of Arlington, Texas
v. FCC, 133 S. Ct. 1863, 1874 (2013); Qwest Servs. Corp. v. FCC, 509
F.3d 531, 536-37 (D.C. Cir. 2007) (``Most norms that emerge from a
rulemaking are equally capable of emerging (legitimately) from an
adjudication, and accordingly agencies have very broad discretion
whether to proceed by way of adjudication or rulemaking'' (internal
citations and quotations omitted)).
    Determining that PHOs are no longer GRAS for use in human food in a
declaratory order issued as a product of informal adjudication is well
within FDA's discretion under the FD&C Act and the APA. Whether PHOs
are GRAS for use in human food is a ``concrete and narrow question[] of
law the resolution[] of which would have an immediate and determinable
impact on specific factual scenarios'' (City of Arlington v. FCC, 668
F.3d 229, 243 (5th Cir. 2012)). (See also Qwest Servs. Corp.,

509 F.3d at 536-37; Chisholm v. FCC, 538 F.2d 349, 364-66 (D.C. Cir.
1976); American Bar Association, A Guide to Federal Agency Adjudication
8 (Jeffrey B. Litwak, ed., 2012) (Agency order to withdraw certain food
from the market, which has particular applicability and future effect,
provided as an example of adjudication)). We are issuing this
declaratory order to remove uncertainty as to the status of PHOs as
food additives. The order is a product of an informal adjudication that
included notice to affected parties via publication of the tentative
determination in the Federal Register and an opportunity for affected
parties to be heard by submitting comments to the Agency. Such
procedures are appropriate for the formulation of declaratory orders.
(See, e.g., Weinberger v. Hynson, Westcott and Dunning Inc., 412 U.S.
609, 626 (1973); American Airlines v. Dep't. of Transportation, 202
F.3d 788, 796-797 (5th Cir. 2000). See also Lubbers, Jeffrey S. and
Blake D. Morant, A Reexamination of Federal Agency Use of Declaratory
Orders, 56 Admin. L. Rev. 1097, 1112-1114 (2004) and cases cited
therein). Moreover, ``adjudicatory decisions are not subject to the
APA's notice-and-comment requirements'' (Blanca Telephone Co. v. FCC,
743 F.3d 860 (D.C. Cir. 2014)).
    Issuance of a declaratory order is also consistent with our
regulations (Sec.  170.38(c)(3)), which provide that we may publish a
notice in the Federal Register that requires discontinuation of the use
of these additives, and do not specify that we must do so through
rulemaking. Notably, other subsections of Sec.  170.38(c) mention
promulgation of regulations, but Sec.  170.38(c)(3), providing for
prohibition of use, does not. Moreover, when we make a determination
under Sec.  170.38 that a substance is not GRAS, we must take one (or a
combination) of the actions listed in Sec.  170.38(c). See
Heterochemical Corp. v. FDA, 741 F. Supp. 382, 384 (E. D. N.Y. 1990).
    The purpose of a declaratory order is ``to develop predictability
in the law by authorizing binding determinations which dispose of legal
controversies without the necessity of any party's acting at his peril
upon his own view'' (U.S. Department of Justice, Attorney General's
Manual on the Administrative Procedure Act (1947) at 59, reprinted in
Federal Administrative Procedure Sourcebook (William F. Funk et al.
ed., ABA Section of Administrative Law and Regulatory Practice 3rd ed.
2000)). Members of industry are not, as some comments suggested, faced
with a choice between complying with a non-binding statement of policy
and facing enforcement action. This is not a statement of policy. This
declaratory order has the force and effect of law.
    (Comment 13) Some comments assumed that this order was a statement
of policy, and, on that basis, argued that this action violates Due
Process requirements.
    (Response) As explained in our response to comment 10, that
assumption is incorrect. Further, FDA's order and the process used in
its formulation raise no Due Process concern.
    (Comment 14) Some comments argued that FDA did not conduct a full
Regulatory Impact Analysis in issuing the tentative determination.
    (Response) As discussed previously in this section, this final
determination is a declaratory order issued as the result of informal
adjudication to remove uncertainty regarding the status of PHOs. We
have prepared a memorandum (Ref. 17) updating our previous estimate of
economic impact published in the November 2013 notice, using
information available to us as well as information we received during
the comment period. See discussion in section VII. Further, we have
stated our intention to conduct rulemaking regarding uses of PHOs in
our existing regulations, and such rulemakings will be subject to the
procedural requirements pertaining to rulemaking.
    (Comment 15) One comment stated that FDA must provide a more
detailed justification for this action than what was provided in the
tentative determination because it is a change in FDA's position
regarding PHOs and industry has a substantial reliance interest in the
GRAS status of PHOs.
    (Response) In the tentative determination (78 FR 67169 at 67172)
and in this order, FDA has explained the factual findings supporting
this action in detail. In section IV.B, we describe how the scientific
evidence, and consensus among qualified experts regarding the safety of
PHOs, has changed over time. We are not changing our interpretation of
the GRAS standard or the relevant regulations. We are determining that
PHOs are no longer GRAS by applying the GRAS standard to current
scientific evidence and the views of qualified experts about the safety
of PHOs. Moreover, reliance interests are implicated whenever FDA makes
a determination that removes a substance from the food supply that has
been previously used in food. FDA is aware of such concerns; however,
the statutory standard for GRAS does not allow FDA to consider the
extent to which industry has relied on GRAS uses of a substance. We
encourage industry to submit food additive petitions under section 409
of the FD&C Act if industry believes that it is possible to establish,
by regulation, safe conditions of use of PHOs. We are establishing a
compliance date of June 18, 2018 for this order to allow time for
submission of such petitions and their review and approval, if
applicable requirements are met.

IV. Discussion of Scientific Issues, and Related Comments With FDA
Responses

A. Intake Assessment

    In the November 2013 notice, we discussed dietary intake of trans
fat from PHOs, estimated in 2010 and updated in 2012 (78 FR 67169 at
67171). The intake assessment was done for four reasons: (1) To
determine the impact of the 2003 labeling rule and subsequent
reformulations; (2) to assist in our review of the citizen petitions,
which are discussed in section V; (3) to consider strategies for
further trans fat reduction, if warranted; and (4) to better understand
the current uses of PHOs and identify products that still contain high
levels of trans fat. Our determination regarding the GRAS status of
PHOs relies on an analysis of whether PHOs meet the GRAS standard based
on available scientific evidence; the intake assessment was not the
basis for this determination.
    In 2012, we estimated the mean trans fat intake from the use of
PHOs to be 1.0 grams per person per day (g/p/d; 0.5 percent of energy
based on a 2,000 calorie diet \1\) for the U.S. population aged 2 years
or more. We also estimated intake for high-level consumers (represented
by intake at the 90th percentile), as well as a ``high-intake''
scenario that assumed consumers consistently chose products with the
highest trans fat levels. We received a number of comments on our
intake assessment, including comments on assumptions, methodology, and
recommendations for future studies.
---------------------------------------------------------------------------

    \1\ (1.0 g/p/d x 9 kcal/g x 100)/2,000 kcal/d = 0.5% of energy.
---------------------------------------------------------------------------

    (Comment 16) One comment challenged FDA's statement that intake of
trans fat did not significantly change between 2010 and 2012. The
comment indicated that the intake of trans fat from the use of PHOs
decreased by roughly 23% in that time period due to significant
reformulation efforts by the food industry.
    (Response) FDA agrees that a comparison of the assessments from
2010 and 2012 demonstrates that reformulation has occurred and intake
has decreased. While the intake estimates did show a 23 percent

decrease in trans fat intake between 2010 and 2012 (1.3 g/p/d to 1.0 g/
p/d), this change is small compared to the 3.3 g/p/d difference between
FDA's intake estimate in the 2003 trans fat labeling final rule of 4.6
g/p/d and the 2010 estimate of 1.3 g/p/d (about a 72 percent decrease).
This was the context for the statement in the tentative determination
that, ``We do not consider this to be a significant change in the
overall dietary intake of trans fat since 2010. However, it suggests a
continued downward trend in the dietary intake of trans fat.''
    (Comment 17) Many comments stated that a substantial number of
products have been reformulated since the 2012 intake assessment and
that we should revise our intake assessment for trans fat before
issuing our final determination on the GRAS status of PHOs.
    (Response) FDA agrees that reformulation efforts by industry are
continuing. However, the 2012 intake assessment was intended to be a
snapshot in time and was based on products containing PHOs that were in
the market at that time, and was done for the reasons described
previously in this section. Given the evidence FDA has reviewed and our
determination that PHOs are not GRAS for any use in human food, an
updated intake assessment for trans fats from PHOs is not needed at
this time. Our determination that PHOs are not GRAS for use in human
food does not rely on the intake assessment.
    (Comment 18) Some comments stated that FDA should not use the
``high intake scenario'' as justification for a determination that PHOs
are not GRAS. Related comments stated that the intake for the highest
level consumers should be determined directly rather than using worst-
case scenario assumptions.
    (Response) FDA disagrees that the high intake assessments provide
justification for our determination regarding the GRAS status of PHOs;
the determination is based on our assessment of whether any use of PHOs
in human food meets the GRAS standard, based on available scientific
evidence. Our determination did not rely on the intake assessment.
    (Comment 19) Several comments stated that FDA's estimate did not
calculate intake from animal products that contain trans fat, and that
FDA should update the intake assessment to include the intake of total
trans fat from both ruminant sources and IP-TFA. The comments noted
this was necessary to understand if dietary recommendations are being
met. One comment indicated that a recent publication suggests that the
intake of trans fat from ruminant sources may be decreasing, thereby
indicating a more inclusive review of dietary intake of trans fat is
warranted. Another comment stated that we did not consider the
cumulative effect of trans fat because it did not present data on
intake from all sources, including ruminant TFA.
    (Response) Our study was designed to assess trans fat intake from
the use of PHOs, because they are the primary source of IP-TFA, and IP-
TFA was the focus of the intake assessment. As stated in our tentative
determination (78 FR 67169 at 67172), the IOM's recommendation is that
trans fat consumption should be kept as low as possible while consuming
a nutritionally adequate diet, recognizing that trans fat occurs
naturally in meat and dairy products from ruminant animals and that
naturally-occurring trans fat is unavoidable in ordinary, non-vegan
diets without significant dietary adjustments that may introduce
undesirable effects. Therefore, our intake assessment focused only on
trans fat from the use of PHOs, the primary dietary source of IP-TFA,
in which trans fat is produced intentionally and is an integral
component.
    (Comment 20) One comment urged FDA to reevaluate the intake of
trans fat using the most recent National Health and Nutrition
Examination Survey (NHANES) data. The comment suggested that the intake
of trans fat would be lower if the more recent NHANES data were used
because the mandatory labeling rule for trans fat became effective on
January 1, 2006.
    (Response) While the 2003-2006 NHANES food consumption data were
used in the 2010 and 2012 intake assessments, the levels of trans fat
in the food products were determined based on products that were
available in the market from 2009 to 2012, therefore capturing trans
fat reductions due to product reformulation as a result of the
regulation in Sec.  101.9(c)(2)(ii) (effective in 2006) requiring
declaration of the trans fat content of food in the nutrition label.
The consumption of products in the food categories in which PHOs are
used would not be expected to change significantly over a few years
because for the most part, foods tend to be commonly consumed with
little or no change in consumption patterns over short periods of time.
Further, we compared the typical intake of trans fat using the 2003-
2006 and 2003-2008 NHANES food consumption data and found that there
were no significant differences in the intakes (Ref. 16).
    (Comment 21) Several comments suggested that using a value of 0.4 g
trans fat per serving for foods that declared 0 g trans fat on the
label, but contained a PHO was an overestimation of intake. One comment
stated that this assumption represents 40% of the estimated daily
intake of 1.0 g/p/d.
    (Response) FDA disagrees with the comments. For most of the food
products that declared 0 g trans fat on the label, but contained a PHO,
a level based on analytical data was used. A value of 0.4 g trans fat/
serving was used for only 2 percent of all of the food codes included
in the intake assessment (Ref. 16). The value of 0.4 g is the amount of
trans fat estimated to be in in the food(s) that corresponds to a given
food code that was used in the intake assessment, and does not
represent a percentage of total estimated intake. As a result, we do
not expect that using a lower value would significantly affect the
overall estimated intake of trans fat from the use of PHOs. The use of
0.4 g trans fat/serving was reserved for those cases where no other
information was available (i.e., analytical data or an appropriate
surrogate). Furthermore, while numerically 0.4 g is 40 percent of 1.0
g, it is not appropriate to compare these two parameters. Many factors
(i.e., the amount of the particular food consumed, the percent of the
population consuming the given food, and the level of trans fat in the
particular food) were used to derive the overall estimated trans fat
intake.
    (Comment 22) One comment suggested that American Oil Chemists
Society (AOCS) methods should be used for the intake assessment instead
of the AOAC method 996.06 since the AOAC method is outdated and has not
undergone validation.
    (Response) FDA disagrees. This AOAC method is widely used by
industry and other international organizations as a method for
determining the trans fat content in food products. Therefore, we
considered the AOAC method to be appropriate for analyzing food samples
for the purposes of our intake assessment. Our choice of the AOAC
method is not intended to imply that industry must use this method to
analyze food products.
    (Comment 23) Two comments indicated that a new intake assessment
should be performed using modeling to explore potential unintended
consequences of decreasing the trans fat intake given the possible
replacements for trans fat (e.g., saturated fat, carbohydrate) and
their impact on CHD risk.
    (Response) The safety of other substances that are possible
replacements for PHOs is outside the scope of this order. However,
although we have not updated the intake

assessment since 2012, we have used this intake assessment to calculate
the expected impact of this order on CHD events, taking into account
possible replacements for PHOs (see section IV.B for detailed
discussion).
    (Comment 24) One comment noted that FDA did not examine the use of
each PHO and the probable consumption of each use.
    (Response) FDA disagrees that we need to examine the intake of each
PHO individually; the intent of the intake estimate was to evaluate the
overall intake of trans fat from the use of all PHOs for the purposes
described previously in this section. Estimating trans fat intake from
individual PHOs would be an impractical undertaking, and was not
necessary for the purposes of the intake assessment.
    (Comment 25) Two comments stated that intake should be evaluated
based on the presumption that all products with PHOs as an ingredient
contain trans fat at a specified level (e.g., 0.2 g/serving or per
reference amount customarily consumed). These comments suggested that
such an assessment could provide support for an alternative approach
such as setting an allowable level of trans fat in foods.
    (Response) Because we have concluded that PHOs are no longer GRAS,
evaluating intake for alternative approaches, such as setting an
allowable level of trans fat in foods, is not planned at this time.

B. Safety

    In the Federal Register of November 17, 1999 (64 FR 62746), we
issued a proposed rule entitled ``Food Labeling: Trans Fatty Acids in
Nutrition Labeling, Nutrient Content Claims, and Health Claims.'' The
proposed rule would require that trans fat content be provided in
nutrition labeling, and concluded that dietary trans fats have adverse
effects on blood cholesterol measures that are predictive of CHD risk,
specifically low-density lipoprotein cholesterol (LDL-C) levels (64 FR
62746 at 62754). In the Federal Register of July 11, 2003 (68 FR
41434), we issued a final rule (the July 2003 final rule) amending the
labeling regulations to require declaration of trans fat content of
food in the nutrition label of conventional foods and dietary
supplements (68 FR 41434). In the July 2003 final rule, we cited
authoritative reports that recommended limiting intake of trans fat to
reduce CHD risk (68 FR 41434 at 41442).
    In the November 2013 notice containing our tentative determination
that PHOs are no longer GRAS for any use in human food, we summarized
findings reported in the literature since 2003, when we had last
reviewed the adverse effects of dietary trans fat in support of the
July 2003 final rule (68 FR 41434 at 41442 through 41449). We noted
that since 2003, both controlled feeding trials and prospective
observational studies published on trans fat consumption have
consistently confirmed the adverse health effects of trans fat
consumption on risk factor biomarkers (e.g., serum lipoproteins
including LDL-C) and increased risk of CHD (78 FR 67169 at 67172). We
describe these two types of studies (controlled feeding trials and
prospective observational studies) in further detail later in this
section. We also cited a variety of different kinds of studies and
review articles showing that, in addition to an increased risk of CHD,
trans fat consumption (and, accordingly, consumption of food products
containing PHOs) has also been connected to a number of other adverse
health effects (id.). These effects included worsening insulin
resistance, increasing diabetes risk, and adverse effects on fetuses
and breastfeeding infants, such as impaired growth.
    Since publication of the November 2013 notice, we re-reviewed key
literature and expert panel reports published since the 1990s on the
relationship between trans fat consumption and CHD risk (Ref. 18). Our
review focused on the two main lines of scientific evidence linking
trans fat intakes and CHD: (1) The effect of trans fat intake on blood
lipids in controlled feeding trials, a type of randomized clinical
trial; and (2) observational (epidemiological) studies of trans fat
intake and CHD risk in populations. Additionally, we reviewed the
conclusions of recent U.S. and international expert panels on the
health effects of trans fat. As summarized in our review memorandum
(Ref. 18), the scientific evidence, including combined analyses of
multiple studies (meta-analyses), supports a progressive and linear
cause and effect relationship between trans fatty acid intake and
adverse effects on blood lipids that predict CHD risk, including LDL-C,
high-density lipoprotein cholesterol (HDL-C) and ratios such as total
cholesterol (total-C)/HDL-C and LDL-C/HDL-C. The observational
(epidemiological) studies demonstrating increased CHD risk associated
with trans fat intake do not prove cause and effect, but the results
are consistent with and supportive of the evidence from controlled
feeding trials of the adverse effect of trans fatty acid intake on
blood lipids that predict CHD risk. The consistency of the evidence
from two different study methodologies provides strong support for the
conclusion that trans fatty acid intake has a progressive and linear
effect that increases the risk of CHD.
    Risk factors are variables that correlate with incidence of a
disease or condition. Risk factors include social and environmental
factors in addition to biological factors. A biomarker is a
characteristic that can be objectively measured and indicates
physiological processes. A risk biomarker or risk factor biomarker is a
biomarker that indicates a risk factor for a disease. In other words,
it is a biomarker that indicates a component of an individual's level
of risk for developing a disease or level of risk for developing
complications of a disease (Ref. 19). LDL-C, HDL-C, total-C/HDL-C ratio
and LDL-C/HDL-C ratio are all currently considered to be risk
biomarkers for CHD (Refs. 19, 20, 21, and 22). LDL-C is a risk factor
biomarker that is also a surrogate endpoint for CHD; a ``surrogate'' is
a validated predictor of CHD and can substitute for actual disease
occurrence in a clinical trial (Refs. 19, 20, and 21). HDL-C, total-C/
HDL-C and LDL-C/HDL-C are recognized as major risk factor biomarkers
that, although they are not validated surrogate endpoints, are
predictive of CHD risk (Refs. 19 and 22).
    Effect of trans fat intake on blood lipids in controlled feeding
trials. In controlled feeding trials, a type of randomized clinical
trial, trans fatty acid intake increased LDL-C (``bad'' cholesterol),
decreased HDL-C (``good'' cholesterol) and increased ratios of total-C/
HDL-C and LDL-C/HDL-C compared with the same amount of energy intake
(calories) from cis-unsaturated fatty acids. Increases in LDL-C, total-
C/HDL-C and LDL-C/HDL-C and decreases in HDL-C are adverse changes with
respect to CHD risk. These adverse effects of trans fat intake on blood
lipids are based on controlled feeding trials, a study design that is
able to reveal cause and effect relationships between changes in trans
fat intake and changes in blood lipids. In addition, increases in CHD
risk with increases in LDL-C also demonstrate cause and effect. As
described in our review memorandum (Ref. 18), combined analyses (meta-
analyses) of multiple controlled feeding trials demonstrate a
progressive and linear relationship between trans fatty acid intake and
adverse effects on blood lipids including LDL-C, HDL-C, total-C/HDL-C
and LDL-C/HDL-C. The meta-analyses describe consistent quantitative
relationships between trans

fat intake and blood lipids and show no evidence of a threshold below
which trans fatty acids do not adversely affect blood lipids.
    Observational (epidemiological) studies of trans fat intake and CHD
risk in populations. Epidemiology is the study of the distribution and
causes of disease in human populations. Analytic epidemiology studies
are those designed to test hypotheses regarding whether or not a
particular exposure is associated with causing or preventing a specific
disease outcome. In prospective observational (cohort) studies,
subjects are classified according to presence or absence of a
particular factor (such as usual dietary intake of trans fat) and
followed for a period of time to identify disease outcomes (such as
heart attack or death from CHD). Strengths of the prospective
observational study design are that the time sequence of exposure and
disease is clearly shown; exposures are identified at the outset of the
study; and measurement of exposure is not affected by later disease
status. Results of four major prospective studies, some with one or
more updates during the followup period, consistently show higher trans
fat intake associated with increased CHD risk. The association is
positive and progressive, with no indication of a threshold. A 2009
meta-analysis of the major prospective studies, based on almost 5,000
CHD events in almost 140,000 subjects, found that each additional 2
percent of energy intake from trans fat increased CHD risk by 23
percent compared with the same energy intake from carbohydrate.
    Conclusions of recent U.S. and international expert panels on the
health effects of trans fat. As described in our review memorandum
(Ref. 18), international and U.S. expert panels, using additional
scientific evidence available since 2002, have continued to recognize
the positive linear trend between LDL-C and trans fat intake and the
consistent association of trans fat intake and CHD risk in prospective
observational studies. The panels have concluded that trans fats are
not essential nutrients in the diet, and have recommended that
consumption be kept as low as possible. Recommendations to avoid
industrial trans fat intake have come from panels with both clinical
and public health focus. Moreover, international and U.S. panels have
expressed concern regarding population mean intakes of industrial trans
fat intakes of 1 percent of energy and lower, recognizing that
subgroups may be consuming relatively high levels.
    Since publication of the November 2013 notice, we also conducted a
systematic search of the peer-reviewed literature published since 2008
and summarized the findings (Ref. 23). The major human health endpoints
evaluated for associations with trans fat intake reported in the
literature included CHD, all-cause mortality, cardiovascular disease
and stroke. Other human health endpoints addressed in our search
included various types of cancer, metabolic syndrome and diabetes, and
adverse effects on fertility, pregnancy outcome, cognitive function,
and mental health. The literature search identified meta-analyses of
published data; quantitative estimations to predict effects of
replacing TFA in commercial products; cross-sectional, case-control and
prospective observational cohort studies; and randomized controlled
trials, including controlled feeding trials. Regarding cardiovascular
diseases, the results of the literature search (Ref. 23) are consistent
with findings discussed in our November 2013 notice (78 FR 67169 at
67172). Findings associated with higher TFA intakes included increased
risk of CHD, adverse effects on biomarkers associated with CHD, and
increased subclinical atherosclerosis. Some recent prospective
observational studies also found associations between increased trans
fat intake and increased risk of stroke, which was a new finding (Refs.
18 and 23). Further understanding of the apparent association between
increased trans fat intake and increased risk of stroke requires
additional research, such as whether the association may differ by age,
sex, aspirin use, geographic region and other risk factors (Refs. 18,
23, and 24). For the association of trans fat intake with other human
health effects, such as various types of cancer, metabolic syndrome and
diabetes, and adverse effects on fertility, pregnancy outcome,
cognitive function and mental health, the literature reports remained
limited or inconclusive.
    Since publication of the November 2013 notice, we also conducted a
quantitative estimate of the potential health benefits expected to
result from removal of IP-TFA from PHOs from the food supply (Ref. 25).
We did this to analyze the expected public health benefit of removing
PHOs from the food supply. We used four methods for estimating changes
in CHD risk likely to result from replacement of IP-TFA: Method 1,
based on effects of TFA on LDL-C, a validated surrogate endpoint
biomarker for CHD, as shown through controlled feeding trials; Method
2, based on effects of TFA on LDL-C plus HDL-C, a major CHD risk factor
biomarker, as shown through controlled feeding trials; Method 3, based
on effects of TFA on total-C/HDL-C plus a combination of emerging CHD
risk factor biomarkers (lipoprotein(a), apolipoproteinB/
apolipoproteinA1 and C-reactive protein), as shown through controlled
feeding trials; and Method 4, based on association of TFA with CHD risk
as shown through prospective observational studies. Methods 1 and 2
were also used by FDA in analyzing the 1999 and 2003 labeling
regulations (64 FR 62746 at 62768 and 68 FR 41434 at 41479) and Methods
3 and 4 were based on published methods (Ref. 26). We estimated the
change in CHD risk using each of these four methods as applied to two
different sets of scenarios for replacement of IP-TFA, as follows.
    In general, fats and oils in foods have carbon chains of various
lengths, with the carbon atoms in these chains connected by single or
double bonds. If the carbon chain contains no double bonds, the fatty
acid is called saturated. If the carbon chain contains a single double
bond, the fatty acid is called monounsaturated, and if the carbon chain
contains two or more double bonds, the fatty acid is called
polyunsaturated. Most naturally-occurring dietary unsaturated fatty
acids have double bonds in a ``cis'' configuration, that is, the two
hydrogen atoms attached to two carbons are on the same side of the
molecule at the double bond. Thus, the major chemical forms of fatty
acids in foods are saturated fatty acids (SFAs), cis-monounsaturated
fatty acids (cis-MUFAs) and cis-polyunsaturated fatty acids (cis-
PUFAs). (By comparison, in a ``trans'' configuration, the hydrogen
atoms attached to the carbon atoms at a double bond are not on the same
side of the double bond). (See definitions in 64 FR 62746 at 62748 to
62749 (November 17, 1999).)
    One set of scenarios focuses solely on IP-TFA and the estimated
change in CHD risk by hypothetically replacing IP-TFA with each of the
major chemical forms of macronutrient fatty acids in foods--i.e., SFAs,
cis-MUFAs or cis-PUFAs. The other set of scenarios focuses not only on
IP-TFA but also on the other fatty acids contained in PHOs. This
hypothetical set of scenarios illustrates the estimated change in CHD
risk with replacing PHOs in the marketplace that contain 20 percent, 35
percent, or 45 percent IP-TFA, with other likely replacement fats and
oils. Therefore, this scenario accounts for not only the replacement of
IP-TFA with macronutrient fatty acids but also the replacement of the
overall fatty acid components (or profiles) of the PHOs with the fatty
acid components (or

profiles) found in the various replacement fats and oils.
    In the first set of scenarios, we assumed that the current mean
intake of 0.5 percent of total daily calories (energy) from IP-TFA
among U.S. adults was replaced by the same percent of energy from three
types of macronutrient fatty acids, cis-mono- or polyunsaturated fatty
acids and saturated fatty acids) (cis-MUFAs, cis-PUFAs, and SFAs). As
measures of risk reduction, we calculated estimated percent changes in
CHD risk and estimated reduction in annual total cases of CHD,
including CHD-related deaths. We based changes in CHD cases and deaths
on a baseline of 915,000 annual new and recurrent fatal and non-fatal
cases of CHD in U.S. adults, with a 41 percent fatality rate (Ref. 27).
    Results showed an estimated reduction in CHD with replacement of
IP-TFA with each of the fatty acids (cis-MUFA, PUFA, or SFA), using
each of the four estimation methods. The estimated decrease in CHD
ranged from 0.1 percent to 6.0 percent. This corresponded to prevention
of 1,180 to 7,510 annual CHD cases, including 490 to 3,120 deaths, in
Method 1 (0.1 percent to 0.8 percent decrease in CHD risk based on LDL-
C), 9,230 to 15,560 cases, including 3,830 to 6,460 deaths, in Method 2
(1.0 percent to 1.7 percent decrease in CHD risk based on LDL-C and
HDL-C), and 18,660 to 54,900 cases, including 7,740 to 22,770 deaths,
in Method 3 (2.0 percent to 2.5 percent decrease in CHD risk using a
combination of biomarkers) and Method 4 (4.2 percent to 6.0 percent
decrease in CHD risk using observed CHD outcomes). Method 4, based on
long-term observations of CHD outcomes in prospective studies, produced
greater reduction estimates in risk than did Methods 1 and 2, which
were based on short-term changes in blood lipid risk factors in
controlled feeding trials. This suggests that there may be additional
mechanisms, besides changes in blood lipids, through which trans fat
consumption contributes to CHD risk. Thus, the adverse effects from
trans fat intake may be greater than predicted solely by changes in
blood lipids. The greater estimated reduction in CHD in Method 3,
compared with Methods 1 and 2, suggests that the emerging risk factor
biomarkers in Method 3 may help to identify additional mechanisms
through which trans fat contributes to CHD risk.
    In the second set of scenarios, we estimated the reduction in risk
by replacing the same 0.5 percent of energy from IP-TFA, along with the
other component fatty acids in three different formulations of PHOs,
with eight alternative fats and oils (soybean oil, canola oil,
cottonseed oil, high oleic sunflower oil, high oleic soybean oil, palm
oil, lard, and butter). This approach covers a range of composition of
replacement fats and oils, from highly saturated (high in SFAs) to
highly unsaturated (high in cis-MUFAs and/or cis-PUFAs), and is based
on that reported in 2009 by Mozaffarian and Clarke as part of the World
Health Organization (WHO) scientific update on trans fatty acids (Refs.
25 and 26). Among the eight fats and oils, soybean oil and cottonseed
oil contain the highest amounts of cis-PUFAs. Canola oil, high oleic
acid sunflower oil, and high oleic acid soybean oil have the highest
amounts of cis-MUFAs. Butter has the highest amount of SFAs; lard and
palm oil are also high in SFAs. We used the same four methods to
estimate risk reduction in this analysis. These calculations take into
account the fatty acid profiles of the replacement fats and oils and
the other fatty acids in the PHOs in addition to IP-TFA.
    Overall, the analysis showed that removing 0.5 percent of energy
from IP-TFA by replacing an example PHO containing 35 percent IP-TFA
with each of eight alternative fats and oils would reduce CHD risk by
0.4 percent to 1.5 percent across the respective replacement fats and
oils using Method 2, 2.3 percent to 3.0 percent using Method 3, and 2.7
percent to 6.4 percent using Method 4. This would correspond to
prevention of 3,900 to 58,210 CHD cases including 1,620 to 23,350 CHD
deaths per year.
    In a few instances, the analysis in the second set of scenarios
estimated that there would be increased CHD risk when examples of PHOs
were replaced entirely with fats or oils high in saturated fat (Ref.
25) using Method 1. This reflects the saturated fatty acids in
alternative fats and oils replacing the cis-unsaturated fatty acids
present in the PHO in addition to IP-TFA. Method 1 alone likely
underestimates the overall change in risk that would result from
replacing PHOs containing IP-TFA because it analyzes only impacts on
LDL-C alone and therefore does not account for the demonstrated adverse
effects of IP-TFA on HDL-C, or the adverse effects of IP-TFA on other
emerging CHD risk factors. Methods 2, 3, and 4 in the second set of
scenarios, which consider other known risk factors as well as LDL-C,
provides a more thorough estimate of risk reduction than considering
only LDL-C in isolation, and leads us to conclude that there would be
an expected benefit to public health from PHO replacement even if PHOs
are replaced by oils high in saturated fat. Consistent with published
analyses, our results show that estimated changes in CHD risk expected
to occur with replacement of PHOs depends on the fatty acid profiles of
both the PHOs and the replacement fats and oils (Refs. 25, 26, and 28).
We also note that research indicates removal of trans fat over the past
decade has generally not been accompanied by extensive increases in
saturated fat (Ref. 29), suggesting that all IP-TFA currently in the
marketplace would not likely be replaced by oils high in saturated fat.
    Among the strengths of our quantitative analyses is the use of
established cause and effect relationships between IP-TFA intakes and
adverse changes in CHD biomarker risk factors, including LDL-C and HDL-
C, derived from high quality, controlled feeding trials. Our
assessments also relied on a set of emerging risk factors for CHD,
including total cholesterol to HDL-C ratios, Apo-lipoprotein B to Apo-
lipoprotein A-I ratios, lipoprotein(a) and C-reactive protein changes
obtained from these same feeding trials. In addition, we relied on
information from direct observations of CHD outcomes associated with
frequent usual intake assessments of trans fatty acids and other
macronutrient fatty acids in meta-analyses of four large cohorts with
long-term followups. These estimates build on the agency's previous
quantitative assessment based on short-term changes in LDL-C and HDL-C
alone (68 FR 41434 at 41466 to 41492).
    We acknowledge that there are always some uncertainties in
assessing risk. The estimates we used were based on 100 percent
replacement of IP-TFA by a group of individual types of fatty acids or
by individual alternative fats and oils, when actual replacement mixes
of fats and oils might vary and individual diets would reflect a
combination of replacement fatty acids and replacement fats and oils.
We assumed a no threshold, linear relationship between changes in IP-
TFA intakes and changes in biomarker risk factors for CHD because
current scientific evidence indicates that the relationship between
trans fatty acid intake and LDL-C, HDL-C and the total cholesterol to
LDL cholesterol ratio is progressive and linear.
    Given these uncertainties, our assessments for the change of CHD
risk at the current U.S. mean daily intake of 0.5 percent of energy
derived from IP-TFA are conservative estimates. The results also
suggest that a small shift to lower CHD risk could prevent large
numbers of annual cases of CHD and CHD-related deaths. The current U.S.

background rates for CHD are already high, with considerable baseline
variability due to abnormal serum lipid profiles in large percent of
U.S. adults (33.5 percent have elevated LDL-C) and other risk factors
for CHD (Ref. 25). More people may be vulnerable to CHD at the current
mean intake of IP-TFA from PHOs than the risk reduction estimates as
discussed above.
    In sum, our quantitative estimates demonstrate that large numbers
of CHD events and deaths may be prevented with the elimination of PHOs.
We also note that our estimates are in line with published results
regarding potential effects of replacing PHOs (Refs. 26 and 28). In
replacing PHOs containing IP-TFA, a more significant reduction in CHD
risk is estimated by replacement with vegetable oils containing higher
amounts of cis-unsaturated fatty acids than with those high in
saturated fatty acids, but we expect a risk reduction even if IP-TFA is
replaced with fats and oils high in saturated fatty acids, based on our
conservative risk estimates using combinations of the four peer-
reviewed methods with two different sets of likely scenarios for IP-TFA
replacement for each method. Additional details of these results, and
results for replacement of example PHOs containing 20 percent IP-TFA
and 45 percent IP-TFA, are provided in our review memorandum (Ref. 25).
    We have also analyzed the comments we received regarding the
scientific basis for our tentative determination in the November 2013
notice. Comments regarding the safety of PHOs that were opposed to our
tentative determination were generally related to one of four subject
areas: (1) Dose-response relationship of trans fat intake and adverse
health effects in human studies and whether there is a threshold below
which intake of trans fats is generally recognized as safe; (2)
reliance on expert panel reports and recommendations; (3) health
benefits and clinical significance of replacements for PHOs; and (4)
alternative approaches. Comments regarding the safety of PHOs that were
in support of our determination raised concerns about other adverse
health effects besides effects on LDL-C, such as adverse effects on
other risk factors for CHD (e.g., HDL-C, total-C/HDL-C ratio, LDL-C/
HDL-C ratio, and other lipid and non-lipid biomarkers), inflammatory
effects, harm to subpopulations, and increased diabetes risk.
1. Dose-Response and Evidence of a Threshold Level
    (Comment 26) A number of comments stated that the studies relied
upon by FDA were not designed to address the impact of lowering TFA
intake below 1% of energy. The comments asserted that although the
expert panel reports state that there is no threshold intake level for
IP-TFA that would not increase an individual's risk of CHD or adverse
effects on risk factors for CHD, a review of the supporting
documentation accompanying the reports does not support this statement;
rather, the comments noted that panel reports indicate that due to the
paucity of evidence in the 0 to 4% energy range, no evidence-based
conclusions could be made.
    (Response) FDA disagrees; the published research described in our
review memorandum (Ref. 18) includes six regression analyses of
controlled feeding trials summarizing the dose-response relationship of
IP-TFA on blood cholesterol levels, published from 1995 to 2010. In
addition, a 2010 meta-analysis included 23 trans fat feeding trials and
28 TFA levels, including a low-dose level of 0.4 percent of energy (or
less than the current mean intake) (Ref. 30). Across these regression
analyses, the reported effect of TFA on LDL-C, a validated surrogate
biomarker that serves as a direct causal link to CHD, was very
consistent and the analyses showed a linear dose-response, with an
increase in LDL-C of about 0.038 to 0.049 millimoles per liter (mmol/L)
for each 1 percent of energy intake from replacement of cis-
monounsaturated fat with trans fat (Table 3 in Ref. 18). The regression
analyses also showed a consistent linear dose response for HDL-C, with
a decrease of about 0.008 to 0.013 mmol/L for each 1 percent of energy
from replacement of cis-monounsaturated fat with trans fat (Table 3 in
Ref. 18). Therefore, we conclude that the available data show that even
at low intake levels (e.g., below 3 percent energy) there is no
identifiable threshold, rather the available data support a conclusion
that IP-TFA causes a linear increase in blood levels of LDL-C, a
validated surrogate biomarker of CHD risk and a linear decrease in
blood levels of HDL-C, a major risk biomarker for CHD. If interested
parties are or become aware of information and data supporting
establishment of a threshold, such information and data could be
submitted to FDA as part of a food additive petition(s) proposing safe
conditions of use for PHOs.
    (Comment 27) Many comments disagreed with our conclusion that there
is a linear relationship between TFA intake and LDL-C at low TFA intake
levels. Some comments stated that we did not establish causality
between low doses of TFA (less than 1% of caloric energy) and increased
CHD risk. Other comments stated that the review of available data shows
that low levels of TFA intake (3% of energy or less) have no effect on
serum LDL-C and total-C levels. Some comments criticized FDA's reliance
on the Ascherio et al. 1999 paper (Ref. 31) and raised issues with this
paper and the linear extrapolation used by the researchers. One comment
suggested that using a different dose-response model is a more
appropriate approach to determine the relationship between PHOs and
LDL-C and HDL-C, rather than defaulting to a linear function, due to
the quantity and type of data available at low intake levels. One
comment stated that, in general, linear regression is an inappropriate
tool to determine a safe or unsafe level of a dietary substance and
questioned the use of low-dose linear extrapolation in this instance.
    (Response) FDA disagrees with these comments. Given that effects of
trans fat on LDL-C have been demonstrated at doses as low as 0.4
percent and 2.8 percent of caloric energy (Table 2 in Ref. 18), FDA
disagrees that there is no evidence of an adverse effect from trans fat
intake below 3 percent of energy. In addition, results of regression
analyses published from 1995 to 2010, including Ascherio et al. 1999
(Refs. 26, 30, 31, 32, 33, and 34), are very consistent regarding the
effect of TFA on serum lipids, thus indicating that the relationship
between TFA intake and CHD risk is progressive and linear with no
evidence of a threshold at which effects would not be expected to
occur. Furthermore, we are not aware of any published study that
supports an abrupt reduction in the adverse effects of TFA across the
relatively narrow intake range of 0 percent to 3 percent of energy nor
are we aware of any published scientific reports that provide a dose-
response model that might reveal a different relationship for TFA
intake and CHD risk that is generally accepted by qualified experts.
FDA is aware of an unpublished meta-regression analysis, including
consideration of the low-intake range (Ref. 35), suggesting that the
data on dietary trans fat intake and changes in LDL-C may fit a dose-
response curve that is non-linear. However, this analysis is neither
published (generally available) nor does it demonstrate a consensus of
expert opinion that the use of PHOs at low levels in food is safe as
required for general recognition of safety.\2\
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    \2\ FDA also reviewed and considered an unpublished report of
this analysis and its executive summary, which were submitted to FDA
with the request that they be kept confidential. FDA is including
these documents in the administrative record for this matter but is
not placing them in the public docket because they are confidential.

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    Further, we did not rely solely on the Ascherio et al. 1999 paper
regarding the effect of IP-TFA intake on serum LDL-C and other lipid
biomarkers. Over time, the number of studies covered by the published
regression analyses or meta-analyses increased from 5 studies and 6 TFA
levels in 1995 (Ref. 32) through 8 studies and 12 TFA levels in 1999
(Ref. 31) to 23 studies and 28 TFA levels in 2010 (Ref. 30). Across
these studies, the reported magnitude of the effect of IP-TFA on LDL-C
and HDL-C levels is very consistent. Furthermore, FDA notes that the
2009 National Research Council report, Science and Decisions: Advancing
Risk Assessment (Ref. 36), describes conceptual models in which low-
dose linearity with no threshold can arise. Absent evidence of a
threshold intake level for TFA that does not increase an individual's
risk of CHD or adverse effects on risk factors for CHD, FDA concludes
that a linear low-dose extrapolation is appropriate for assessing the
dose-response relationship between TFA intake and risk of CHD (as
evidenced by effects on LDL-C, a validated surrogate biomarker for CHD,
and HDL-C, a risk biomarker (Ref. 18)).
    Our conclusion that there is a linear relationship (also known as a
proportional effect, or proportionality) between trans fat intake and
CHD risk is consistent with the body of evidence from controlled
feeding studies on the proportionality of fatty acid intake and blood
lipids, beginning with landmark studies in the 1950s and 1960s (Refs.
18, 37, 38, 39, and 40). Meta-analyses in the 1990s and early 2000s
showed that the proportionality in the earlier landmark studies
extended not only to total cholesterol but to LDL-C, HDL-C, total-C/
HDL-C ratio and LDL-C/HDL-C ratio (Refs. 33, 41, and 42). Authors of a
1992 meta-analysis noted, ``a simple linear model in which diets are
characterized solely by their contents of saturated, monounsaturated
and polyunsaturated fatty acids goes a long way toward predicting group
mean changes in serum lipid and lipoprotein levels'' (Ref. 42). Results
of an early controlled feeding trial of trans fat intake and LDL-C and
HDL-C were questioned because of the high trans fat intake (Ref. 43).
However, when combined with a subsequent study at a lower dose,
preliminary data from these two studies suggested that the effect of
trans fat intake on LDL-C and HDL-C is proportional (Ref. 18).
Subsequent meta-analyses discussed previously supported the linear
proportionality of the data, and the quantitative relationships of
dose-response are very consistent across the analyses (Ref. 18). The
proportional relationship of trans fat intake and blood lipids has also
been repeatedly affirmed by a series of expert panels (Ref. 18).
Therefore, we conclude that the totality of the data supports the
proportionality of changes in trans fat intake and changes in blood
lipids (and therefore, CHD risk) and supports the use of a linear
regression model to describe this relationship.
    (Comment 28) Some comments objected to the approach of ``forcing''
the regression line of the dose-response curve through zero (the
origin), as done by Ascherio et al. 1999 (Ref. 31) and believed this
was not appropriate.
    (Response) FDA disagrees. Whether or not to fix the intercept at
zero depends on the meaning of the data, the research question to be
answered, and the particular study design. (We further discuss the
methodology for the meta-analyses in our review memorandum (Ref. 18)).
In feeding studies where the total energy intake remains the same for
both control and treatment groups, the zero intercept means that, with
zero intake of trans fat, there is no effect of trans fat on (that is,
no change in) the LDL-C, the LDL-C/HDL-C ratio, or other serum lipid
biomarker being studied. This is the one data point that is known to be
true by virtue of the study design, and many analyses using this
approach have been published in peer-reviewed literature (Refs. 30, 31,
32, 44, and 45). In these analyses, the authors calculated the
differences in serum lipid levels between the trans fat diet and the
control diet for each controlled feeding trial, with adjustment for
differences in intake of the other fatty acids between the two diets,
using published dose-response coefficients (Refs. 33 and 42). The serum
lipid and trans fat intake differences for each study were included in
a linear regression model and expressed with respect to a specific
replacement macronutrient (such as cis-monounsaturated fatty acids or
carbohydrate). Therefore, we conclude that it is logical and
appropriate to fit (not ``force'') the regression lines through zero
because a zero change in trans fat intake results in zero change in
blood lipids attributable to trans fat intake.
    (Comment 29) Some comments criticizing our scientific review stated
that prospective observational (epidemiological) studies which we
relied on were not designed to demonstrate a cause and effect
relationship between a substance and a disease, and are subject to
various forms of bias.
    (Response) Although observational studies with long-term followup
do not prove cause and effect, the results are consistent with and
supportive of the conclusions from the controlled feeding trial
evidence discussed previously in this section (which does demonstrate
cause and effect). The consistency of the evidence from two different
study methodologies is strong support for the conclusion that trans
fatty acid intake has a progressive and linear effect that increases
the risk of CHD. Our review memorandum (Ref. 18) provides a summary of
the scientific evidence from the observational studies on the
association of TFA intake and actual CHD outcomes in large populations
and addresses in detail the study designs and adjustments for
confounding variables. There are four major prospective observational
studies (Refs. 46, 47, 48, 49, 50, 51, and 52), some with one or more
updates during the followup period (e.g., the Nurses' Health Study had
followups at 8, 14, and 20 years), that are further discussed in detail
in one of our review memoranda (Ref. 18). These are prospective
(cohort) studies, which is the strongest study design for observational
studies, and the results consistently show that higher trans fat intake
is associated with increased CHD risk. In several studies, not only was
the association of the highest versus lowest level (category) of trans
fat intake with greater CHD risk statistically significant, but also
there was a significant test for linear trend, indicating a positive
and progressive association of trans fat intake with CHD risk (or CHD
deaths) across levels (low, intermediate, or high categories) of intake
(Refs. 46, 48, 49, 50, and 51). In addition to the analysis of trans
fat intake grouped in several levels or categories, in certain studies,
numerical trans fat intake, as a continuous variable, was significantly
associated with CHD risk, again indicating a positive and progressive
association of increased trans fat intake with increased CHD risk
across the range of observed intake (Refs. 49 and 51).
    There are also a number of meta-analyses of the major prospective
studies (Refs. 26, 51, 52, 53, 54, and 55). In a 2009 meta-analysis,
based on almost 5,000 CHD events in almost 140,000 subjects, each
additional 2 percent of energy intake from trans fat increased CHD risk
by 23 percent compared with the same energy intake from carbohydrate
(Ref. 52). The magnitude of the increase in CHD risk associated with
trans fat intake among

meta-analyses has remained consistent over time, including the studies
with additional updates during the followup periods. Further, the
prospective studies measure actual CHD occurrence in large groups of
people over long time periods, and describe all CHD risk associated
with trans fat intake, regardless of the mechanism of action by which
trans fat intake may be associated with CHD (i.e., these studies do not
rely on biomarkers or risk factors but instead measure actual
occurrence of disease). The magnitude of the observed CHD risk from TFA
intake is greater in the prospective observational studies than from
the controlled feeding studies.
    We also reviewed related observational studies of TFA intake and
cardiovascular disease health outcomes that considered all causes of
mortality and cardiovascular disease endpoints other than CHD, as well
as studies that used blood and tissue levels as biomarkers of TFA
intake instead of dietary questionnaires, and retrospective case
control studies (Ref. 18). The results from these studies generally
showed trans fat intake or biomarkers associated with adverse health
outcomes. The consistent findings of adverse health effects of trans
fat from these studies with different methodologies strengthen our
conclusions based on the evidence from the major prospective
observational studies and controlled feeding studies summarized
previously.
    (Comment 30) Several comments cited a 2011 publication by FDA
authors (Ref. 56) as evidence of PHO safety and evidence that a
threshold can be determined below which there is general recognition of
safety. The comments argued that these authors reviewed data from
clinical trials to assess the relationship between trans fat intake and
LDL-C and total-C and that their regression analysis showed no
association between trans fat consumption and either LDL-C or total-C
levels. Also, the comments stated that the authors do not ``force'' the
regression line through zero unlike in the Ascherio et al. 1999 paper,
relied upon by FDA in the tentative determination.
    (Response) FDA disagrees. We note that the authors of this paper
stated that their regression analysis of TFA intake and LDL-C
``supports the IOM's conclusion that any intake level of trans fat
above 0 percent of energy increased LDL cholesterol concentration.''
This paper did not identify a threshold level at which LDL-C began to
increase. The analysis in the paper was limited to validated surrogate
endpoint biomarkers of CHD, total cholesterol and LDL-C, and did not
consider other CHD risk factor biomarkers such as HDL-C, or total-C/
HDL-C or LDL-C/HDL-C ratios. The paper focused on methodology for
attempting to identify a tolerable upper intake level for trans fat.
The appropriateness of fitting the intercept through zero in a
regression analysis depends on the meaning of the data, the research
question to be answered, and the particular study design, and is
discussed further in our response to Comment 28.
    In addition to the feeding trial data discussed in the 2011
publication, the authors of the 2011 paper presented data from
prospective observational studies showing that, compared with the
lowest trans fat intake level, there was a statistically significant
increase in CHD risk at some levels of trans fat intake, but not at
others. Based on this, they stated that, at least theoretically, ``a
threshold level could be identified for trans and saturated fat,'' but
they were not actually able to identify any specific threshold level.
We note that other data from prospective studies that were not
discussed in this paper support the conclusion that there is a direct
and progressive relationship between TFA intake and CHD risk, and no
threshold has been identified. Several studies showed a positive trend
for higher CHD risk with higher intake categories of TFA that was
statistically significant (Refs. 46, 48, 49, 50, and 51) and certain
studies also analyzed numerical TFA intake without using categories
(that is, as a continuous variable) and found a significant positive
linear association of TFA intake with CHD risk across the range of
usual TFA intake levels of participants in the studies (Refs. 49 and
51). These results, not discussed in the paper, are inconsistent with
the existence of a threshold. Therefore, we conclude that there is no
currently identifiable threshold below which there is general
recognition that PHOs may be safely used in human food. However, if
there are data and information that demonstrates to a reasonable
certainty that no harm will result from a specific use of a PHO in
food, that information could be submitted as part of a food additive
petition to FDA seeking issuance of a regulation to prescribe
conditions under which the additive may be safely used in food.
    (Comment 31) Some comments stated that FDA made conclusions that
any incremental increase in trans fat intake increases the risk of CHD
based on endpoints that are not considered validated surrogate
biomarkers for CHD, such as LDL-C/HDL-C ratio in the Ascherio et al.
1999 paper (Ref. 31).
    (Response) We used LDL-C, a validated surrogate endpoint biomarker
for CHD (Ref. 21), as the primary endpoint for evaluating the adverse
effects of IP-TFA intake from PHOs. As discussed previously in this
section, validated surrogate endpoint biomarkers are those that have
been shown to be valid predictors of disease risk and may therefore be
used in place of clinical measurement of the incidence of disease
(Refs. 19 and 20). In addition, we considered the adverse effects of
trans fat intake on other risk factor biomarkers, including HDL-C and
the LDL-C/HDL-C and total-C/HDL-C ratios. In fact, these other risk
factor biomarkers indicate additional adverse effects of IP-TFA, beyond
the primary adverse effect of raising LDL-C. Although these other risk
factor biomarkers are not validated surrogate endpoint biomarkers for
CHD, they raise significant questions about the safety of PHOs and are
therefore relevant to our determination that PHOs are not GRAS. For
example, HDL-C levels have been shown to be a useful predictor of CHD
risk (Refs. 22 and 57). Because it has not been shown that drug therapy
to raise HDL-C decreases CHD in clinical trials, HDL-C is not
considered a validated surrogate endpoint for CHD (Ref. 19). We did not
primarily rely on the relationship between trans fat intake and adverse
effects on HDL-C and CHD risk, we recognize that a relationship is
known to exist and therefore considered it in our analysis. We
discussed this issue in detail in the July 2003 final rule (68 FR at
41434 at 41448 through 41449).
    Recent studies have affirmed HDL-C and total-C/HDL-C ratio as risk
factors that predict CHD (Ref. 18). In a large, pooled meta-analysis of
prospective observational studies, including 3,020 CHD deaths during
1.5 million person-years of followup, each 1.33 unit decrease in the
total-C/HDL-C ratio was associated with a 38 percent decrease in risk
of CHD death (Ref. 22). Each 0.33 mmol/L decrease in HDL-C was
associated with a 61percent higher risk of CHD death. The authors
concluded: ``HDL cholesterol added greatly to the predictive ability of
total cholesterol.'' They stated: ``Higher HDL cholesterol and lower
non-HDL cholesterol levels were approximately independently associated
with lower IHD [CHD] mortality, so the ratio of total/HDL cholesterol
was substantially more informative about IHD mortality than either, and
was more than twice as informative as total cholesterol'' (Ref. 22).
    (Comment 32) One comment stated that safety evaluation of
macronutrients,

such as PHOs, is very complex and requires a far more robust assessment
of the totality of technical and scientific evidence. The comment
criticized FDA for relying on ``an isolated physiological endpoint such
as serum lipoproteins'' as predictive of CHD, and states that this
methodology is not appropriate for a GRAS assessment.
    (Response) FDA disagrees; the results of feeding trials showing
changes in LDL-C, a validated surrogate endpoint biomarker for CHD, and
other risk factor biomarkers, are supported by the results of
observational studies showing actual CHD disease outcomes (heart
attacks and deaths) associated with TFA intake in large populations.
The consistency of the evidence from two different study methodologies
is strong support for the conclusion that trans fatty acid intake has a
progressive and linear effect that increases the risk of CHD. Such
health effects are appropriate for FDA to consider when assessing the
safety of food ingredients.
2. Expert Panel Reviews and Recommendations
    The November 2013 notice discussed expert panel conclusions and
recommendations, including the 2002/2005 IOM reports. The conclusions
and recommendations of this report have since been affirmed by a series
of U.S. and international expert panels. The recent expert panels have
continued to recognize the progressive linear relationship between LDL-
C (increase) and HDL-C (decrease) and trans fat intake, and have
concluded that trans fats are not essential nutrients in the diet and
consumption should be kept as low as possible. We have compiled a
detailed summary of the expert panel reports in a review memorandum
(Ref. 18).
    (Comment 33) Some comments stated that FDA should convene an expert
panel to specifically address whether evidence exists to indicate the
effect of TFA on LDL-C is linear at low intakes (below 3% energy).
Other comments stated that there is consensus among qualified experts
that TFA intake should be less than 1% of energy, and cited expert
panel reviews as evidence. Similar comments stated that PHOs are safe
at current intake levels, and TFA intake is already below levels
recommended by nutrition experts.
    (Response) We decline to convene another expert panel in light of
the substantial evidence available on the adverse effects of consuming
trans fat. FDA notes that a 2013 National Institutes of Health,
National Heart, Lung, and Blood Institute (NIH/NHLBI) expert panel
conducted a systematic evidence review and concluded with moderate
confidence that, for every 1 percent of energy from TFA replaced by
mono- or polyunsaturated fatty acids (MUFA or PUFA), LDL-C decreases by
an estimated 1.5 milligrams per deciliter (mg/dL) and 2.0 mg/dL,
respectively (Ref. 58). The panel also concluded that replacement of
TFA with saturated fatty acids (SFA), MUFA, or PUFA increases HDL-C by
an estimated 0.5, 0.4 and 0.5 mg/dL, respectively. This panel's
conclusions were not limited to a specific TFA dose range and did not
indicate any threshold TFA intake. The conclusions were based on
previously published linear regression analyses (Refs. 26 and 33).
    We also disagree that, based on generally available information,
there is a consensus among qualified experts that trans fats are safe
at some level, and we note that recommendations from expert panels
either: (1) Do not state a recommended level (Ref. 13); or (2)
recommend consideration of further reduction in IP-TFA intake, below
current levels (Refs. 59, 60, 61, and 62). Since 2002, many expert
panels have considered the adverse effects associated with trans fat
consumption. Table 1 provides a list of organizations that have
published reports on trans fat and indicates whether they have
conducted an evidence review and/or made formal intake recommendations
regarding trans fat consumption. The conclusions and recommendations
made by these organizations further demonstrate a lack of consensus
regarding the safety of PHOs, as the primary dietary source of IP-TFA.

                     Table 1--List of Organizations That Have Published Reports on Trans Fat
----------------------------------------------------------------------------------------------------------------
                                                                                Formal trans fat
            Organization                    Report title           Year      Evidence  review        intake
                                                                             and  conclusions    recommendation
----------------------------------------------------------------------------------------------------------------
IOM.................................  Dietary Reference          2002/2005                 X                  X
                                       Intakes for Energy and
                                       Macronutrients (Ref.
                                       7).
European Food Safety Authority,       Opinion on the presence         2004                 X   .................
 Scientific Panel on Dietetic          of trans fatty acids
 Products, Nutrition and Allergies.    in foods and the
                                       effect on human health
                                       of the consumption of
                                       trans fatty acids
                                       (Ref. 63).
FDA Food Advisory Committee,          Subcommittee Meeting,           2004                 X   .................
 Nutrition Subcommittee.               Summary Minutes (Ref.
                                       14).
Dietary Guidelines Advisory           Report of the 2005 DGAC         2005                 X   .................
 Committee (DGAC).                     (Ref. 64).
U.S. Dept. of Health and Human        Dietary Guidelines for          2005  .................                 X
 Services, U.S. Dept. of Agriculture   Americans (Ref. 12).
 (DHHS/USDA).
World Health Organization (WHO).....  Scientific Update on            2009                 X                  X
                                       Trans Fatty Acids
                                       (Ref. 60).
Food and Agriculture Organization,    Background Papers for           2009                 X   .................
 World Health Organization (FAO,       Expert Consultation on
 WHO).                                 Fats and Fatty Acids
                                       in Human Nutrition
                                       (Ref. 59).
FAO, WHO............................  Expert Consultation on          2010                 X                  X
                                       Fats and Fatty Acids
                                       in Human Nutrition
                                       (Ref. 61).
DGAC................................  Report of the 2010 DGAC         2010                 X   .................
                                       (Ref. 65).
DHHS/USDA...........................  Dietary Guidelines for          2010  .................                 X
                                       Americans (Ref. 13).
NHLBI...............................  Evidence Report on              2013                 X   .................
                                       Lifestyles
                                       Interventions to
                                       Reduce Cardiovascular
                                       Risk (Ref. 58).
American College of Cardiology,       Guideline on Lifestyle     2013/2014  .................                 X
 American Heart Association.           Management to Reduce
                                       Cardiovascular Risk
                                       (Ref. 62).
----------------------------------------------------------------------------------------------------------------

3. Safety of Replacements for IP-TFA in PHOs
    (Comment 34) Several comments questioned whether further reductions
in TFA intake will be clinically significant and subsequently affect
public health.
    (Response) Since publication of the November 2013 notice, we have
quantitatively analyzed the public health significance of removing PHOs
from the food supply (Ref. 25), and the results show that removing PHOs
from human food would have an expected positive impact on public
health. We note that further reductions in IP-TFA intake below current
levels may result in small reductions in LDL-C and small improvements
in other biomarkers that may not seem clinically significant for an
individual; however, when considered across the U.S. population, small
reductions in CHD risk would be expected to prevent large numbers of
heart attacks and deaths, as illustrated in FDA estimates (Ref. 25).
Moreover, the 2013 Guideline on Lifestyle to Reduce Cardiovascular Risk
from the American College of Cardiology and the American Heart
Association (Ref. 62) strongly recommends that clinicians advise adults
who would benefit from LDL-C reduction to reduce their percentage of
calories from trans fat (the report notes that the majority of U.S.
adults have one or more risk factors involving abnormal lipids, high
blood pressure or pre-high blood pressure; 33.5 percent of adults have
elevated LDL-C). Therefore, further reduction in IP-TFA intake below
current levels is expected to be clinically significant and to prevent
a large number of heart attacks and deaths in the United States.
    (Comment 35) Some comments stated that the safety implications of
replacing TFA with other nutrients (e.g., saturated fat, unsaturated
fat, carbohydrates) have yet to be determined.
    (Response) We recognize that removing PHOs from the food supply
will result in replacing the IP-TFA from PHOs with other
macronutrients, most likely other fatty acids, but disagree that the
safety implications of these changes have not been considered. The
adverse effect of TFA on LDL-C and other blood lipids and non-lipids
when replacing other macronutrients (such as carbohydrate, saturated
fat and cis-unsaturated fat) was extensively demonstrated in controlled
feeding trials and summarized in regression analyses (Refs. 18, 26, 30,
31, 32, 33, 44, and 45). In prospective observational studies,
reduction in CHD risk was also associated with replacement of TFA with
other macronutrients (Refs. 18 and 49). These analyses, as well as FDA
estimates discussed previously in section IV, demonstrate that
replacement of TFA with other macronutrients is expected to result in
decreased CHD risk.
    We also recognize that replacement of PHOs will result in fatty
acids from other fats and oils replacing not only IP-TFA but also the
other fatty acids in the PHOs, but disagree that the safety
implications of these changes have not been considered. One recent
study estimated the change in CHD risk from changes in blood lipids due
to replacing soybean oil PHOs with application specific oils (Ref. 28).
Results showed that each of the TFA replacement strategies modeled
changed the fatty acid intake profile in a manner predicted to decrease
CHD risk, with differences in the projected decreased risk due to
different replacement oils. Another recent study estimated the effect
of the replacement of three example PHOs with seven replacement fats
and oils, based on changes in blood lipids and non-lipids and other
risk factor biomarkers from controlled feeding trials and on changes in
CHD risk from prospective observational studies (Ref. 26). Results
showed that replacement of PHOs with other fats and oils would
substantially lower CHD risk (Ref. 26). Both studies estimated a
greater reduction in CHD risk with replacement of PHOs with vegetable
oils containing higher amounts of cis-unsaturated fatty acids than with
those high in saturated fat (Refs. 26 and 28). FDA also notes that
replacement of PHOs containing IP-TFA with other fats and oils over the
past decade has not been accompanied by extensive increases in
saturated fat (Ref. 29), which could have diminished the impact of
removing trans fat.
    The safety implications of replacing IP-TFAs in PHOs with other
macronutrients and replacing PHOs containing IP-TFAs with other fats
and oils have been addressed in published studies (Refs. 18, 26, 28,
30, 31, 32, 33, 44, 45, and 49) and are also addressed in our
quantitative estimate of decrease in CHD risk with replacement of IP-
TFA, summarized previously in section IV.B (Ref. 25).
4. Alternative Approaches and Evidence for Safety
    In the tentative determination, we requested data to support other
possible approaches to address the use of PHOs in food, such as setting
a specification for trans fat levels in food (78 FR 67169 at 67174).
    (Comment 36) Several comments proposed that we should limit the
percentage of trans fat in finished foods or oils, or set a threshold
in foods for the maximum grams (g) of trans fat per serving. Some
comments suggested various specification levels ranging from 0.2 to 0.5
g trans fat per serving or as a percentage of total fat in foods or
oils. Another comment urged FDA to establish a reasonable level for
trans fat in food to specifically account for minor uses of PHOs as
processing aids.
    Some comments urged us to declare that certain uses of PHOs in
foods are GRAS, or to issue interim food additive regulations for
specific low level uses. Examples of such uses provided by comments
included emulsifiers, encapsulates for flavor agents and color
additives, pan release agents, anti-caking agents, gum bases, and use
in frostings, fillings, and coatings. The use of PHOs in chewing gum
was specifically noted in some comments as deserving special
consideration due to the claim that there is no meaningful PHO intake
from this use. Several comments suggested we issue interim food
additive regulations that would allow certain uses of PHOs in food,
pending completion of studies evaluating the health effects of low
level consumption of trans fat that reflect current intake levels.
Furthermore, one comment advised that if we decide to treat certain
low-level uses of PHOs as food additives, then the GRAS status for
these uses should not be revoked until a food additive approval is
issued.
    In contrast, we also received numerous comments opposed to
establishing limits of trans fat in foods. Most of these comments noted
that scientific evidence has shown that no amount of trans fat in food
is safe and therefore, supported our tentative determination. One
comment noted that trans fat threshold limits in food would be too
difficult to monitor and enforce, and therefore, should not be
established.