[Federal Register Volume 75, Number 235 (Wednesday, December 8, 2010)]
[Proposed Rules]
[Pages 76526-76571]
[FR Doc No: 2010-30386]

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Part II

Department of Health and Human Services

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Food and Drug Administration

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21 CFR Part 101

Food Labeling; Health Claim; Phytosterols and Risk of Coronary Heart
Disease; Proposed Rule

Federal Register / Vol. 75 , No. 235 / Wednesday, December 8, 2010 /
Proposed Rules

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 101

[Docket Nos. FDA-2000-P-0102, FDA-2000-P-0133, and FDA-2006-P-0033;
Formerly Docket Nos. 2000P-1275, 2000P-1276, and 2006P-0316,
Respectively]

Food Labeling; Health Claim; Phytosterols and Risk of Coronary
Heart Disease

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
the regulation authorizing a health claim on the relationship between
plant sterol esters and plant stanol esters and reduced risk of
coronary heart disease (CHD) for use on food labels and in food
labeling. The agency is taking this action based on evidence previously
considered by the agency, and FDA's own review of data on esterified
and nonesterified plant sterols and stanols (collectively,
phytosterols) \1\ published since the agency first authorized the
health claim by regulation. FDA is also taking these actions, in part,
in response to a health claim petition submitted by Unilever United
States, Inc. The proposal would amend the authorized use of the claim
by modifying the nature of the substances that may be the subject of
the claim for conventional foods to include nonesterified, or free,
phytosterols, by expanding the types of foods that may bear the claim
to include a broader range of foods, by modifying the daily dietary
intake of the substance specified in the claim as necessary for the
claimed benefit, by adjusting the minimum amount of the substance
required for a food to bear the claim, and by making other minor
changes.
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    \1\ The term ``phytosterols'' is used as a collective term for
plant sterols and their hydrogenated stanol forms, whether used in
the free form or esterified with fatty acids. As discussed in more
detail elsewhere in this proposal, phytosterol is a term commonly
used by manufacturers and distributors of these substances.

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DATES: Submit written or electronic comments by February 22, 2011.

ADDRESSES: You may submit comments, identified by Docket Nos. FDA-2000-
P-0102, FDA-2000-P-0133, and FDA-2006-P-0033, by any of the following
methods:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following ways:
     Fax:<PHONE_NUMBER>.
     Mail/Hand delivery/Courier (for paper, disk, or CD-ROM
submissions): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the agency name
and docket numbers for this rulemaking. All comments received will be
posted without change to http://www.regulations.gov, including any
personal information provided. For detailed instructions on submitting
comments and additional information on the rulemaking process, see the
``Comments'' heading of the SUPPLEMENTARY INFORMATION section of this
document.
    Docket: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov and insert the
docket numbers, found in brackets in the heading of this document, into
the ``Search'' box and follow the prompts and/or go to the Division of
Dockets Management (HFA-305), Food and Drug Administration, 5630
Fishers Lane, rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Blakeley Denkinger, Center for Food
Safety and Applied Nutrition (HFS-830), 5100 Paint Branch Pkwy.,
College Park, MD 20740,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
II. Petition and Grounds for Amending the Health Claim on Plant
Sterols/Stanols and CHD
III. Eligibility for a Health Claim/Overview of Data
IV. Review of the Preliminary Requirements
V. Proposed Modifications to Current Sec.  101.83
    A. Nature of the Substance
    1. Esterification
    2. Mixtures of Plant Sterols and Plant Stanols
    3. Sources of Phytosterols
    4. Designation of Substance as Phytosterols
    5. Determining the Amount and Nature of the Substance
    B. Nature of the Claim
    1. Effective Cholesterol-Lowering Daily Dietary Intake
    2. Servings per Day
    3. Consuming Phytosterols With Meals
    C. Nature of the Food Eligible to Bear the Claim
    1. Qualifying Amount of Phytosterols per Serving
    2. Nature of the Food
    a. Conventional foods
    b. Dietary supplements
    3. Other Requirements
    a. Disqualifying total fat level
    b. Low saturated fat and low cholesterol criteria
    c. Trans fat considerations
    d. Minimum nutrient contribution requirement
    D. Model Claims
    E. Cautionary Statements
    F. Status Under Section 301(ll) of Foods Containing
Nonesterified and Esterified Phytosterols
VI. Enforcement Discretion
VII. Environmental Impact
VIII. Analysis of Economic Impacts--Preliminary Regulatory Impact
Analysis
    A. Need for the Rule
    B. An Overview of the Changes in Behavior From the Regulatory
Options
    C. Costs of Option 2 (the Proposed Rule)
    D. Benefits of Option 2 (the Proposed Rule)
    1. The importance of the health risk addressed by the claim
    2. The benefits model
    3. The increase in dietary intake of phytosterols
    E. Costs and Benefits of Option 3
    F. Costs and Benefits of Option 4
IX. Small Entity Analysis (or Initial Regulatory Flexibility
Analysis)
X. Paperwork Reduction Act of 1995
XI. Federalism
XII. Comments
XIII. References

I. Background

    The Nutrition Labeling and Education Act of 1990 (NLEA) (Pub. L.
101-535) amended the Federal Food, Drug, and Cosmetic Act (the act) in
a number of important ways. The NLEA clarified FDA's authority to
regulate health claims on food labels and in food labeling by amending
the act to add section 403(r) to the act (21 U.S.C. 343(r)). Section
403(r) of the act specifies, in part, that a food is misbranded if it
bears a claim that expressly or by implication characterizes the
relationship of a nutrient to a disease or health-related condition
unless the claim is made in accordance with section 403(r)(3) (for
conventional foods) or 403(r)(5)(D) (for dietary supplements).
    The NLEA directed FDA to issue regulations authorizing health
claims (i.e., labeling claims that characterize the relationship of a
nutrient to a disease or health-related condition) for conventional
foods only if the agency determines, based upon the totality of
publicly available scientific evidence (including evidence from well-
designed studies conducted in a manner that is consistent with
generally recognized scientific procedures and principles) that there
is significant scientific

agreement (SSA), among experts qualified by scientific training and
experience to evaluate such claims, that the claim is supported by such
evidence (21 U.S.C. 343(r)(3)(B)(i)). Congress delegated to FDA the
authority to establish the procedure and standard for health claims for
dietary supplements (21 U.S.C. 343(r)(5)(D)).
    FDA issued regulations establishing general requirements for health
claims in labeling for conventional foods on January 6, 1993 (58 FR
2478). Among the regulations issued under that final rule were: (1)
Section 101.14 (21 CFR 101.14), which sets out the rules for the
authorization of health claims by regulation based on significant
scientific agreement, and prescribes general requirements for the use
of health claims; and (2) section 101.70 (21 CFR 101.70), which
provides a process for petitioning the agency to authorize health
claims about the substance-disease relationship and sets out the types
of information that any such petition must include. Each of these
regulations became effective on May 8, 1993. On January 4, 1994 (59 FR
395), FDA issued a final rule applying the requirements of Sec. Sec.
101.14 and 101.70 to health claims for dietary supplements.
    On February 1, 2000, Lipton, a subsidiary of Unilever United States
Inc. (Unilever), submitted to FDA a health claim petition (Docket No.
FDA-2000-P-0102 (formerly Docket No. 2000P-1275)) seeking authorization
of a claim characterizing a relationship between consumption of plant
sterol esters and the risk of CHD. The petition limited its request to
health claims in the labeling of spreads and dressings for salad \2\
containing at least 1.6 gram (g) of plant sterol esters per reference
amount customarily consumed (RACC) and the risk of CHD. On February 15,
2000, McNeil Consumer Healthcare (McNeil) submitted to FDA a health
claim petition (Docket No. FDA-2000-P-0133 (formerly Docket No. 2000P-
1276)) requesting that the agency authorize a health claim
characterizing the relationship between plant stanol esters and the
risk of CHD. Both petitioners requested that FDA exercise its authority
under section 403(r)(7) of the act to make any authorizing regulation
effective on publication, pending consideration of public comment and
publication of a final rule.
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    \2\ The agency is using the term ``dressings for salad''
throughout this document in lieu of the term ``salad dressing'' used
by the petitioners because the standard of identity for ``salad
dressing'' in Sec.  169.150 (21 CFR 169.150) refers to a limited
class of dressings for salad, i.e., those that contain egg yolk and
meet certain other specifications and resemble mayonnaise type
products. ``Salad dressing'' as defined in Sec.  169.150 does not
include a number of common types of dressings for salad, such as
Italian dressing.
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    On September 8, 2000 (65 FR 54686),\3\ the agency issued an interim
final rule (IFR) in response to these two health claim petitions to
provide for health claims on the relationship between plant sterol/
stanol esters and the reduced risk of CHD (codified in Sec.  101.83 (21
CFR 101.83)). FDA concluded that, based on the totality of the publicly
available scientific evidence, there was significant scientific
agreement among qualified experts that a health claim for plant sterol/
stanol esters and a reduced risk of CHD was supported by such evidence
(65 FR 54686 at 54700).
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    \3\ A correction notice published in the Federal Register on
November 24, 2000 (65 FR 70466).
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    Specifically, the agency determined that there is significant
scientific agreement that diets that include plant sterol esters and
plant stanol esters may reduce the risk of CHD. FDA found that high
blood (serum or plasma) total and low density lipoprotein (LDL)
cholesterol are major modifiable risk factors in the development of
CHD. The agency determined that the scientific evidence established
that including plant sterol and plant stanol esters in the diet helps
to lower blood total and LDL cholesterol levels.
    Current Sec.  101.83 now provides for a health claim on the label
or labeling of a food meeting certain criteria provided the claim among
other things: (1) States that plant sterol and plant stanol esters
should be consumed as part of a diet low in saturated fat and
cholesterol, (2) uses the term plant (or vegetable oil) sterol esters
or plant (or vegetable oil) stanol esters, (3) specifies that the daily
dietary intake necessary to reduce the risk of CHD is 1.3 g or more for
plant sterol esters or 3.4 g or more for plant stanol esters, (4)
specifies the contribution a serving of the product makes to the daily
dietary intake level, and (5) specifies that the daily dietary intake
of plant sterol or stanol esters should be consumed in two servings
eaten at different times of the day with other foods.
    The IFR was effective upon publication on September 8, 2000, with a
75-day comment period that closed on November 22, 2000. On June 6,
2001, the agency issued a notice of an extension of the period for
issuance of a final rule (66 FR 30311). In this notice, the agency
stated that, due to the complexities of the issues involved and the
lack of agency resources, the agency would be unable to issue a final
rule within the prescribed 270 days from date of publication of the
IFR.
    After the comment period had closed, the agency received two
requests to extend the comment period. Because several additional
substantial issues had been raised in these comments, FDA reopened the
comment period on October 5, 2001 (66 FR 50824). The agency
specifically requested comment on the following: (1) The eligibility of
nonesterified (free) plant sterols and plant stanols to bear a health
claim, (2) daily intake levels necessary to reduce the risk of CHD, (3)
the eligibility of mixtures of plant sterols and plant stanols to bear
a health claim, (4) the significance of serum apolipotrotein B
concentration as a surrogate marker for CHD risk, and (5) issues
regarding safe use of plant sterol and stanols in foods and the
necessity of an advisory label statement.
    On February 14, 2003, FDA issued a letter announcing its intentions
to consider the exercise of enforcement discretion, pending publication
of the final rule, with respect to certain requirements of the health
claim (Ref. 1). Under the conditions of the letter, FDA said it would
consider enforcement discretion if: (1) The food contains at least 400
milligrams (mg) of phytosterols per RACC; (2) mixtures of phytosterol
substances (i.e., mixtures of sterols and stanols) contain at least 80
percent beta-sitosterol, campesterol, stigmasterol, sitostanol, and
campestanol (combined weight); (3) the food meets the requirements of
Sec.  101.83(c)(2)(iii)(B), (c)(2)(iii)(C), and (c)(2)(iii)(D); \4\ (4)
products containing phytosterols, including mixtures of sterols and
stanols in esterified or nonesterified forms, use a collective term in
lieu of the terms required by Sec.  101.83(c)(2)(i)(D) \5\ in the
health claim to describe the substance (e.g., ``plant sterols'' or
``phytosterols''); (5) the claim

specifies that the daily dietary intake of phytosterols that may reduce
the risk of CHD is 800 mg or more per day, expressed as the weight of
nonesterified phytosterol; (6) vegetable oils for home use that exceed
the total fat disqualifying level bear the health claim along with a
disclosure statement that complies with Sec.  101.13(h) (21 CFR
101.13(h)); \6\ and (7) use of the claim otherwise complies with Sec.
101.83.
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    \4\ Section 101.83(c)(2)(iii)(B)--The food must be ``low in
saturated fat'' and ``low in cholesterol'' as defined in Sec.
101.62 (21 CFR 101.62); Sec.  101.83(c)(2)(iii)(C)--the food must
meet the limits for total fat in Sec.  101.14(a)(4) (e.g., for
individual foods, 13.0 g fat per RACC, per labeled serving and if
the RACC is 30 g or less or 2 tablespoons or less, per 50 g) except
that spreads and dressings for salad are not required to meet the
limit per 50 g if the label of the food bears a disclosure statement
per Sec.  101.13(h) (e.g., ``See nutrition information for fat
content''); and Sec.  101.83(c)(2)(iii)(D)--the food must meet the
minimum nutrient contribution requirement in Sec.  101.14(e)(6)
(e.g., except for dietary supplements, the food contains 10 percent
or more of the Daily Value of vitamin A, vitamin C, iron, calcium,
protein, or fiber per RACC prior to any nutrient addition) unless it
is a dressing for salad.
    \5\ The IFR required that the substance for the claim be
specified as ``plant sterol esters'' or ``plant stanol esters''
except that if the sole source of the substance was vegetable oil,
the terms ``vegetable oil sterol esters'' or ``vegetable oil stanol
esters'' may be used.
    \6\ E.g., ``See nutrition information for fat content.''
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II. Petition and Grounds for Amending the Health Claim on Plant
Sterols/Stanols and CHD

    In response to the IFR, and the October 5, 2001 (66 FR 50824),
reopening of the comment period, the agency received approximately 37
comments from a variety of sources. These comments came from
professional organizations, industry, consumer groups, health care
professionals, academia, and research scientists. The majority of the
comments supported authorization of the health claim for phytosterol
esters and CHD but requested modification of one or more provisions.
    The agency has conducted an extensive re-evaluation of the
scientific evidence regarding the relationship between consumption of
phytosterols and the risk of CHD. This re-evaluation focused primarily
on evidence from intervention studies that address the specific
amendments that are being considered in this proposed rule. (These
studies are summarized in Tables 1 and 2 at the end of this document
and are discussed below.) FDA's process for this re-evaluation took
into consideration all available scientific evidence of which FDA was
aware and was consistent with FDA evidence-based review approach to
health claims (Ref. 2).
    The more recent scientific evidence affirms the agency's conclusion
regarding the validity of the relationship between consumption of
phytosterol esters and a risk of CHD under the SSA standard. FDA has no
reason at this time, based on either public comment or on currently
available scientific evidence, to reconsider that basic conclusion. The
re-evaluation, however, did cause the agency to reconsider the scope of
the substances eligible for the health claim and the requirements for
use of the health claim in the labeling of food.
    Based on evidence from those intervention studies, and in light of
the comments received in response to the IFR, the agency has determined
that current Sec.  101.83 should be amended to reflect the current
state of the science under the SSA standard. Because the agency has not
provided a formal opportunity for public comment on the modifications
proposed to current Sec.  101.83, and because of the time that has
elapsed since publishing the IFR, the agency has decided to issue a
proposed rule to amend current Sec.  101.83 rather than finalizing,
with modification, the IFR. This approach provides an opportunity for
public comment prior to issuance of the final rule.
    On May 5, 2006, Unilever submitted a health claim petition under
section 403(r)(4) of the act (Docket No. FDA-2006-P-0033 (formerly
Docket No. 2006P-0316)). The petition requested that FDA amend Sec.
101.83 to permit use of the health claim for phytosterols in a food
that provides the full daily intake in a single serving. On August 18,
2006, FDA notified the petitioner that it had completed its initial
review of the petition and that the petition had been filed for further
action in accordance with section 403(r)(4) of the act. The agency is
issuing this proposed rule, in part, in response to Unilever's
petition.

III. Eligibility for a Health Claim/Overview of Data

    FDA concluded in the IFR that there was significant scientific
agreement that the consumption of phytosterol esters may reduce the
risk of CHD. FDA's prior evaluation of the scientific evidence to
substantiate a relationship between phytosterols and CHD risk focused
on results from intervention studies designed to investigate the effect
of phytosterol ester consumption on blood total and LDL cholesterol
levels. FDA's evaluation of the scientific evidence to substantiate a
relationship between phytosterol ester consumption and CHD risk
included the review of 20 phytosterol-ester intervention studies that
measured blood (serum or plasma) total or LDL cholesterol levels.
    Since issuance of the IFR, there have been a substantial number of
studies conducted and published on the relationship between esterified
and nonesterified phytosterols and risk of CHD. As part of the re-
evaluation of the scientific evidence, FDA requested the Agency for
Healthcare, Research and Quality (AHRQ) to identify intervention
studies that had been conducted since 2000 on the relationship between
phytosterols and CHD risk. FDA identified additional relevant
intervention studies based on comments submitted in response to the
IFR, the 2001 reopening of the comment period and by conducting its own
literature review. In total, FDA identified 66 intervention studies in
which the cholesterol-reducing effect of conventional foods containing
phytosterols was evaluated. FDA identified seven intervention studies
in which the cholesterol-reducing effect of dietary supplements
containing phytosterols was evaluated. Consistent with FDA's prior
evaluation and its evidence-based review approach to the evaluation of
health claims, the agency recognizes elevated blood (serum or plasma)
total cholesterol and LDL cholesterol levels to be valid surrogate
endpoints for CHD risk (Ref. 3). Although other types of study
endpoints, such as measurement of intestinal absorption of cholesterol,
are useful for examining issues such as mechanism of action, they do
not provide direct evidence of an effect on disease risk.\7\ Thus, FDA
evaluated only intervention studies that used the valid surrogate
endpoints of CHD (i.e., blood total and LDL cholesterol), to evaluate
the potential effects of phytosterol intake on CHD risk. Consistent
with the agency's prior evaluation of phytosterol esters, FDA also
reviewed intervention studies that evaluated the effect of phytosterol
intake in individuals who were generally healthy and not yet diagnosed
with CHD.
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    \7\ Although FDA sought comment on whether use of serum
apolipoprotein B is an appropriate surrogate endpoint for CHD (66 FR
50824 at 50825 and 50826), the agency has concluded that it is not
because it has not been adequately validated.
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    Following FDA's evidence-based review approach to the scientific
evaluation of health claims, the agency excluded intervention studies
that included patients diagnosed with CHD. Of the 66 intervention
studies on conventional foods containing phytosterols identified by
FDA, scientific conclusions could not be drawn from 15 intervention
studies for the following reasons. Five intervention studies did not
include an appropriate control group (Refs. 4, 5, 6, 7, and 8). Without
an appropriate control group, it cannot be determined whether changes
in the endpoint of interest were due to phytosterol consumption or to
unrelated and uncontrolled extraneous factors. Four intervention
studies did not conduct statistical analysis between the control and
treatment group (Refs. 9, 10, 11, and 12). Statistical analysis of the
substance/disease relationship is a critical factor because it provides
the comparison between subjects consuming phytosterols and those not
consuming phytosterols to determine whether there is a reduction of CHD
risk. When statistics are not performed on the specific substance/
disease relationship, it cannot be determined

whether there is a difference between the two groups. Five intervention
studies provided a combination of phytosterols and other food
components (e.g., polyunsaturated oils, soy protein, beta-glucan and
other viscous fibers) that may be beneficial in reducing total and/or
LDL cholesterol levels (Refs. 13, 14, 15, 16, and 17). Therefore, it is
not possible to evaluate the independent relationship between
phytosterols and CHD risk. One study did not provide baseline and post-
study blood total and LDL cholesterol levels, including statistical
data (Ref. 18). Without knowing if baseline and/or post-intervention
total and/or LDL levels were significantly different, it is difficult
to interpret the findings of the intervention. Thus, FDA identified 51
intervention studies from which scientific conclusions could be drawn
about the relationship between phystosterols in conventional foods and
risk of CHD. (These studies are summarized in table 1 at the end of
this document and are discussed below).
    The intervention studies included in this review are studies that
tested phytosterols, derived from either vegetable oils or from tall
oil; \8\ as sterols, their stanol derivatives, or sterol/stanol
mixtures; and used in the form of fatty acid esterified phytosterols or
nonesterified phytosterols. A number of techniques were used to
solublize and disperse nonesterified phytosterols in food (e.g.,
lecithin emulsion, microcrystalline forms, dissolving in heated oil).
The majority of intervention studies used phytosterol-enriched
conventional foods, most frequently margarine-like spreads. A very
limited number of intervention studies provided phytosterols as
ingredients in dietary supplements. With few exceptions, the subjects
were instructed to consume the enriched foods with meals, and either
once a day or up to three times a day. Intake levels in these
intervention studies ranged from 0.45 to 9 g per day, though most
intervention studies added phytosterols to the diet in the range of
about 1 to 3 g per day.\9\ With a few exceptions, the participants in
these intervention studies were moderately hypercholesterolemic. The
results of these intervention studies are consistent with the results
of the intervention studies that had been considered in the IFR in that
consumption of 1 to 3 g of phytosterols per day in phytosterol-enriched
foods resulted in statistically significant reductions (5 to 15
percent) in blood LDL cholesterol levels relative to a placebo control
(see table 1 at the end of this document).
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    \8\ As explained in more detail in section V.A.3 in this
proposed rule, tall oil is the term FDA is using in this proposed
rule to describe the byproducts of the kraft process of wood pulp
manufacture.
    \9\ Weight of phytosterols is represented as nonesterified
sterols and/or stanols. One g of nonesterified stanols is equivalent
to 1.7 g stanol esters. One g of nonesterified sterols is equivalent
to 1.6 g sterol esters.
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    As discussed elsewhere in this proposal, FDA tentatively concludes
that the results of the intervention studies involving the consumption
of dietary supplements containing phytosterols are limited and
inconsistent in demonstrating that such dietary supplements reduce
blood cholesterol levels. The available scientific evidence indicates
that dietary supplements containing phytosterol esters reduce
cholesterol as effectively as conventional foods containing
phytosterols. Although one intervention study showed cholesterol-
lowering efficacy for one formulation of dietary supplement containing
nonesterified phytosterols, there also is evidence that other types of
nonesterified phytosterol formulations were not effective in reducing
cholesterol. We tentatively conclude that the available evidence is
insufficient to establish what factors are key in predicting which
nonesterified phytosterol formulations will be effective and which will
not be when consumed as ingredients in dietary supplements.

IV. Review of the Preliminary Requirements

    A health claim characterizes the relationship between a substance
and a disease or health-related condition (Sec.  101.14(a)(1)). A
substance means a specific food or component of food, regardless of
whether the food is in conventional food form or a dietary supplement.
(Sec.  101.14(a)(2)). To be eligible for a health claim, if to be
consumed at other than decreased dietary levels, the food or food
component must contribute taste, aroma, nutritive value, or some other
technical effect to the food and be safe and lawful under the
applicable safety provisions of the act at levels necessary to justify
the claim (Sec.  101.14(b)(3)).
    As noted in the IFR, CHD is a disease for which the U.S. population
is at risk and it therefore qualifies as a disease for which a health
claim may be made under Sec.  101.14(b)(1) (65 FR 54686 at 54687).
Current Sec.  101.83 authorizes a health claim regarding CHD for two
substances: (1) Plant sterol esters prepared by esterifying a mixture
of plant sterols from edible oils with food-grade fatty acids; the
mixture consisting of at least 80 percent beta-sitosterol, campesterol,
and stigmasterol (combined weight) and (2) plant stanol esters prepared
by esterifying a mixture of plant stanols derived from edible oils, or
from byproducts of the kraft paper pulping process, with food-grade
fatty acids; the mixture consisting of at least 80 percent sitostanol
and campestanol (combined weight) (Sec.  101.83(c)(2)(ii)). The
regulation does not currently authorize health claims for mixtures of
the two substances. Moreover, the regulation requires a health claim
regarding one of the two substances to specify which one is the subject
of the claim (Sec.  101.83(c)(2)(i)(C)).
    For reasons discussed elsewhere in this preamble, FDA is proposing
to amend Sec.  101.83 to expand the substances eligible for the
authorized health claim regarding CHD. Under the proposed amendments,
phytosterols would be the subject of the regulation. As the agency
noted in the IFR, plant sterols occur throughout the plant kingdom and
are present in many edible fruits, vegetables, nuts, seeds, cereals,
and legumes in both nonesterified and esterified forms (65 FR 54686 at
54687 and 54688). As the hydrogenated form of plant sterols, plant
stanols are also present in foods such as wheat, rye, corn, and certain
vegetable oils (65 FR 54686 at 54688). Therefore, phytosterols qualify
as substances for which a health claim may be made under Sec.
101.14(a)(2).
    As was true of phytosterol esters, the scientific evidence suggests
that phytosterols achieve their intended effect by functioning to
assist the digestive process. Upon the same reasoning provided for
phytosterol esters in the IFR, therefore, phytosterols provide
nutritive value through assisting in the efficient functioning of a
classical nutritional process and of other metabolic processes
necessary for the normal maintenance of human existence (see 65 FR
54686 at 54688). Accordingly, the agency concludes that the preliminary
requirement of Sec.  101.14(b)(3)(i) is satisfied.
    Finally, under Sec.  101.14(b)(3)(ii), phytosterols, at levels
necessary to justify the claim, must be safe and lawful under the
applicable food safety provisions of the act. For conventional foods,
this evaluation involves considering whether the substance is generally
recognized as safe (GRAS), listed as a food additive, or authorized by
a prior sanction issued by FDA. (See Sec.  101.70(f).) Dietary
ingredients in dietary supplements are not subject to the food additive
provisions of the act (see section 201(s)(6) of the act (21 U.S.C.
321(s)(6))). Rather, they are subject to the adulteration provisions in
section 402 of the act (21 U.S.C. 342) and, if applicable, the new
dietary

ingredient provisions in section 413 of the act (21 U.S.C. 350b).
    Through the agency's GRAS notification program, FDA has received
numerous submissions from food manufacturers regarding the GRAS status
of phytosterols when used in certain conventional foods at levels
necessary to justify the claim under the proposed amendments to Sec.
101.83. These submissions have included data to support the
manufacturer's self-determinations that phytosterols under the intended
conditions of use identified in the submissions are GRAS.\10\ FDA did
not object to the conclusions in those submissions. The GRAS
submissions include conditions of use for a variety of conventional
foods, but not all conventional foods. The agency has not made its own
determination that phytosterols are GRAS. However, FDA is not aware of
any scientific evidence that phytosterols, whether free or esterified,
would be harmful. For those conventional foods that have been the
subject of a GRAS notification reviewed by FDA with conditions of use
that meet the eligibility criteria for the use of the health claim, and
for which FDA had no further questions, FDA concludes that the
preliminary requirement under Sec.  101.14(b) that phytosterols be safe
and lawful has been met for use in such conventional foods. We note, in
section C.1 of this document, the minimum level of phytosterols
necessary for a food to contain in order to be eligible to bear a claim
is 0.5 g per RACC. Not all conventional foods for which a GRAS
notification for phytosterols was submitted, to which the agency had no
further questions, are under conditions of use in food that would be
consistent with the eligibility requirements for the health claim,
e.g., certain foods may contain phytosterols at a level that is less
than the minimum of 0.5 g per RACC. Such foods would not be eligible to
bear the health claim if the rule is finalized as proposed. The agency
notes that authorization of a health claim for a substance should not
be interpreted as an affirmation that the substance is GRAS.
---------------------------------------------------------------------------

    \10\ See, e.g., GRAS Notification Numbers (GRN) 000039, GRN
000048, GRN 000176, GRN 000177, GRN 000112, GRN 000181, GRN 000053,
and GRN 000206).
---------------------------------------------------------------------------

    FDA has also received new dietary ingredient (NDI) notifications,
under section 413(a)(2) of the act, for the use of plant stanol esters
(Ref. 19) and for all plant sterols derived from tall oil (Ref. 20) as
dietary ingredients.\11\ In FDA's judgment, the data submitted with
these NDIs, considered in combination with the GRAS notifications it
has also received for phytosterols in conventional foods, provide an
adequate basis to conclude that a dietary supplement containing
phytosterol esters would reasonably be expected to be safe. Therefore,
FDA concludes that the preliminary requirement under Sec.  101.14 that
the use of phytosterols in dietary supplements be safe and lawful is
satisfied. However, the agency notes that the authorization of a health
claim for phytosterol esters in dietary supplements does not relieve
manufacturers and distributors of such products from ensuring that
their products are not adulterated under section 402 or 413 of the act.
---------------------------------------------------------------------------

    \11\ Section 413(a) of the act requires that manufacturers and
distributors of dietary supplement ingredients that had not been
used for food or as a dietary supplement ingredient prior to October
15, 1994, or that are in a form that has been chemically modified
from the form in which it was used in food, submit to FDA at least
75 days before the ingredient is introduced into interstate
commerce, information that is the basis on which the manufacturer or
distributor determined that the dietary supplement containing the
ingredient will reasonably be expected to be safe.
---------------------------------------------------------------------------

V. Proposed Modifications to Current Sec.  101.83

A. Nature of the Substance

1. Esterification
    Current Sec.  101.83 limits the substances eligible for the health
claim to those specified in the two original health claim petitions as
follows: (1) Plant sterols derived from vegetable oils and prepared by
esterifying, with food-grade fatty acids, a mixture of plant sterols,
consisting of at least 80 percent beta-sitosterol, campesterol, and
stigmasterol (combined weight); and (2) plant stanol esters derived
from vegetable oils or from byproducts of the kraft paper pulping
process derived from vegetable oils or from byproducts of the kraft
paper pulping process and prepared by esterifying, with food-grade
fatty acids, a mixture of plant stanols, consisting of at least 80
percent sitostanol and campestanol (combined weight) (Sec.
101.83(c)(2)(ii)). The regulation does not authorize a health claim for
nonesterified phytosterols. Several comments received in response to
the IFR requested that the agency permit foods containing nonesterified
phytosterols to bear the health claim.
    In finding that the phytosterol esters specified in the current
regulation reduce the risk of CHD under the SSA standard, FDA expressed
agreement in the IFR with the petitioners that the fatty acid portion
of plant sterol/stanol esters is likely to be readily hydrolyzed by
digestive lipases upon ingestion and that the resultant free
phytosterol is left to be incorporated into intestinal micelles in a
manner that prohibits the absorption of cholesterol. The phytosterol is
therefore the active portion of the ester (65 FR 54686 at 54690, 54691,
54694, and 54705). Although the scientific evidence on which FDA relied
in issuing the IFR included studies of both esterified and
nonesterified phytosterols FDA had not considered, in the IFR,
cholesterol-lowering efficacy of nonesterified phytosterols.
    In response to the IFR, FDA received a number of comments asserting
that the IFR should be modified to allow use of the health claim for
nonesterified phytosterols, as well as phytosterol esters. Other
comments argued that nonesterified phytosterols should not be eligible
for the health claim because the available evidence on the efficacy of
nonesterified plant sterols and stanols is too limited and the
characterization of the substance is too scant to support their
inclusion in the final rule. In FDA's notice to reopen the comment
period (66 FR 50824, October 5, 2001), the agency asked for any
additional data on the effectiveness of nonesterified phytosterols in
reducing the risk of CHD.
    Esterification with fatty acids was one of the initial techniques
used to increase lipid solubility of phytosterols and facilitate
incorporation of phytosterols into foods. However, other techniques
have also been demonstrated effective in enhancing the solubility of
nonesterified phytosterols in conventional foods. Techniques for
solubilization of phytosterols include the following: (1) Dissolving
them into heated fats (Refs. 21 and 22), (2) re-crystallization by
cooling after dissolution in heated oil (Refs. 23 and 24), (3)
mechanically pulverizing crystalline phytosterols to a fine particle
size (Refs. 25 and 26), and (4) emulsifying them with lecithin (Ref.
27).
    Nonesterified phytosterols dissolved in oils are as effective in
lowering cholesterol as are equivalent amounts of phytosterol esters.
However, due to the limited lipid solubility of nonesterified
phytosterols, the amount of fat needed to dissolve an effective amount
of phytosterols is substantially greater for nonesterified phytosterols
than for phytosterol esters. The solubility of sitosterol/sitostanol in
rape seed oil mayonnaise increased about tenfold when esterified with
fatty acids (Ref. 28).
    Although current Sec.  101.83 provides only for a claim about
phytosterol esters, the evidence that was considered in the IFR
included five intervention

studies that investigated the effects of nonesterified phytosterols on
serum total and/or LDL cholesterol levels (Refs. 21, 28, 29, 30, and
31). In addition, 12 intervention studies published since the IFR have
involved nonesterified phytosterols added to conventional foods (Refs.
22, 24, 25, 26, 27, 32, 33, 34, 35, 36, 37, and 38) (see table 1 at the
end of this document). In these 17 intervention studies, subjects
consumed conventional foods providing from 0.7 to 5 g per day of
nonesterified plant sterols, plant stanols, or plant sterol/stanol
mixtures during intervention periods of 3 weeks to 6 months. Thirteen
of the seventeen intervention studies reported finding statistically
significant reductions in blood total and/or LDL cholesterol from the
consumption of foods containing nonesterified phytosterols.
    Two intervention studies directly compared the cholesterol lowering
efficacy of similar amounts of nonesterified and esterified
phytosterols in conventional foods (Refs. 35 and 38) (see table 1 at
the end of this document). Nestel et al., 2001 (Ref. 35) reported that
consumption of 2.4 g per day of soy phytosterols, as either plant
sterol esters or as nonesterified plant stanols, suspended in
conventional foods and consumed with meals over a 4-week period,
significantly lowered serum LDL cholesterol levels and that there was
no statistically significant difference in the cholesterol-lowering
effect between the two forms of phytosterols. Abumweiss et al., 2006
(Ref. 38) reported that 1.7 g per day of phytosterols, provided as
either nonesterified plant sterols or fatty acid esterified plant
sterols dissolved in margarine did not significantly lower total or LDL
cholesterol compared to the placebo.
    In the majority of these 17 intervention studies, nonesterified
phytosterols were suspended in fat-free or low-fat foods (e.g., orange
juice, low-fat dairy foods or other fat-free beverage, bread, cereal,
and jam); in other studies nonesterified phytosterols were suspended in
high-fat foods (e.g., margarine, butter, chocolates and meats) (see
table 1 at the end of this document). In most of these intervention
studies, the study design specified that the food enriched with
phytosterols be consumed with meals. In the few nonesterified
phytosterol intervention studies that did not specify the phytosterol-
enriched foods be consumed with meals (Refs. 24 and 25), the types of
food used (meats, bread, jam, and margarine) make it likely that they
would have been consumed concurrently with other foods.
    Based on the totality of available scientific evidence, FDA agrees
with the comments asserting that the blood cholesterol-lowering
efficacy of conventional foods containing nonesterified forms of
phytosterols is comparable to that of fatty acid esterified
phytosterols. Although esterification with fatty acids is one technique
that facilitates dispersion of phytosterols in foods with a high fat
content, FDA tentatively concludes that there is significant scientific
agreement that fatty acid esterification is not necessary for
phytosterols to be incorporated into food matrices or for phytosterols
to be effective in lowering blood cholesterol when added to
conventional foods. FDA also tentatively concludes that, for
conventional foods, it is reasonable to expand the substance that is
the subject of the claim to include both nonesterified and esterified
phytosterols.
    Therefore, the agency is proposing to amend current Sec.
101.83(c)(2)(ii) to define the substances eligible for the health claim
to include both phytosterols esterified with certain food-grade fatty
acids and, for the conventional foods for which the claim is
authorized, nonesterified phytosterols as substances for which the
health claim may be made. As discussed elsewhere in this document,
however, FDA is not proposing that dietary supplements containing only
nonesterified phytosterols be eligible for the health claim.
2. Mixtures of Plant Sterols and Plant Stanols
    Current Sec.  101.83 distinguishes between plant sterol esters and
plant stanol esters. The plant sterol component of the plant sterol
ester that is the subject of current Sec.  101.83 must be comprised of
at least 80 percent (combined weight) of beta-sitosterol, campesterol,
and stigmasterol (Sec.  101.83(c)(2)(ii)(A)(1)). Similarly, the plant
stanol component of the plant stanol ester that is the subject of the
health claim must be comprised of at least 80 percent (combined weight)
sitostanol and campestanol (Sec.  101.83(c)(2)(ii)(B)(1)). The
effective cholesterol-lowering daily intake specified in the current
regulation for plant sterol esters is 1.3 g per day (equivalent to 0.8
g per day of nonesterified sterol) and that for plant stanol esters is
3.4 g per day (equivalent to 2 g per day of nonesterified stanol)
(Sec.  101.83(c)(2)(i)(G)).
    The agency requested comment on the variability of beta-sitosterol,
campesterol, and stigmasterol composition in the plant sterol ester
products reported to be effective in lowering cholesterol (65 FR 54686
at 54705) and requested similar information with respect to the
variability of stanol composition of plant stanol products (65 FR 54686
at 54706). FDA further requested comment on the requirements that
sterol composition of plant sterol esters be at least 80 percent
(combined weight) beta-sitosterol, campesterol, and stigmasterol (65 FR
54686 at 54705) and that the stanol composition of plant stanol esters
be at least 80 percent (combined weight) sitostanol and campestanol.
The 2001 reopening of the IFR comment period (66 FR 50824) specifically
sought submission of additional data on the effectiveness of plant
sterol and stanol mixtures in reducing serum cholesterol levels.
    Some comments requested that the scope of the health claim be
broadened to include mixtures of plant sterols and stanols as eligible
substances. One comment stated that for purposes of the health claim
the effective cholesterol-lowering daily intake level for plant
sterols, plant stanols, or plant sterol/stanol mixtures must be
considered the same because available scientific evidence shows plant
sterols and plant stanols to be equivalent in their serum cholesterol-
lowering effect. Other comments asserted that the IFR should not be
broadened to include plant sterol/stanol mixtures because these
substances have not been the subject of a health claim petition. These
comments asserted that FDA should only consider health claims for other
phytosterol substances based on petitions submitted by proponents of
such claims.
    The totality of scientific evidence includes reports from five
intervention studies of cross-over design that directly compared the
cholesterol-lowering effects of similar intake levels of plant sterols
and plant stanols within each study and at intake levels ranging from
1.8 and 3 g per day (Refs. 22, 35, 39, 40, and 41) (see table 1 at the
end of this document). Three of the five intervention studies reported
that equivalent intake levels of plant sterols and plant stanols were
equally effective in lowering of blood total and/or LDL cholesterol
levels (Refs. 22, 39, and 41). The other two intervention studies
reported that plant sterols resulted in a greater reduction in LDL
cholesterol compared to an equivalent intake level of plant stanols
(Refs. 35 and 40).
    There are nine intervention studies that investigated the
cholesterol-lowering effects of mixtures of plant sterols and plant
stanols added to conventional foods (Refs. 21, 22, 24, 25,

32, 34, 37, 42, and 43) (see table 1 at the end of this document).
Eight of the nine studies, which provided 1.7 to 5 g per day of such
mixtures foods consumed with meals, reported finding significant LDL
cholesterol reductions of 5 to 15 percent relative to a placebo
control. The magnitude of the effect on lowering LDL cholesterol did
not vary meaningfully between the intervention studies involving
mixtures of plant sterols and plant stanols and interventions studies
involving plant sterols or plant stanols alone. Only one of the plant
sterol/stanol mixture intervention studies reported finding no
statistically significant lowering of LDL cholesterol (Ref. 34). The
phytosterol composition of the mixtures used in most of these
intervention studies was approximately 75 to 85 percent sterols and 10
to 15 percent stanols; two intervention studies used phytosterol
mixtures that contained 50 percent sterol and 50 percent stanol (Refs.
42 and 22).
    Based on the intervention studies demonstrating no meaningful
difference between the effectiveness of plant sterols and plant stanols
in lowering cholesterol and the intervention studies demonstrating that
mixtures of plant sterols and plant stanols effectively lower
cholesterol, FDA tentatively concludes that there is significant
scientific agreement among qualified experts to support the
relationship between foods containing mixtures of plant sterols and
plant stanols and CHD.
    FDA is therefore proposing to combine current Sec.
101.83(c)(2)(ii)(A)(1) and (c)(2)(ii)(B)(1), and to adopt the term
``phytosterol'' as inclusive of both plant sterols and plant stanols.
Proposed Sec.  101.83(c)(2)(ii) would specify the eligible substance as
``phytosterols.'' The proposal would also add a new paragraph (Sec.
101.83(a)(3)) in the background section of amended Sec.  101.83 to
define the term ``phytosterols'' and to clarify the regulation's use of
that collective term. As discussed in section V.4 of this document, the
proposal would further establish the permissible terminology that could
be used to describe the substances subject to the health claim (Sec.
101.83(c)(2)(i)(D)).
3. Sources of Phytosterols
    Current Sec.  101.83(c)(2)(ii) specifies that eligible plant sterol
esters must be derived from edible oils and that eligible plant stanols
must be derived from either edible oils or from byproducts of the kraft
paper pulping process. Some comments to the IFR urged FDA to broaden
the nature of the substance to include both sterols and stanols derived
from either vegetable oils or from wood oils.
    The restriction on the source of plant sterol esters to edible oils
in current Sec.  101.83(c)(2)(ii)(A)(1) reflects the original health
claim petition's specifications. The petition for a health claim
characterizing a relationship between plant sterol esters and CHD
limited itself to plant sterols derived from edible oils (i.e., those
edible oils that are vegetable oils). The origin of FDA's use of the
``byproducts of the kraft paper pulping process'' in current Sec.
101.83(c)(2)(ii)(B)(1) was the terminology used by the original health
claim petition for plant stanol esters. The petitioner submitted
documentation to support its self-determination that plant stanol
esters, whether obtained from vegetable oils or byproducts of the kraft
paper pulping process, were GRAS (65 FR 54686 at 54706). FDA notes,
however, that some of the intervention studies that were considered for
purposes of re-evaluating the scientific basis for the authorized
health claim identified the source of the phytosterols as ``tall oil.''
Tall oil is a byproduct of the wood pulp industry, usually recovered
from pine wood ``black liquor'' of the kraft paper process, containing
rosins, fatty acids, long chain alcohols and phytosterols (Ref. 44).
FDA is proposing to use the term ``tall oil'' in lieu of ``byproducts
of the kraft paper pulping process.''
    The phytosterols derived from tall oil are predominantly sterols.
These wood-derived plant sterols are hydrogenated to convert a
predominantly plant sterol product to plant stanols. The available
scientific evidence includes five of six intervention studies that
demonstrated cholesterol-lowering effects of conventional foods
containing plant sterols derived from tall oil (Refs. 21, 24, 32, 37,
and 43) (see table 1 at the end of this document). Jones (Ref. 34) did
not observe a significant reduction in total or LDL cholesterol levels
when 1.8 g of nonesterified sterols from tall oil was consumed in a
nonfat or low fat beverage. The composition of the phytosterols used in
these intervention studies was approximately 85 to 90 percent sterols
and 10 to 15 percent stanols. FDA concurs with the comments that argued
that there is no justification for not including plant sterols derived
from byproducts of the kraft paper pulping process. FDA is proposing to
amend the nature of the substance paragraph in current Sec.
101.83(c)(2)(ii) to specify that the source for any phytosterol
eligible for the claim may be either vegetable oils or tall oil.
    Amended Sec.  101.83(c)(2)(ii) would specify that eligible plant
sterols and stanols are derived from vegetable oils or from tall oil.
4. Designation of Substance as Phytosterols
    Current Sec.  101.83(c)(2)(i)(D) requires that the claim statement
identify the substance as either ``plant sterol esters,'' or ``plant
stanol esters,'' except that if the sole source of the plant sterols/
stanols is vegetable oil, the claim may use the term ``vegetable oil
sterol esters'' or ``vegetable oil stanol esters.'' Because FDA is now
proposing to expand the substance that is the subject of the health
claim to include, in addition to plant sterol/stanol esters,
nonesterified phytosterols and mixtures of sterols and stanols, the
agency is proposing to replace the terms ``plant sterol esters'' and
``plant stanol esters'' with the single term ``phytosterols''
throughout Sec.  101.83.
    In addition, FDA does not believe that requiring the claim to
distinguish plant sterol esters from nonesterified plant sterols would
provide meaningful information to the average consumer. On the other
hand, it is likely that consumer recognition of the potential health
benefit of phytosterol-enriched foods would be served by encouraging
consistent use of a single term to identify the variations of
phytosterol substances proposed to be included in the health claim. FDA
believes that permitting the health claim statement to use the term
``phytosterol'' to identify all forms of the substance rather than
distinguishing between sterol and stanol forms of esterified and
nonesterified forms would encourage manufacturers to take that
approach.
    Therefore the agency proposes amending current Sec.
101.83(c)(2)(i)(D) to include the single term ``phytosterols.'' To be
consistent with other revisions made to substances eligible for the
health claim in this proposal, we are also proposing to permit accurate
use of the terms ``plant sterols,'' ``plant stanols,'' or ``plant
sterols and stanols,'' and to permit ``vegetable oil phyosterols'' or
``vegetable oil sterols and stanols'' if the sole source of the plant
sterols or stanols is vegetable oil.
5. Determining the Amount and Nature of the Substance
    Current Sec.  101.83(c)(2)(ii)(A)(2) and (c)(2)(ii)(B)(2) specify
that, when FDA measures phytosterols in foods bearing the claim, it
will use particular analytical methods, which are the methods specified
in the original health claim petitions. The analytical methods
specified in the current regulation are direct saponification/gas

chromatographic methods for the determination of phytosterols in
various food matrices. FDA is proposing to amend the health claim to
revise the analytical methods for phytosterols, because the current
methods would be inadequate to measure phytosterols in the range of
foods eligible to bear the health claim under the proposed amendments
to the regulation.
    In table 3 of this document, FDA has summarized the key features of
several recent methods used for quantitation of phytosterols. Analytes,
sample handling, matrices studied, and types and lengths of gas
chromatography columns are listed. The types of validation data
obtained for these methods are also listed. Each of these methods
provides starting points for possible extensions to other analytes and
other food matrices. The validation data provide guidelines regarding
the types of validation that would be needed should these methods be
extended or modified.
    The agency solicited comments on the suitability of the
petitioners' analytical methods for ensuring that foods bearing the
health claim contain the qualifying levels of phytosterol esters (65 FR
54686 at 54706 and 54707). Comments received from several manufacturers
recommended that, until a general method is developed and validated for
determining the phytosterol content of foods, the regulation should
allow manufacturers to use any reliable analytical method for
determining the amount of phytosterols in their products and that the
records of their testing, or records of other reliable methods to
verify phytosterol content such as production records, should be
available to FDA upon request.
    FDA emphasizes that the purpose for identifying a specific
analytical method in a health claim regulation is not to bind
manufacturers to the use of any one analytical method. Rather, the
purpose is to inform manufacturers of the analytical method that will
be used by FDA to verify that foods bearing the claim comply with the
requirements of the claim. Because there is no Association of Official
Analytical Chemists (AOAC) Official Method for phytosterols in foods,
FDA has considered the comments from manufacturers that the agency
could review manufacturers' records (production and/or testing) as a
method of determining compliance with the requirements of the claim
regulation. A specific quantitative analytical method for the substance
that is the subject of the health claim is one means for verifying
compliance with the requirements of a health claim, although it is not
an absolute requirement for a health claim regulation. In the absence
of a validated analytical method for determining the amount of a
substance in a food, FDA has previously included a record inspection
requirement to determine the amount and nature of a substance in the
food to assure that it was in compliance with the requirements of the
health claim. In the soy protein/CHD health claim regulation (Sec.
101.82(c)(2)(ii)(B)), manufacturers of foods bearing the claim must
maintain records sufficient to substantiate the level of soy protein
when the food contains other sources of protein and make such records
available to FDA upon request.
    Although FDA recognizes that using food manufacturers' production
and/or analytical records is one option for compliance verification,
recent developments in analytical methodology have provided an
additional possibility for verifying compliance with the claim
requirements. For the reasons discussed below, FDA is proposing to
replace both the Unilever and McNeil methods specified in the current
regulation with AOAC Official Method 994.10, ``Cholesterol in Foods''
(Ref. 45) as modified by Sorenson and Sullivan (Ref. 46) for assaying
phytosterols. FDA recognizes that this method may need to undergo
further validation studies if analytes other than those already studied
are included in the analyses.
    When adopted in the IFR, as the analytical methods FDA would use
for determining plant stanol ester content of foods, neither the McNeil
nor the Unilever methods had been subjected to validation through a
collaborative study or peer-verified validation process, nor had they
been published in the scientific literature (65 FR 54686 at 54706 and
54707). FDA is not aware that this situation has changed for the McNeil
methods. The Unilever analytical method has subsequently been validated
through a collaborative study and published (Ref. 47). However, this
method quantifies total 4-desmethyl sterol content only and is not
recommended for identification of unknown sterols. As such, this method
is not suitable for one of the primary analytical needs for determining
compliance with the claim requirements (i.e., identifying the
phytosterols present in a food). Further, the method was validated only
for measurement of plant sterols in vegetable oil blends and plant
sterol concentrates. For these reasons, FDA is proposing to remove the
McNeil and Unilever methods cited in Sec.  101.83(c)(2)(ii)(A)(2) and
(c)(2)(ii)(B)(2) from the regulation.

        Table 3--Summary of Key Features of Several Recent Methods Used for Quantitation of Phytosterols
----------------------------------------------------------------------------------------------------------------
                                                           Analytes,        Validation data
             Method                   Description     analytical ranges,      available,           Comments
                                                        other features     matrices studied
----------------------------------------------------------------------------------------------------------------
1. McNeil--Sec.                   Direct              Analytes:           In-house            Method is
 101.83(c)(2)(ii)(B)(2).           saponification,     sitosterol,         validation data     applicable to the
                                   silyl               sitostanol,         on linearity,       determination of
                                   derivatization,     campesterol,        accuracy,           added
                                   GC.                 campestanol.        precision, and      phytosterols.
                                  Lipids are          Ranges: 3-8 g/100    reproducibility.   Alkaline
                                   saponified at       g dressing; 6-18   Matrices:            saponification
                                   high temp with      g/100 g tub         dressings, tub      hydrolyses sterol-
                                   ethanolic KOH.      spread; 2.5-7.5 g/  spreads, snack      ester bonds;
                                   The                 100 g snack bars;   bars, softgel       analytes are
                                   unsaponifiable      464-696 mg/         capsules.           nonesterified
                                   fraction is         softgel capsules.                       sterols.
                                   extracted into
                                   hexane. Sterols
                                   are derivatized
                                   to trimethylsilyl
                                   (TMS) ethers and
                                   quantified by
                                   capillary GC with
                                   FID.
                                  Internal standard:
                                   5[beta]-cholestan-
                                   3[alpha]-ol
                                   System
                                   suitability
                                   standards:
                                   cholestanol +
                                   stigmastanol.
                                  Column: capillary,
                                   30 m x 0.32 mm x
                                   0.25 [mu]m film
                                   thickness; cross-
                                   linked 5% phenyl-
                                   methyl silicone
                                   or methyl
                                   silicone gum (HP-
                                   5).
2A. Unilever--Sec.                Direct
 101.83(c)(2)(ii)(A)(2).           saponification,
                                   no
                                   derivatization,
                                   GC.

                                  Lipids are          Analytes: total 4-  Validation results  Method has been
                                   saponified at       desmethyl sterols.  for recovery, and   validated through
                                   high temp with     Range: 7-60 g/100    repeatability.      a collaborative
                                   ethanolic KOH..     g product.         Matrices:            study; however,
                                  Unsaponifiable                           margarines,         this method
                                   fraction is                             dressings, fats,    quantifies total
                                   extracted into                          fat blends, and     4-desmethyl
                                   heptane.                                phytosterol ester   sterol content
                                   Quantitation by                         concentrates.       only and is not
                                   GC with FID.                                                recommended for
                                  Internal standard:                                           identification of
                                   [beta]-                                                     unknown sterols.
                                   cholestanol (CAS                                            Method is not
                                   No. 80-97-7).                                               suitable for one
                                  Column: capillary,                                           of the primary
                                   10 m x 0.32 mm x                                            analytical needs
                                   0.12 [mu]m film                                             for determining
                                   thickness; CP-Sil-                                          compliance with
                                   5CB.                                                        the claim
                                                                                requirements
                                                                                (i.e.,
                                                                                identifying the
                                                                                phytosterols
                                                                                present in a
                                                                                food). Method
                                                                                validated only
                                                                                for measurement
                                                                                of plant sterols
                                                                                in vegetable oil
                                                                                blends and plant
                                                                                sterol
                                                                                concentrates.
----------------------------------------------------------------------------------------------------------------
2B. Duchateau et al., 2002 (Ref.  Direct              Analytes:           International       Method is that of
 47).                              saponification,     cholesterol,        collaborative       Unilever (2A).
                                   no                  brassicasterol,     study performed    Phytosterols
                                   derivatization,     campesterol,        with 8 samples      analyzed as
                                   GC.                 stigmasterol,       from 4 different    nonesterified
                                  Sample is            [beta]-             products and        sterols.
                                   saponified with     sitosterol,         batches.
                                   ethanolic KOH at    [Delta]5-           Validation data
                                   70[deg] C for 50    avenasterol.        for recovery,
                                   min.               Ranges: 15-20 g/     accuracy, and
                                   Unsaponifiable      100 g vegetable     repeatability.
                                   fraction is         oils; 8 g/100 g     Instrument
                                   extracted into      vegetable oil       details (GC
                                   heptane.            spreads; 60 g/100   brand, type;
                                   Quantitation by     g phytosterol       columns, injector
                                   GC with FID.        ester               type, temperature
                                  Internal standard:   concentrates.       program) for all
                                   [beta]-                                 participants
                                   cholestanol                             provided.
                                   (5[alpha]-
                                   cholestane-
                                   3[beta]-ol).
                                  Reference
                                   standards:
                                   cholesterol,
                                   campesterol,
                                   stigmasterol,
                                   [beta]-sitosterol.
                                  Column: capillary,
                                   10 m x 0.32 mm x
                                   0.12 [mu]m film
                                   thickness; CP-Sil-
                                   5CB.
----------------------------------------------------------------------------------------------------------------
3. AOAC Official Method 994.10    Direct              Analyte:            Collaborative       The method is
 ``Cholesterol in Foods.''         saponification,     cholesterol Test    study matrices:     applicable to the
 Direct saponification-gas         silyl               sample should       Butter cookies,     determination of
 chromatographic method (Ref.      derivatization,     contain <= 1 g      vegetable bacon     >= 1 mg
 45).                              GC.                 fat or <= 5 g       baby food,          cholesterol/100 g
                                  Lipids are           water. Suggested    chicken vegetable   of foods, food
                                   saponified at       sample weights      baby food,          products.
                                   high temperature    provided for pure   skinless wieners,  Collaborative
                                   (not specified)     oils, salad         NIST egg powder     study reference:
                                   with ethanolic      dressings,          (SRM 1845)          Journal of AOAC
                                   KOH.                substances with     commercial          International,
                                   Unsaponifiable      high moisture       powdered eggs,      78(6):1522-1525,
                                   fraction            content..           Cheese Whiz.        1995. (Ref. 48).
                                   containing         LOQ: 1.0 mg/100 g
                                   cholesterol and     Calibration curve
                                   other sterols is    2.5-200 [mu]g/ml.
                                   extracted with
                                   toluene. Sterols
                                   are derivatized
                                   to TMS ethers and
                                   quantified by GG
                                   with FID.
                                  Internal standard:
                                   5[alpha]-
                                   cholestane.
                                  Column: capillary,
                                   25 m x 0.32 mm x
                                   0.17 [mu]m film
                                   thickness; cross-
                                   linked 5% phenyl-
                                   methyl silicone
                                   or methyl
                                   silicone gum (HP-
                                   5, Ultra 2 of HP-
                                   1).

4. Sorenson and Sullivan, 2006    Direct              Analytes:           Single laboratory   Full collaborative
 (Ref. 46).                        saponification,     campesterol,        validation:         study said to be
                                   silyl               stigmasterol,       precision,          in progress.
                                   derivatization,     [beta]-sitosterol.  stability,
                                   GC.                LOQ: 1.0 mg/100 g    accuracy, and
                                  Modification of      Calibration         ruggedness.
                                   AOAC Official       curve: 2.5-200     Matrices: powdered
                                   Method 994.10       [mu]g/ml.           saw palmetto
                                   (see item 3. of                         berry, saw
                                   this table) to                          palmetto dried
                                   include                                 fruit CO2
                                   determination of                        extracts, saw
                                   phytosterols.                           palmetto 45%
                                  Lipids are                               powdered extract,
                                   saponified at                           dietary
                                   high temperature                        supplement
                                   (not specified)                         samples.
                                   with ethanolic
                                   KOH.
                                   Unsaponifiable
                                   fraction
                                   containing
                                   cholesterol and
                                   other sterols is
                                   extracted with
                                   toluene. Sterols
                                   are derivatized
                                   to TMS ethers and
                                   quantified by GG
                                   with FID.
                                  Internal standard:
                                   5[alpha]-
                                   cholestane.
                                  Column: capillary,
                                   25 m x 0.32 mm x
                                   0.17 [mu]m film
                                   thickness; cross-
                                   linked 5% phenyl-
                                   methyl silicone
                                   or methyl
                                   silicone gum (HP-
                                   5, Ultra 2 of HP-
                                   1).
----------------------------------------------------------------------------------------------------------------
5. Quaker Method 210     Direct extraction,  Analytes:           In-house            Intended for use
 (Ref. 49).                        silyl               sitosterol,         validation data     in only
                                   derivatization,     sitostanol,         for specificity,    relatively low-
                                   GC.                 campesterol,        accuracy            fat foods
                                  Lipids are           campestanol..       linearity,          enriched with
                                   extracted from     Range: 0.7-2.25 g/   precision, and      nonesterified
                                   homogenized food    100 g bars; 0.13-   stability..         plant sterols/
                                   sample into         0.38 g/100 g       Matrices: food       stanols.
                                   toluene. Sterols    beverages; 3-9 g/   bars, beverages,   Applicable for
                                   are derivatized     100 g cereals.      ready-to-eat        determination of
                                   to TMS ethers and                       cereals.            added
                                   quantified by                                               nonesterified
                                   capillary GC with                                           phytosterols.
                                   FID.
                                  Internal standard:
                                   5[alpha]-
                                   cholestane (CAS
                                   No. 481-21-0).
                                  Reference
                                   standards:
                                   mixture of
                                   nonesterified
                                   sitosterol,
                                   sitostanol,
                                   campesterol,
                                   campestanol.
                                  Column: capillary,
                                   30 m x 0.25 mm x
                                   0.25 [mu]m film
                                   thickness; (DB-5).
----------------------------------------------------------------------------------------------------------------
6. Toivo, J. et al. 2001 (Ref.    Acid hydrolysis,    Analytes:           Single laboratory   Intended for use
 50).                              saponification,     cholesterol,        validation          in determining
                                   silyl               sitosterol,         includes method     levels of
                                   derivatization,     sitostanol,         optimization,       endogenous
                                   GC.                 campersterol,       accuracy, and       phytosterols in
                                  First step uses      campestanol,        repeatability..     foods.
                                   HCL hydrolysis to   stigmasterol,      Matrices: flour,    Acid hydrolysis
                                   liberate            [Delta]5-           canola oil, corn    step included to
                                   glycosylated        avenasterol.        meal, dried         release
                                   phytosterols       Range: 0.5-800 mg/   onion, sunflower    conjugated forms
                                   bound in food       100 g for           seed, diet          of phytosterols.
                                   matrices. Lipids    individual          composite.          Important for
                                   are extracted       phytosterols.                           grains, flours;
                                   into                                                        not so for oils.
                                   hexane:ether,                                               Use of acid
                                   dried and the                                               hydrolysis prior
                                   lipid extract is                                            to or following
                                   saponified at                                               lipid extraction
                                   high temp with                                              discussed.
                                   ethanolic KOH.                                             Method has been
                                   Unsaponifiable                                              used for analysis
                                   fraction is                                                 of hundreds of
                                   extracted into                                              foods to create
                                   cyclohexane.                                                database of
                                   Sterols are                                                 phytosterol in
                                   derivatized to                                              foods.
                                   TMS ethers and
                                   quantified by
                                   capillary GC with
                                   FID.
                                  Internal standard:
                                   dihydrocholestero
                                   l (cholestanol).
                                  Reference
                                   standard:
                                   dihydrocholestero
                                   l (cholestanol),
                                   cholesterol,
                                   cholesteryl
                                   palmitate, and
                                   mixture of
                                   soybean steryl
                                   glucosides
                                   containing
                                   sitosterol,
                                   campesterol, and
                                   stigmasterol as
                                   their glucosides.
                                  Column: capillary,
                                   60 m x 0.25 mm x
                                   0.1 [mu]m film
                                   thickness; cross-
                                   linked 5%
                                   diphenyl-95%
                                   dimethyl
                                   polysiloxane.
----------------------------------------------------------------------------------------------------------------
ABREVIATIONS: GC--gas chromatography; TMS--trimethylsilyl; FID--flame ionization detector; KOH--potassium
  hydroxide; CAS--Chemical Abstract Service; LOQ--limit of quantitation.

    At the present time, the method that appears to be the most
appropriate for the current regulation is that of Sorenson and Sullivan
(2006) (Ref. 46). This method, which has undergone AOAC's single
laboratory validation procedures, is a modification of AOAC Official
Method 994.10 for the determination of cholesterol in foods. AOAC
Official Method 994.10 was validated in a variety of food matrices
(Ref. 48) and, with the modifications and validation data provided by
Sorenson and Sullivan (Ref. 46), can likely be extended further to
include campestanol and sitostanol and additional food matrices.
    At this time, FDA is not aware of any publicly available analytical
methods that have already been validated through collaborative studies
that apply to a wider range of food matrices and that adequately
resolve the specific phytosterols that are the subject of this health
claim (i.e., [beta]-sitosterol, campesterol, stigmasterol, sitostanol,
and campestanol) from other phytosterols potentially present in foods.
FDA is therefore requesting submission of validation data for any
analytical methods that may apply to a wider range of food matrices or
more fully validated for separation and quantitation of the specific
phytosterols of this health claim.
    FDA is tentatively concluding that the modification of AOAC
Official Method 994.10 provided by Sorenson and Sullivan (Ref. 46) for
the evaluation of campesterol, stigmasterol, and beta-sitosterol is an
appropriate method for use to assess compliance for this health claim
for those foods for which such method has been validated. This method
will need to be validated to include campestanol and sitostanol and to
include additional matrices for other foods that may be eligible for
this claim. Method validation is a process that is used to establish
that, if the method is performed properly, it produces results which
are of acceptable quality. The validation process involves determining
statistical parameters of a method to decide if the method is fit for a
specified purpose. Methods documented by published interlaboratory
validation data are generally selected over those that are not.
Attributes of methods include the following: Range, limit of detection,
limit of quantitation, accuracy, precision (repeatability and
reproducibility), specificity (selectivity), sensitivity, robustness
(ruggedness), practicality, and applicability. We request comment on
whether validated methods are available for analytes and matrices that
are not included in the Sorenson and Sullivan method. If so, FDA may
adopt such methods in a final rule. If no other validated methods are
available, FDA would likely require, in a final rule, a requirement for
manufacturers to maintain records to demonstrate that the method used
to identify the presence of the phytosterols in its product, that bears
the phytosterol health claim, and the level of each phytosterol source
in such product, is capable of accurately quantifying phytosterols in
the product. FDA also would likely require that manufacturers maintain
records of test results. Further, FDA would likely require that the
manufacturer make such records available to FDA upon request.
    FDA is proposing to replace the analytical methods now specified in
current Sec.  101.83 (Unilever's method in Sec.  101.83(c)(2)(ii)(A)(2)
and McNeil's methods in Sec.  101.83(c)(2)(ii)(B)(2)) with Sorenson and
Sullivan's modifications of AOAC Official Method 994.10 (Ref. 46), for
those foods for which the Sorenson and Sullivan method has been
validated.

B. Nature of the Claim

1. Effective Cholesterol-Lowering Daily Dietary Intake
    Current Sec.  101.83(c)(2)(i)(G) requires that the health claim
specify the daily dietary intake of plant sterol or stanol esters that
is necessary to reduce the risk of CHD and the contribution one serving
of the product makes to the specified daily dietary intake level.
Current Sec.  101.83(c)(2)(iii)(A) further specifies that the amount of
plant sterol or stanol esters that a food product eligible to bear the
health claim is required to contain per RACC. Such amount is one half
of the daily dietary intake level associated with reduced CHD risk
(i.e., the total daily intake divided between two meals). FDA concluded
in the IFR that the daily dietary intake levels of plant sterol and
stanol esters that are associated with reducing the risk of CHD, based
on the consistently demonstrated effective lowering of blood total and/
or LDL cholesterol, were at least 1.3 g per day of plant sterol esters
(equivalent to 0.8 g per day expressed as plant sterol) and at least
3.4 g per day of plant stanol esters (equivalent to 2 g per day
expressed as plant stanols) (65 FR 54686 at 54704).
    In its original health claim petition, Unilever (then acting under
its subsidiary Lipton) proposed 1.6 g per day of plant sterol esters
(equivalent to 1 g per day expressed as nonesterified plant sterols) as
the daily dietary intake level of plant sterols necessary to justify a
claim about reduced risk of CHD. The agency agreed that an intake level
of 1 g per day of nonesterified plant sterols had been demonstrated to
consistently reduce blood total and LDL cholesterol, but the agency
also considered three intervention studies (Refs. 29, 30, and 51) in
which a daily intake level of approximately 0.8 g per day plant sterols
was reported to significantly lower blood cholesterol. The agency
therefore concluded that the intake level of plant sterols consistently
shown to lower blood total and LDL cholesterol was 0.8 g per day or
more of nonesterified plant sterols (equivalent to 1.3 g per day or
more expressed as plant sterol esters) (65 FR 54686 at 54704).
    McNeil proposed a total daily intake of at least 3.4 g per day of
plant stanol esters (equivalent to 2 g per day expressed as
nonesterified plant stanols), which represents an amount that had been
consistently shown to be effective in reducing blood cholesterol (65 FR
54686 at 54704). The agency found no consistent scientific evidence for
blood cholesterol-lowering associated with plant stanol ester intake
levels less than 3.4 g per day. Although one study (Refs. 28 and 52)
reported significant lowering of blood cholesterol at 1.36 g plant
stanol esters per day (equivalent to 0.8 g per day expressed as
nonesterified stanols), another study (Ref. 53) reported no significant
reduction of blood cholesterol levels at approximately the same plant
stanol ester intake level.
    FDA requested comment on the determination of the daily intake of
plant sterol esters and plant stanol esters associated with the risk of
CHD (65 FR 24686 at 24704). A majority of comments to the IFR suggested
that the efficacy of plant sterols and stanols was similar and that the
daily intake levels should be the same for both substances. Many of
these comments suggested that the equivalent amount should be in line
with the minimum effective level for plant sterol esters. Some comments
argued for adopting approximately 2 g per day (expressed as
nonesterified phytosterols) as a more highly effective level, but most
comments favored the lower level. Some comments provided scientific
data and analysis to support this contention; others did not.
    The phytosterol intervention studies that FDA considered in this
reevaluation (see table 1 at the end of this document) included dietary
phytosterol intervention levels ranging between 0.45 g per day (Ref.
54) and 9 g per day (Ref. 55). Most commonly, phytosterol intake levels
ranged from 1 to 3 g per day. Intervention studies demonstrated
statistically significant reductions in total and/or LDL

cholesterol levels for plant sterol intake levels ranging from 1 to 3 g
per day. Similar to plant sterols, intervention studies demonstrated
statistically significant reductions in total and/or LDL cholesterol
levels for plant stanol intake levels ranging from 1.6 to 3 g per day.
There are also five intervention studies of cross-over design that
directly compared the cholesterol-lowering effects of similar intake
levels of plant sterols and plant stanols within each study and at
intake levels ranging from 1.8 and 3 g per day across the five
intervention studies (Refs. 22, 35, 39, 40, and 41). All five of these
intervention studies demonstrated that both plant sterols and plant
stanols significantly reduce blood total and/or LDL cholesterol levels.
Three of the five intervention studies reported that equivalent intake
levels of plant sterols and stanols were equally effective in lowering
of blood LDL cholesterol levels (Refs. 22, 39, and 41). The other two
intervention studies reported that plant sterols resulted in a greater
reduction in LDL cholesterol compared to an equivalent intake level of
plant stanols (Refs. 35 and 40).
    Based on the scientific evidence regarding the relationship of
consuming phytosterols with a reduced risk of CHD, FDA tentatively
concludes that 2 g of phytosterols per day is the daily dietary intake
necessary to achieve the claimed effect. Two g per day of plant sterols
is the midpoint of the daily intake range of 1 to 3 g used in the
majority of intervention studies designed to evaluate their
effectiveness in lowering cholesterol. Two g of phytosterols per day is
also at the lower end of the daily intake range in the intervention
studies designed for evaluating the effectiveness of plant stanols and
mixtures of plant stanols and sterols. In addition, 2 g per day is
commonly cited as an optimal level for cholesterol-lowering effects
(Refs. 3, 56, 57, and 58) and FDA's own evaluation of the publicly
available evidence supports that conclusion. FDA has thus tentatively
determined that, for purposes of authorizing a health claim relating
phytosterol consumption and CHD risk, the daily dietary intake
necessary to achieve the claimed effect for phytosterols is 2 g per
day. The agency invites comments on this tentative determination.
    Current Sec.  101.83(c)(2)(i)(G) identifies the daily dietary
intake levels of plant sterols/stanols in terms of ``------ grams or
more per day * * *.'' Likewise, the model health claims provided in the
IFR preface the daily dietary intake levels with the phrase ``at
least,'' e.g., ``Food containing at least 1.7 g per serving * * * for a
total daily intake of at least 3.4 g * * *'' (Sec.  101.83(e)). The
agency is also proposing to eliminate the ``or more'' and ``at least''
qualifications from the specification of the daily dietary phytosterol
intake level. The agency is proposing to amend Sec.  101.83(c)(2)(i)(G)
to require that a claim that is the subject of this regulation specify
that the daily dietary intake of phytosterols that is necessary to
justify the CHD risk reduction claim is 2 g per day.
2. Servings per Day
    Current Sec.  101.83(c)(2)(i)(H) requires the health claim to
specify that the daily dietary intake of plant sterol or stanol esters
should be consumed in two servings eaten at different times of the day
with other foods. FDA explained that the conditions for the consumption
of phytosterols to be specified in the claim were consistent with the
way phytosterols were used in those intervention studies showing
significant blood cholesterol-lowering effects of phytosterols. In
these intervention studies, the study subjects were instructed to
consume the daily intake of phytosterols divided over two or three
servings at different times of the day or were instructed to replace a
portion of their typical dietary fat with equal portions of
phytosterol-enriched test margarines over the course of the day,
usually during meals (65 FR 54686 at 54705). FDA also noted that given
the limited variety of phytosterol-enriched foods to be included in the
claim, it would be difficult for many consumers to eat more than two
servings of phytosterol-enriched foods per day. FDA further noted that
recommending more than two servings per day of phytosterol-enriched
foods would not be appropriate, considering the fat content of the
phytosterol-enriched conventional foods (primarily fat-based foods) to
be eligible to bear the claim (65 FR 54686 at 54708).
    FDA requested comments on whether it was reasonable, in light of
the fat content of products eligible to bear a claim and the limited
number of available products, to divide the daily dietary intake of
plant sterol esters and plant stanol esters by two and specify that the
product should be consumed in two servings eaten at different times of
the day (65 FR 54686 at 54707 and 54708, respectively). Some comments
supported the agency's requirement that the label specify that the
daily dietary intake of phytosterols should be consumed in two servings
at different times during the day. Several comments stated that the
claim statement should state ``at least two * * *'' or ``two or more *
* *'' servings a day rather than two servings per day and asserted that
consumers would benefit more from consuming phytosterols on more
occasions during the day. Most comments disagreed with the agency's two
servings per day requirement. Some of these comments noted that,
because the technology exists to disperse phytosterols into non-fat
foods, there is no reason to deviate from the usual assumption that the
total daily intake of a food component is divided among four eating
occasions. Several comments requested that the claim make the servings
per day statement optional rather than a mandatory component of the
claim. One comment said that optional claim language about the number
of servings of phytosterol-enriched foods per day could vary, depending
on the phytosterol content of a food.
    The 2006 Unilever petition (Docket No. FDA-2006-P-0033 (formerly
Docket No. 2006P-0316)) asserted that there is now significant
scientific agreement that phytosterols will significantly reduce
cholesterol levels when consumed once per day. The petition requested
that Sec.  101.83 be amended to permit a food containing 2g of
phytosterols to state that consuming phytosterols once per day has been
associated with a reduced risk of CHD. FDA is proposing to amend Sec.
101.83 to permit the health claim Unilever requested.
    The design of most phytosterol intervention studies specified that
the daily intake of phytosterols be divided between two or three
servings eaten at different times with meals. However, scientific
evidence that has become available since issuance of the IFR
demonstrates that dividing the daily intake over two or more servings
is not necessary for the cholesterol-lowering effect of phytosterols.
Seven of the more recently completed phytosterol intervention studies
had their study subjects consume all phytosterol-enriched test foods in
one serving per day (Refs. 8, 35, 38, 42, 43, 59, and 60) (see table 1
at the end of this document).
    Six of the seven ``once-per-day'' studies that FDA considered
reported significant reductions of total and/or LDL cholesterol in
phytosterol groups compared to the control group (Ref. 38). AbuMweis et
al., 2006 reported no cholesterol-lowering effect, at 1.0 to 1.8g per
day, when the phytosterols were incorporated into margarine and
consumed as part of the breakfast meal for 4 weeks. Each of the six
studies that reported once-per-day consumption of phytosterols to be
effective in reducing cholesterol had incorporated the phytosterols
into test foods (margarine,

bread, low fat milk, cereal, yogurt, or ground beef) that were consumed
with a meal. These once-per-day studies reported that daily intakes
ranging from 1.6 to 3 g per day resulted in reductions in cholesterol
of between 5.6 and 12.4 percent compared to controls. The cholesterol-
lowering effect from ``once-per-day'' consumption was similar to the
cholesterol reductions observed for comparable daily intake levels
divided over multiple servings eaten at different times of the day.
    Based on this evidence, FDA tentatively concludes that the
requirement for the health claim to specify that the daily dietary
intake of phytosterols should be consumed in two servings eaten at
different times during the day is no longer consistent with the
available scientific evidence for the cholesterol-lowering effect of
phytosterol consumption. FDA also notes that the other reasons cited in
the IFR for requiring the claim statement to specify that phytosterols
should be eaten in two different servings (i.e., the health claim was
to be available to a limited number of foods and the conventional foods
were mostly high fat content), would no longer be valid arguments due
to other changes in the claim criteria that are being proposed at this
time.
    Therefore the agency is proposing to amend Sec.  101.83(c)(2)(i)(H)
by removing the requirement that the health claim include a
recommendation that phytosterols be consumed in two servings eaten at
different times of the day.
3. Consuming Phytosterols With Meals
    Current Sec.  101.83(c)(2)(i)(H) requires that the health claim
specify that phytosterols should be consumed in two servings eaten at
different times of the day with other foods. As discussed in section
V.B.2 of this document, FDA has concluded that requiring the claim to
state that the total daily dietary intake of phytosterols should be
divided over two servings eaten at different times is no longer
supported by available scientific evidence. The agency is also
proposing to amend Sec.  101.83 to require the claim to recommend that
phytosterols be consumed with ``meals.''
    The design used in a majority of phytosterol intervention studies
specified that the phytosterol-enriched test foods were to be consumed
with meals. The experimental design of most all other intervention
studies that did not specify the phytosterol-enriched test foods were
to be consumed ``with meals'' involved fat-based phytosterol-enriched
test foods (margarine, butter, mayonnaise) and specified that the
phytosterol test food be used to replace an equivalent amount of the
subjects' typical daily fat consumption. As such, it is likely that in
these studies the phytosterol-enriched foods would have been consumed
with other foods. One intervention study investigated the impact of
consuming phytosterols with meals (Ref. 43). The study subjects in this
study were instructed to consume a daily single serving of phytosterol-
enriched yogurt either in the morning at least 0.5 hour before
breakfast, or with lunch. Significant lowering of total and LDL
cholesterol was reported for both phytosterol-enriched yogurt consumed
while fasting and when consumed with a meal; however, the cholesterol-
lowering effect was significantly greater when consumed with a meal
than when not consumed with a meal (Ref. 43).
    Intestinal absorption of cholesterol requires cholesterol be
incorporated into mixed micelles of the intestinal digesta. Intestinal
micelles form when dietary fatty acids, pancreatic juice, and bile
salts come together at the same time in the small intestine. The
process of eating food stimulates secretion of pancreatic juice and of
bile salts into the intestine. The presumptive primary site of
phytosterol interaction with cholesterol is within the micelles, where
phytosterols are thought to block the transfer of cholesterol from
micelles to intestinal mucosal cells. This mechanism supports the
theory that the effectiveness of dietary phytosterols in reducing blood
cholesterol levels depends upon the phytosterols being consumed
concurrently with food and dietary fat to ensure maximal incorporation
of phytosterols into intestinal micelles. Current Sec.  101.83
authorizes a health claim only for phytosterols esterified with fats
and incorporated into types of fat-based foods (margarines and salad
dressings) that typically are consumed with other foods and therefore
the theoretical conditions that facilitate interference with
cholesterol absorption (i.e., phytosterols consumed with food and with
dietary fat) would be met.
    Changes to current Sec.  101.83 in this proposed rule include: (1)
Expanding the substance of the claim to include nonesterified
phytosterols in conventional foods, (2) removing restrictions on types
of conventional foods eligible for the claim such that fat-free foods
and beverages will not be precluded from making the claim, and (3)
removing the requirement that the claim statement specify that
phytosterols should be consumed in two servings eaten at different
times during the day. The cholesterol-lowering efficacy of
phytosterols, when not consumed with dietary fat and a substantial
amount of food, has not been demonstrated. Without a recommendation
that phytosterols be consumed with meals or snacks, it is probable that
the types of foods (including dietary supplements) likely to be
enriched with phytosterols for the purpose of bearing the health claim
would be consumed without sufficient dietary fat or amounts of food to
be consistent with the circumstances under which phytosterols are
likely to be effective in lowering cholesterol.
    FDA is proposing to amend Sec.  101.83(c)(2)(i)(H) to require that
the health claim specify that phytosterol-enriched foods should be
consumed ``with meals or snacks.'' The ``with meals or snacks''
specification will replace the current requirement that the claim
specify the daily dietary phytosterol intake should ``be consumed in
two servings eaten at different times of the day with other foods.''

C. Nature of the Food Eligible To Bear the Claim

1. Qualifying Amount of Phytosterols per Serving
    Current Sec.  101.83(c)(2)(iii) requires that, in order to bear the
health claim, a product must contain at least 0.65 g of plant sterol
esters (equivalent to 0.4 g nonesterified plant sterols) or 1.7 g of
plant stanol esters (equivalent to 1 g nonesterified plant stanols)
that comply with paragraphs Sec.  101.83(c)(2)(ii)(A)(1) and
(c)(2)(ii)(B)(1) respectively, per RACC. These values are one-half of
the plant sterol/stanol ester daily intake specified in the IFR as that
necessary to achieve the CHD risk-reduction benefit. As discussed in
section V.B.2 of this document, FDA is proposing to amend Sec.  101.83
to remove the current requirement that the health claim specify that
phytosterols should be consumed in two servings at different times of
the day. Also, the proposed changes to Sec.  101.83 would result in a
greater variety of phytosterol-enriched foods eligible for the claim
than now included in current Sec.  101.83, including conventional foods
with a lower fat content. Therefore, FDA is reconsidering the initial
decision to base the minimum amount of phytosterol in a food eligible
to use the health claim on two servings per day.
    The agency generally assumes that a typical food consumption
pattern includes three meals and one snack per day (see 58 FR 2302 at
2379, January 6, 1993). Currently available evidence demonstrates that
it is feasible and effective to enrich low fat and fat free foods with
phytosterols. Due to the

wider variety of conventional foods that may potentially be fortified
with phytosterols (as evidenced by the variety of phytosterol-enriched
test foods used in intervention study reports published since 2000), it
may be feasible for consumers to select four servings per day without
having to depend exclusively on conventional foods with a high fat
content. As a result, FDA believes it would be reasonable to base the
minimum qualifying amount of phytosterol in a food on four servings per
day. As discussed in section V.B.1 of this document, FDA has
tentatively concluded that, for the purpose of the health claim, the
phytosterol daily dietary intake necessary to achieve the claimed
effect is 2 g per day. Dividing this daily intake over four servings
per day, the minimum eligible phytosterol content of a food would be
0.5 g per RACC, expressed as the weight of nonesterified phytosterols.
    Therefore, the agency is proposing to amend Sec.
101.83(c)(2)(iii)(A) to permit health claims on foods that contain at
least 0.5 g per RACC of phytosterols, expressed as the weight of
nonesterified phytosterols, and that comply with paragraph (c)(2)(ii)
of this section. Further, the agency is proposing to add new Sec.
101.83(c)(2)(iii)(C) to limit the claim to conventional foods
containing phytosterols for which the agency has received a GRAS
notification, to which it had no further questions, and the conditions
of use are consistent with the eligibility requirements for the health
claim. We note that not all conventional foods for which a GRAS
notification for phytosterols was submitted, to which the agency had no
further questions, are under conditions of use in food that would be
consistent with the eligibility requirements for the health claim,
e.g., certain foods may contain phytosterols at a level that is less
than the minimum of 0.5 g per RACC. Such foods would not be eligible to
bear the health claim if the rule is finalized as proposed.
2. Nature of the Food
    Current Sec.  101.83(c)(2)(iii)(A)(1) limits the plant sterol
ester-enriched food products eligible to bear the health claim to
spreads and dressings for salad. Current Sec.  101.83(c)(2)(iii)(A)(2)
limits the plant stanol ester-enriched food products eligible to bear
the health claim to spreads, dressings for salad, snack bars, and
dietary supplements in softgel form. The term ``spreads'' was used in
the IFR to include both margarine and vegetable oil spreads resembling
margarine but having a fat content less than that required by the food
standard for margarine (Sec.  166.110 (21 CFR 166.110)). The term
``dressings for salad'' was used in the IFR to include both salad
dressing and similar vegetable oil-based food products with vegetable
oil content less than that required by the food standard for salad
dressing (Sec.  169.150 (21 CFR 169.150)), which is typically a product
that resembles mayonnaise.
    FDA explained in the IFR that the use of the plant sterol ester
claim was being restricted to the labeling of spreads and dressings for
salads because of the following: (1) The petitioner limited its
requested health claim to those two types of foods, (2) the petitioner
had satisfied the requirement of Sec.  101.14(b)(3)(ii) only with
respect to the use of plant sterol esters as an ingredient in spreads
and dressings for salads, and (3) the petitioner had provided a
quantitative analytical method for measurement of plant sterol esters
only in spreads and dressings for salads (65 FR 54686 at 54707). FDA
noted that it would consider broadening the types of plant sterol
ester-containing foods eligible to bear the claim if data were
submitted to establish the use of plant sterol esters in other food
products at levels necessary to justify the claim is safe and lawful
and if a validated analytical method that permits accurate
determination of the amount of plant sterol esters in other types of
foods was available (65 FR 54686 at 54707). The agency advanced
analogous reasoning for limiting the foods eligible to bear the
authorized health claim for plant stanol esters to spreads, dressings
for salad, snack bars and dietary supplements in softgel form (65 FR
54686 at 54708).
    Many comments received in response to the IFR addressed the
restrictions on the types of foods eligible for the claim. Most of the
comments objecting to the IFR's specification of eligible food
categories recommended that the final rule be expanded to include
additional types of foods or asserted that the final rule need not
restrict the types of food eligible for the claim. These comments
argued: (1) That evidence now available from clinical trials
established the cholesterol-lowering effectiveness of phytosterols when
incorporated into many types of foods, including low fat and fat free
foods, and (2) that thus there was no evidence to suggest that the food
matrix chosen to carry the phytosterol will have an effect on
cholesterol-lowering efficacy. Some comments asserted that it is
unnecessary to limit the claim to fat-based food matrices because the
technology is available to disperse nonesterified plant sterols and
stanols in a wide variety of non-fat food matrices and because the key
factor is that the plant sterols be consumed with fat, not that the
plant sterols be dispersed in fat. Other comments noted that a growing
number of GRAS notifications, to which the agency has not objected,
expand the categories of food in which phytosterols may be used safely
and lawfully beyond the foods listed in current Sec.  101.83. Some
comments urged authorizing the health claim for other categories of
foods, subject to availability of validated quantitative analytical
methodology for phytosterols in other food matrices. Other comments
argued that it is not necessary to restrict use of the claim to types
of foods for which the petitioners had provided product-specific
phytosterol analytical methods. Rather, these comments contended, that
it is feasible to measure phytosterols in other food matrices using
established general sterol methods and the food industry should be
permitted to use any reliable methods, including maintaining production
records, to document compliance with the phytosterol content
requirements of the claim. Some comments asserted that making more
types of foods eligible for use of the claim would encourage consumer
use of phytosterol-enriched foods through a broader array of food
options accommodating a greater variety of consumer tastes. One comment
opposed broadening of the categories of foods eligible to bear the
claim, arguing that proliferation of the types of foods bearing the
claim would likely result in phytosterol intake exceeding acceptable
daily intake levels and that the long-term safety of higher intake
levels has not been evaluated.
    Finally, some comments received in response to the IFR requested
that FDA expand the regulation to permit health claims for plant
sterol/stanol ester-containing dietary supplements in a variety of
forms including tablets, capsules, softgel capsules, and chewable
wafers. Others were concerned that products in ``pill'' form and
intended for use to help lower blood cholesterol looked too much like
over the counter drugs.
    a. Conventional foods. All the intervention studies involving
phytosterol-enriched conventional foods cited in the IFR were studies
in which the phytosterols were added to the diet as phytosterol-
enriched margarines, butter, mayonnaise, or shortening. Subsequently,
evidence from intervention studies employing a wider variety of
phytosterol-enriched conventional foods has become available (see table
1 at the end of this document). Phytosterol-enriched conventional foods
used in intervention studies now include the following: Margarine and
reduced-fat spreads

resembling margarine, shortening, dressings for salad, mayonnaise,
grain products (bread, croissants, muffins, and breakfast cereal),
dairy products (yogurt, reduced-fat cheese, butter, and dairy-based
beverage), beverages (orange juice, fat-free lemon-flavored drink, and
unspecified fat-free drink), meat (ground beef and cold cuts), and
chocolate. The more recent intervention studies showed that daily
dietary phytosterol (nonesterified and esterified) intake of
approximately 1 to 3 g per day from a variety of types of food enriched
with phytosterols, including fat-free foods, resulted in significant
cholesterol-lowering comparable to that resulting from consuming
phytosterol-enriched spreads and margarines (see table 1 at the end of
this document). The data from available intervention studies show the
average percent reduction of blood LDL cholesterol resulting from a
daily phytosterol of intake between 1 and 3 g per day is independent of
the types of foods enriched with phytosterols. FDA therefore concurs
with the comment that, with respect to conventional foods, there is no
scientific evidence to suggest the food matrix into which the
phytosterols are added is an important factor affecting the
cholesterol-lowering efficacy of phytosterols.
    Therefore, the agency is proposing to amend Sec.
101.83(c)(2)(iii)(A) by eliminating the enumeration of specific
conventional foods that may bear a health claim and thereby broadening
the conventional foods eligible to bear the claim to those meeting the
other requirements of paragraph (c)(2)(iii).
    b. Dietary supplements. While there is an abundance of evidence
from intervention studies to demonstrate the cholesterol-lowering
efficacy of phytosterol-enriched conventional foods, relatively few
trials have been conducted with dietary supplements containing
phytosterols. There is scientific evidence from four intervention
studies to demonstrate the cholesterol-lowering efficacy of dietary
supplements containing phytosterol esters (Refs. 61, 62, 63, and 64).
In the intervention study conducted by Rader and Nguyen (Ref. 61) (see
table 2 at the end of this document), participants were moderately
hypercholesterolemic, but otherwise healthy adults. They consumed three
phytosterol ester or placebo softgel capsules daily for 3 weeks. The
phytosterol ester-containing softgel capsules provided 1 g of
phytosterols per day. A significantly greater reduction in blood total
and LDL cholesterol was reported in the phytosterol ester group than in
the placebo group.
    The cholesterol-lowering efficacy of dietary supplements containing
phytosterols esters has also been confirmed in three additional
intervention studies (Ref. 62, 63, and 64). Woodgate et al. (Ref. 64)
provided six softgel supplements that provided phytosterol esters
equating to 1.6 g of nonesterified phytosterols for 4 weeks. There was
a significantly greater reduction in total cholesterol levels in the
group that received the phytosterol-ester supplement compared to the
placebo group. Participants in the trial by Acuff et al. (Ref. 62) were
hypercholesterolemic, but otherwise healthy adults. They consumed two
phytosterol ester or placebo capsules daily for 4 weeks. The sterol
ester-containing capsules provided 0.8 g per day phytosterols. A
significant blood LDL cholesterol reduction in the sterol ester group
relative to the placebo group was reported. Earnest et al. (Ref. 63)
provided four sterol ester-containing capsules or a placebo for 12
weeks. The sterol ester-containing capsule provided 2.6 g per day of
phytosterols. There was a significantly greater reduction in blood
total and LDL cholesterol in the group that received the sterol ester-
containing capsules compared to the placebo group. Statistical
differences in the change in blood LDL cholesterol between the sterol
ester and placebo group was not determined. In conclusion, esterified
phytosterols were effective in reducing total and/or LDL cholesterol
levels in the blood in all three studies.
    There have been three intervention studies published on the
efficacy of nonesterified phytosterols in reducing blood cholesterol
levels (Refs. 65, 66, and 67) (see table 2 at the end of this
document). Nonesterified phytosterols consumed as ingredients in a
gelatin capsule supplement were reported to have no effect on blood
cholesterol (Ref. 65). The intervention study supplemented moderately
hypercholesterolemic men, consuming a Step I diet, with 3 g of
nonesterified phytosterols per day. The phytosterols were suspended in
safflower oil (20 percent sitostanol by weight in safflower oil)
contained within gelatin capsules and consumed with meals. No changes
in either blood total or LDL cholesterol were observed between Step I
diet alone and a Step I + sitostanol supplements. The concentration of
20 percent sitostanol in the gelatin capsule is much greater than the
solubility of sitostanol of 1 percent (Ref. 68). Thus, it has been
speculated that much of the sitostanol was undissolved (Ref. 57), and
therefore not adequately dispersed in the intestinal contents.
    Although a nonesterified phytosterol/soy lecithin emulsion
formulation has been shown to be effective in lowering cholesterol
under certain circumstances (Refs. 66 and 67), the results have been
inconsistent and highlight how difficult it is to predict the
effectiveness of nonesterified phytosterols in lowering cholesterol
when consumed as ingredients in dietary supplements. McPherson et al.
(Ref. 66) reported that consumption of 1.26 g stanols per day as the
spray-dried phytostanol/lecithin emulsion tablet formulation resulted
in a significant lowering of LDL cholesterol in humans; whereas,
consumption of 1 g per day as the spray-dried phytostanol/lecithin
emulsion capsule formulation had no significant effect on blood
cholesterol. This study identified several physical differences between
the capsule and tablet preparations, but does not provide data
sufficient to identify the physical characteristics responsible for the
differences between capsule and tablet preparations in their abilities
to affect cholesterol absorption. However, the effectiveness of
nonesterified phytosterol/soy lecithin vesicle tablets (1.8 g per day)
on blood cholesterol reduction was confirmed in a subsequent
intervention study done with subjects taking statin drugs for
hypercholesterolemia (Ref. 67). The available scientific evidence for
the cholesterol-lowering effects of phytosterols in dietary supplements
shows that formulation of the supplement product is an important factor
in the effectiveness of the product in lowering cholesterol and that
esterifying the phytosterol is one way to ensure effectiveness. One
explanation for the inconsistent results obtained from dietary
supplements containing nonesterified phytosterols may be the importance
of phytosterol dispersal and solubility in the gastrointestinal tract.
The effectiveness of phytosterols to interfere with cholesterol
absorption depends on their ability to be soluble, adequately dispersed
within the intestinal contents, and incorporated into the mixed
micelles (Refs. 57 and 61).
    Because nonesterified phytosterols have poor solubility,
manufacturers must use a technique such as esterification to facilitate
absorption and dispersal of the phytosterols in the conventional food
itself. For example, as noted in section V.A.1 of this document, the
solubility of phytosterols in rape seed oil mayonnaise increased about
ten-fold when esterified with fatty acids (Ref. 28). No such techniques
are necessarily required, as a practical

matter, for adding phytosterols to dietary supplements, which commonly
come in tablets or capsules. Esterification, however, still serves to
make the phytosterols more soluble and thus suitable for dispersal in
the gastrointestinal tract and incorporation into the mixed micelles.
    The available scientific evidence shows that esterified
phytosterols are effective in lowering cholesterol and thus reducing
the risk of CHD. At this time, however, FDA finds that the totality of
available scientific evidence for the cholesterol-lowering effects of
nonesterified phytosterols in dietary supplements is inconsistent and
tentatively concludes that the scientific evidence for a relationship
between dietary supplements containing nonesterified phytosterols and
CHD does not meet the significant scientific agreement standard. FDA is
therefore proposing to amend Sec.  101.83(c)(2)(iii)(B) to make the use
of the health claim available to phytosterol ester-containing dietary
supplements that meet all the specific requirements of the claim stated
in Sec.  101.83 and the general health claim requirements of Sec.
101.14. However, FDA is not proposing to include nonesterified
phytosterol-containing dietary supplements as foods eligible for the
claim.
    FDA invites submission of additional data that demonstrate the
cholesterol-lowering efficacy of nonesterified phytosterols consumed as
ingredients in dietary supplements. At this time, there are no USP
standards for disintegration and dissolution for dietary supplements
containing phytosterols. Therefore, FDA is also requesting data to
provide a justification for inclusion or exclusion of specific dietary
supplement formulations using USP standards. FDA will reevaluate its
tentative conclusion regarding the eligibility of dietary supplements
containing both esterified and nonesterified phytosterols in light of
any additional data received.
3. Other Requirements
    a. Disqualifying total fat level. Under the general requirements
for health claims, foods are ineligible for health claims if they
contain more than 13 g of total fat: (1) Per RACC; (2) per labeled
serving size; and (3) when the RACC is small (30 g or less or 2
tablespoons or less), per 50 g of food (Sec.  101.14(a)(4) and
101.14(e)(3)). FDA may waive this disqualifying level for an individual
nutrient in a health claim based on a finding that the claim will
assist consumers in maintaining healthy dietary practices despite the
content of that nutrient in the food (Sec.  101.14(e)(3)). FDA had
concluded in the IFR that permitting the use of the phytosterol health
claim on labels of spreads and dressings for salad would assist
consumers to develop a dietary approach that would result in
significantly lower cholesterol levels and an accompanying reduction in
the risk of heart disease. Consequently current Sec.  101.83(c)(1) and
(c)(2)(iii)(C) permit the disqualifying level for total fat level on a
``per 50 g'' basis for foods with a small RACC (i.e., more than 13 g of
fat per 50 g) to be waived for spreads and dressings for salad, which
ordinarily have a high fat content, provided the label bears a
disclosure statement that complies with Sec.  101.13(h) (i.e., ``See
nutrition information for fat content'') (65 FR 54686 at 54706).
Current Sec.  101.83 does not exempt spreads and dressings for salads
from the total fat disqualifying level per RACC, and per label serving
size.
    The agency requested comments to the IFR on its decision to exempt
phytosterol-enriched spreads and dressings for salad from the
disqualifying level for total fat per 50 g (65 FR 54686 at 54710). The
agency also suggested that, despite its reluctance to grant broad
exceptions to the disqualifying levels, it was willing to consider
additional exemptions on a limited case-by-case basis and said that
manufacturers of products other than spreads and dressings for salad
may submit comments with supporting information or petition the agency
for an exemption from the total fat disqualification levels in Sec.
101.14(e)(3).
    FDA received a variety of comments in response to this aspect of
the IFR. Some comments agreed with FDA's exemption for spreads and
dressings for salad from the disqualifying level for total fat per 50
g, while other comments asserted that this exemption was not justified
and argued that foods with a high fat content should not be eligible
for a health claim. Some comments suggested that the exemption should
be extended to other foods, such as vegetable oils, which have a
similar nutrient composition to the foods currently exempted by Sec.
101.83(c)(2)(iii)(C), or extended to include all foods with a small
serving size. Some comments asserted that there should be an expedited
approach to permit additional exemptions to the fat-disqualifying
level.
    The agency believes that the limited exemption from the
disqualifying level of total fat on a per 50 g basis for foods with a
small reference amount continues to be appropriate for dressings for
salads and for spreads that resemble margarine. One of the factors in
FDA's decision to provide a limited exemption to the total fat
disqualifying level under Sec.  101.14(a)(4) was that, without this
exemption for spreads and dressings for salad, the number of foods
eligible for this health claim would be limited to such an extent that
the public health value of the claim would be undermined (65 FR 54686
at 54710). FDA is now proposing to remove the current restrictions on
food categories eligible to bear the phytosterol/CHD health claim.
Consequently the variety of phytosterol-enriched foods not high in
total fat and eligible to bear the health claim available to consumers
would significantly increase. Therefore, the agency does not find it