[Federal Register Volume 75, Number 235 (Wednesday, December 8, 2010)]
[Proposed Rules]
[Pages 76526-76571]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[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  

[[Page 76526]]


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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: 301-827-6870.
     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, 301-436-1450.

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

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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

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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

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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

[[Page 76530]]

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

[[Page 76531]]

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,

[[Page 76532]]

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

[[Page 76533]]

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.

[[Page 76534]]

 
                                  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).

[[Page 76535]]

 
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.


[[Page 76536]]

    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

[[Page 76537]]

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,

[[Page 76538]]

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

[[Page 76539]]

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

[[Page 76540]]

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

[[Page 76541]]

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 
necessary to expand the limited total fat ``per 50 g'' disqualifying 
level exemption to other foods with small servings out of concern that 
the number of foods eligible for the claim is limited. The type of food 
identified as ``spreads'' in current Sec.  101.83 was intended by the 
agency to be specifically vegetable oil spreads resembling margarine 
formulated with a reduced total fat content relative to the minimum 80 
percent fat content required under the standard of identity for 
margarine (Sec.  166.110). FDA realizes that without additional 
specification, the term ``spread'' could be interpreted to include 
other types of foods as well, such as mayonnaise and peanut butter-type 
spreads. Because FDA has tentatively concluded that it is not necessary 
to extend the limited exemption from disqualifying total fat level per 
50 g beyond the limited food categories initially included, the agency 
is proposing to clarify in amended Sec.  101.83(c)(2)(iii)(D) that the 
spreads that are exempt from Sec.  101.14(a)(4) are vegetable oil 
spreads that resemble margarine.
    Some comments recommended an exemption from the total fat 
disqualifying level be made to provide for the use of the health claim 
by liquid vegetable oils. These comments argued that liquid vegetable 
oils have fat composition as do the vegetable oil spreads and dressings 
for salads that can use the health claim. FDA recognizes that providing 
for disclosure of the total fat level rather than disqualification 
reflects an evolution in expert opinion on total fat intake and risk of 
CHD. The ``Dietary Guidelines for Americans, 2005'' (Ref. 69) 
recommends that Americans limit fat intake to between 20 to 35 percent 
of calories, with most fats coming from sources of polyunsaturated and 
monounsaturated fatty acids such as fish, nuts and vegetable oils, and 
limit intake of fats and oils high in saturated and/or trans fatty 
acids. Substituting liquid vegetable oils,

[[Page 76542]]

containing predominantly unsaturated fatty acids, for solid fats high 
in saturated fat and cholesterol is one dietary modification that can 
contribute to reducing dietary saturated fat and cholesterol.
    Several current qualified health claims (see FDA's 2003 Consumer 
Health Information for Better Nutrition Initiative (Ref. 70)) are about 
a relationship of the unsaturated fatty acids of certain vegetable oils 
(olive oil, canola oil, and corn oil) used to replace similar amounts 
of saturated fat without increasing calories consumed, and CHD risk 
(Refs. 71, 72, and 73). When deliberating the merits of these vegetable 
oil unsaturated fatty acid qualified health claims, FDA concluded that 
there was credible but limited scientific evidence that label 
statements informing consumers that they might lower their risk of CHD 
by consuming foods high in unsaturated fatty acids, such as vegetable 
oils, in place of similar foods high in saturated fatty acids, without 
increasing calorie consumption, is information that can help consumers 
develop a dietary approach to lower CHD risk. FDA also concluded that 
such information is consistent with current dietary guidelines, which 
emphasize that consuming diets low in saturated fat and cholesterol is 
more important in reducing CHD risk than is consuming diets low in 
total fat. FDA therefore decided that the disqualifying total fat level 
for health claims would not be a criterion in permitting the qualified 
health claims for unsaturated fats of vegetable oils. Consistent with 
the position taken in permitting the unsaturated fatty acids in 
vegetable oils and CHD qualified health claims, FDA finds that rather 
than disqualifying phytosterol-enriched liquid vegetable oils on the 
basis of total fat content, disclosure of the total fat content along 
with the phytosterol health claim, will help consumers develop a 
dietary approach to lowering blood cholesterol levels.
    Liquid vegetable oils are composed entirely of fat, and the amount 
of fat in a RACC (1 tablespoon, about 13.6 g) exceeds the disqualifying 
total fat level of 13 g. The limited exemption from the disqualifying 
total fat level on a per 50 g basis provided for spreads and dressings 
for salads, if extended to liquid vegetable oils, would still not make 
liquid vegetable oils eligible for a health claim. Therefore, FDA is 
proposing to exempt liquid vegetable oils from the total fat 
disqualifying level on a per RACC, per label serving size, and per 50 g 
basis.
    The agency is proposing to amend Sec.  101.83(c)(2)(iii)(D) to 
specify that the limited exemption from the disqualifying total fat 
level ``per 50 g basis'' for ``spreads'' applies specifically to 
vegetable oil spreads resembling margarine and not to other spreadable 
food products such as peanut butter and mayonnaise. In addition to the 
current exemption per 50 g for dressings for salad, the agency is also 
proposing to exempt liquid vegetable oils from the requirement per 
RACC, per labeled serving, and per 50 g.
    b. Low saturated fat and low cholesterol criteria. Current Sec.  
101.83(c)(2)(iii)(B) requires foods that bear the health claim to meet 
the nutrient content requirements in Sec.  101.62 for a ``low saturated 
fat'' and ``low cholesterol'' food.
    One comment to the IFR objected to the ``low saturated fat'' 
requirement for the phytosterol CHD health claim on the basis that it 
would severely limit the availability of sterol/stanol containing 
foods. The comment recommended that the requirement for ``low'' amounts 
of saturated fat are not appropriate for foods that contain equal 
amounts of saturated fat, monounsaturated fat, and polyunsaturated fat.
    There is strong and consistent scientific evidence that diets high 
in saturated fat and cholesterol are associated with elevated total and 
LDL cholesterol, and that elevated blood cholesterol levels are a major 
modifiable risk factor for CHD. The ``Dietary Guidelines for Americans, 
2005'' recommends lowering dietary saturated fat and cholesterol as a 
primary lifestyle change for reducing heart disease risk (Ref. 69).
    The variety of phytosterol-enriched foods tested in intervention 
studies since publication of the IFR indicates a range of food 
products, many of which are low fat or fat-free, that manufacturers 
contemplate marketing. There also are a number of foods in the food 
categories now eligible for the health claim under current Sec.  101.83 
that can qualify as ``low saturated fat'' and ``low cholesterol.'' As a 
result, FDA does not agree that requiring foods bearing the claim be 
``low saturated fat'' and ``low cholesterol'' would significantly limit 
the number of food products eligible to use the claim. Consequently, 
the agency is not proposing to amend the requirement that foods 
eligible for the claim be ``low in saturated fat'' and ``low in 
cholesterol.''
    c. Trans fat considerations. FDA is concerned about the presence of 
trans fats in foods bearing the phytosterols and risk of coronary heart 
disease claim. There is a positive linear trend between trans fatty 
acid intake and LDL cholesterol concentration, and therefore there is a 
positive relationship between trans fatty acid intake and the risk of 
CHD (Ref. 74). In the Institute of Medicine (IOM) report, Dietary 
Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, 
Cholesterol, Protein, and Amino Acids, in the discussion on dietary 
fats, total fat and fatty acids, the IOM states that trans fatty acids 
are not essential and provide no known benefit to human health (Ref. 
74). The IOM sets tolerable upper intake levels (UL) for the highest 
level of daily nutrient intake that is likely to pose no risk of 
adverse health effects to almost all individuals in the general 
population. In their 2005 report, the IOM does not set a UL for trans 
fatty acid because any incremental increase in trans fatty acid intake 
increases the risk of CHD (Ref. 74).
    Trans fats are naturally occurring in some foods made from ruminant 
animals (e.g., cattle and sheep) such as dairy products and meats (Ref. 
69). Trans fatty acids are created when unsaturated fatty acids are 
chemically changed through the process of hydrogenation \12\ to create 
a more solid food product (Ref. 69). Sources of trans fatty acids 
include partially hydrogenated and hydrogenated vegetable oils used in 
making shortening, margarine, baked goods such as biscuits and pie 
crusts, snack foods, fried foods, and margarine (Ref. 69). Since trans 
fats are naturally occurring in some foods that contribute essential 
nutrients such as protein, calcium and vitamin D, consuming zero 
percent of energy as trans fats would require substantial adjustments 
to the diet that may have undesirable effects (Ref. 74). To date, there 
have been no reports issued by authoritative sources that provide a 
level of trans fat in the diet above which there is a known increased 
risk of CHD and below which there is no risk of CHD. Recommendations 
are for Americans to limit trans fat as much as possible while 
consuming a nutritionally adequate diet (Refs. 3 and 74).
---------------------------------------------------------------------------

    \12\ Hydrogenation is the addition of a carbon-carbon double 
bond to a chain of unsaturated fatty acids. This produces a single 
carbon-carbon bond with two hydrogens attached to each carbon. This 
process converts liquid oils into more solid fats, which are used in 
making products such as margarine and shortening. Trans fats are a 
by-product of hydrogenation of vegetable oils (Ref. 75).
---------------------------------------------------------------------------

    The agency is taking several approaches to address trans fats. On 
July 11, 2003 (68 FR 41507), FDA published an advance notice of 
proposed rulemaking (ANPRM), in part, to solicit information and data 
that

[[Page 76543]]

could potentially be used to establish new nutrient content claims 
about trans fatty acids; to establish qualifying criteria for trans fat 
in current nutrient content claims for saturated fatty acids and 
cholesterol, lean and extra lean claims, and health claims that contain 
a message about cholesterol-raising lipids; and, in addition, to 
establish disclosure and disqualifying criteria to help consumers make 
heart-healthy food choices. On March 1, 2004 (69 FR 9559), FDA reopened 
the comment period to allow interested persons to consider the report 
issued by the Institute of Medicine of the National Academy of Science 
in December 2003 entitled ``Dietary Reference Intakes: Guiding 
Principles for Nutrition Labeling and Fortification.'' FDA extended the 
comment period on April 19, 2004 (69 FR 20838) to receive comment on a 
Food Advisory Committee Nutrition Subcommittee meeting discussing the 
scientific evidence for determining a maximal daily intake value of 
trans fat and how trans fat compares to saturated fat with respect to 
reducing coronary heart disease. Specifically, the agency requested 
comment on whether the available scientific evidence supported listing 
the percent Daily Value (DV) for saturated fat and trans fat together 
or separately on the Nutrition Facts label and what the maximal daily 
intake of trans fat may be. In addition, the agency published an ANPRM 
on November 2, 2007 (72 FR 62149) to request, in part, comment on what 
new reference values the agency should use to calculate the DV for a 
number of nutrients and what factors the agency should consider in 
establishing such values. FDA asked specific questions in the November 
2, 2007 ANPRM about trans fat labeling. Comments are being reviewed by 
the agency from these ANPRMs for consideration in defining nutrient 
content claims for trans fat and in deciding what levels of trans fat 
may be appropriate in foods bearing health claims about a reduced risk 
of coronary heart disease.
    FDA received a citizen petition from the Center for Science in the 
Public Interest (CSPI) in 2004 and one from Dr. Fred Kummerow in 2009 
asking the agency to revoke the GRAS status of partially hydrogenated 
oils. The agency is in the process of reevaluating the GRAS status of 
partially hydrogenated oils in response to the two citizen petitions. 
Finally, the agency is evaluating current analytical methods for the 
detection of trans fat in foods and is working on improving the 
sensitivity of these methods so that trans fat may be reliably detected 
at lower levels in foods.
    The agency is concerned that products containing phytosterols and 
bearing the health claim may also contain significant amounts of trans 
fat that could undermine the beneficial effects from consumption of the 
phytosterols in the product. The agency is not aware of any studies 
that were designed to determine the amount of trans fat that could 
offset the beneficial effects of phytosterols. Based on the available 
data, 0.8g/day of trans fat was the highest intake level from margarine 
at which there was a significant reduction in total and LDL cholesterol 
levels when the consumption of phytosterols was approximately 2 g/day 
(Ref. 41). The agency requests comment on whether these data, alone or 
in combination with other data or information, would support a 
limitation on the level of trans fat in foods, as an eligibility 
criterion, for foods that could bear the phytosterol and risk of 
coronary heart disease claim. Foods that contain more than this level 
of trans fat would be disqualified from bearing a claim. In addition, 
the agency requests comment on whether there are data that may support 
another level of trans fat that the agency should consider as an 
eligibility criterion for foods bearing such a claim. The agency also 
requests comment on available information that provides clarification 
on the effect of trans fat in products that also contain phytosterols.
    d. Minimum nutrient contribution requirement. Current Sec.  
101.83(c)(2)(iii)(D) requires that a conventional food bearing a health 
claim for phytosterol esters meet the minimum nutrient contribution 
requirement specified in Sec.  101.14(e)(6), unless it is a dressing 
for salad. Section 101.14(e)(6) requires that, except for dietary 
supplements or where provided in other health claim regulations, foods 
eligible to bear a health claim contain 10 percent or more of the 
Reference Daily Intake or Daily Reference Value for vitamin A, vitamin 
C, iron, calcium, protein, or fiber per reference amount prior to any 
nutrient addition. The minimum nutrient contribution requirement is 
necessary to ensure that the value of a health claim will not be 
trivialized or compromised by its use on a food of little or no 
nutritional value. In the IFR, the agency concluded that, while 
important, the minimum nutrient requirement for dressings for salad is 
outweighed by the public health importance of communicating the 
cholesterol-lowering benefits from consumption of plant sterol/stanol 
esters (65 FR 54686 at 54711). FDA found that the value of the health 
claim would not be trivialized or compromised by its use on dressings 
for salad because dressings for salad are typically consumed with foods 
rich in fiber and other nutrients. However, the agency decided that 
there was not a sufficient rationale to justify an exemption from this 
requirement for the remaining phytosterol-enriched foods that would 
have otherwise been eligible to bear the health claim. Id.
    The agency requested comments in the IFR on its decision to exempt 
only dressings for salad from the minimum nutrient requirement. FDA 
further stated that manufacturers of foods that do not meet the minimum 
nutrient requirement may submit comments with supporting information by 
a petition to the agency requesting an exemption from this requirement. 
Id.
    Comments were mixed as to whether the minimum nutrient contribution 
requirement should be applied to other foods eligible for the health 
claim. Some agreed with FDA's exemption from the minimum nutrient 
contribution requirement for dressings for salad, while other comments 
suggested that no foods should be exempt. Other comments suggested 
additional specific foods such as fruit drinks, smoothies, liquid 
vegetable oils, vegetable oil spreads or snack bars or groups of foods 
such as small servings to which the minimum nutrient requirement 
exemption might be extended either through fortification or waiving of 
the requirement.
    The purpose of the minimum nutrient contribution requirement is to 
ensure that health claims are used to promote only those foods that are 
consistent with dietary guidelines and to ensure that health claims are 
not to be trivialized or compromised by their use on foods of little or 
no nutritional value (e.g., jelly beans) (58 FR 2478 at 2481 and 2521). 
FDA exempted dressings for salad from the minimum nutrient requirement 
in current Sec.  101.83 in recognition that dressings for salad are 
typically consumed with other foods (specifically salads and 
vegetables) that are rich in a number of important nutrients and fiber. 
FDA is not persuaded by the rationales put forward for other foods, as 
a general matter. It does, however, concur that extending the exemption 
from this requirement for certain vegetable oil spreads and liquid 
vegetable oils is justified because they provide unsaturated fatty 
acids that can be used in place of saturated fatty acids in the diet.
    A key recommendation of the ``Dietary Guidelines for Americans, 
2005'' (Ref. 69) is that most fats in the diet should

[[Page 76544]]

come from sources of polyunsaturated and monounsaturated fatty acids 
such as fish, nuts, and vegetable oils. Using liquid vegetable oils in 
the diet as substitutes for solid and hardened fats is an approach to 
developing a heart-healthy diet that is consistent with the ``Dietary 
Guidelines for Americans, 2005.'' Liquid vegetable oils, like dressings 
for salad, will likely be consumed in small portions with foods rich in 
fiber and other nutrients. Vegetable oils contain none of the six core 
nutrient components of the minimum nutrient content requirement for 
health claims and therefore are ineligible for health claims unless an 
exemption is provided in a specific health claim regulation. The agency 
has concluded that the public health benefit of providing for use of 
the health claim on labels of certain liquid vegetable oil outweighs 
the concerns that health claims are trivialized by their use with foods 
of little nutritional value, and therefore is proposing that liquid 
vegetable oils be exempt from the minimum nutrient requirement in 
amended Sec.  101.83. As noted in section V.C.2.a of this document, FDA 
is proposing to also exempt liquid vegetable oils from the 
disqualifying level for total fat; however liquid vegetable oils will 
be subject to the requirement that foods bearing the phytosterol/CHD 
health claim be ``low saturated fat'' foods.
    Margarine, a standardized food under Sec.  166.110 including those 
that are nutritionally modified and labeled under 21 CFR 130.10 must 
contain not less than 10 percent of the recommended dietary allowance 
(RDA) for vitamin A per reference amount customarily consumed. 
Margarine substitutes may need to be fortified with Vitamin A to be 
nutritionally equivalent to margarine to avoid being categorized as 
``imitation'' margarine (Sec. Sec.  101.3(e)(2) and 104.20(e) (21 CFR 
101.3(e)(2) and 104.20(e))). As FDA stated in the rulemaking for Sec.  
101.14, permitting foods to be fortified with nutrients for the sole 
purpose of making a health claim that complies with the minimum 
nutrient requirement would be misleading and inconsistent with FDA's 
fortification policy in Sec.  104.20 (58 FR 2478 at 2521). FDA also 
stressed, however, that ``the exclusion of fortification pertains only 
to fortification to specifically meet the requirements of this 
provision and not to the fortification of the food itself'' (id.). 
Vegetable oil spreads that resemble and substitute for margarine may be 
required to be fortified with Vitamin A to avoid being categorized as 
an ``imitation'' (as explained in this paragraph) and those not 
required to be so fortified may be optionally fortified under Sec.  
104.20. Such spreads usually serve as substitutes for products higher 
in saturated fats and cholesterol. Thus, the agency believes that 
permitting vegetable oil spreads resembling margarine to meet the 
minimum nutrient contribution requirement through the addition of 
Vitamin A is consistent with FDA's fortification policy and appropriate 
as an exemption to the requirement in Sec.  101.14(e)(6) that the food 
contain 10 percent or more of a nutrient prior to any nutrient 
addition.
    The agency is not convinced that additional modifications to 
current Sec.  101.83(c)(1) and (c)(2)(iii)(D) to provide exemptions 
from the minimum nutrition contribution requirement for additional 
foods are warranted. Because the agency is proposing to drop the 
limitation on eligible food categories and extend the claim to include 
nonesterified phytosterols and mixture of plant sterols and stanols, 
there would be a greater variety of lower fat, heart healthy 
phytosterol-enriched foods that would be able to bear the health claim 
without extending the minimum nutrient contribution requirement. 
Further, the agency believes that dropping the requirement in Sec.  
101.14(e)(6) altogether could lead to indiscriminate use of health 
claims on foods with little or no nutritional value such as snack and 
confectionary items. Therefore, the agency is not proposing to provide 
further exemptions to the minimum nutrient contribution requirement.
    While FDA will consider any further requests for exemptions that it 
receives via the petition process as expeditiously as possible, it 
still expects that any such request will be accompanied with adequate 
justification for the exemption. The agency does not plan to set up an 
expedited notification process for such a review.
    In short, the agency is proposing to amend Sec.  
101.83(c)(2)(iii)(E) to permit liquid vegetable oils to be exempt from 
the minimum nutrient requirement. FDA is also proposing to amend this 
provision to permit the minimum nutrient contribution requirement for 
vegetable oil spreads resembling margarine to be met by the addition of 
vitamin A consistent with FDA's fortification policy.

D. Model Claims

    Current Sec.  101.83(c)(2)(i) prescribes specific requirements for 
health claims that link plant sterol/stanol esters to reduced risk of 
CHD. Current Sec.  101.83(e) provides examples of model health claims 
that may be used to comply with the requirements in Sec.  
101.83(c)(2)(i). As discussed in previous sections of this document, we 
are proposing modifications to Sec.  101.83 that would entail revision 
of specific requirements for health claims and the examples of model 
health claims. Consequently, the agency is proposing to revise Sec.  
101.83(c)(2)(i) and (e) accordingly.

E. Cautionary Statements

    Current Sec.  101.83 does not require cautionary or advisory 
statements regarding the potential effect of consuming phytosterols on 
the absorption of other nutrients or on certain subpopulation groups, 
and FDA did not address the use of such statements in the IFR. However, 
the agency subsequently became aware that regulatory bodies in other 
countries had concluded that requiring such statements on the labels of 
products containing phytosterols or limiting the use of phytosterols in 
food was necessary to guard against such effects. When the IFR comment 
period was reopened, FDA requested comments on ``whether changes to 
[Sec.  101.83], advisory labeling, or other actions are needed'' to 
address concerns regarding the effect of consuming plant/sterol esters 
on the absorption of beta-carotene and on certain subpopulation groups 
(66 FR 50824 at 50826).
    Some comments focused on the safety of consuming plant/sterol 
esters for certain subpopulation groups, such as those taking drugs to 
lower cholesterol or those suffering from phytosterolemia, an autosomal 
recessive disorder characterized by increased intestinal absorption of 
dietary cholesterols and phytosterols. Those comments disagreed whether 
the labels of foods bearing the health claim should provide an advisory 
statement. Other comments asserted that consuming phytosterols inhibits 
intestinal absorption of fat soluble vitamins and carotenoids and that 
requiring an advisory statement on foods bearing the health claim is 
necessary to prevent adverse health consequences, especially in 
vulnerable subpopulation groups, such as children or pregnant or 
lactating women.
    Section 201(n) of the act states that, in determining whether 
labeling is misleading, the agency shall take into account not only 
representations made about the product, but also the extent to which 
the labeling fails to reveal facts material in light of such 
representations made or suggested in the labeling with respect to 
consequences which may result from use of the article to which the 
labeling relates under the conditions of use as are customary or usual 
(see 21

[[Page 76545]]

CFR 1.21). Thus, the omission of certain material facts from the label 
or labeling on a food causes the product to be misbranded within the 
meaning of sections 403(a)(1) and 201(n) of the act. Under that 
authority, FDA has considered the use of cautionary statements to 
address each of the public health issues identified by other regulatory 
bodies and the similar concerns raised in comments.
    With respect to the comments about the effects of consuming 
phytosterols on individuals suffering from rare conditions that make 
them hyper-sensitive to phytosterols, FDA tentatively concludes that no 
cautionary statement regarding those effects in the labeling of foods 
bearing the health claim or any other action is necessary. For the 
consumers at whom such a cautionary statement would be directed, i.e., 
those aware that they have a phytosterol-sensitive condition, the 
health claim itself and the required ingredient declaration (see 21 CFR 
101.4(a)) should provide sufficient warning that the product contains 
phytosterols. Such consumers could consult with their medical 
practitioner regarding the possible consequences of consuming 
phytosterols.
    As for a cautionary statement regarding potential adverse 
interactions with cholesterol-lowering drugs, FDA tentatively concludes 
that Sec.  101.83 should not require such a statement in the labeling 
of food bearing the health claim. FDA is unaware of any scientific 
evidence demonstrating that consuming phytosterols while on 
cholesterol-lowering drugs results in any adverse health consequences. 
The agency thus sees no justification for requiring a statement 
specific to consumers taking cholesterol-lowering drugs. We invite the 
submission of any data or other evidence demonstrating adverse health 
consequences under such circumstances.
    With respect to the comments about the potential effect of 
phytosterols on the absorption of certain nutrients in the population 
as a whole or in certain subpopulation groups, FDA tentatively 
concludes that the available scientific evidence does not support a 
need for a cautionary statement regarding that potential effect. As 
noted in this section of the document, the potential effect of 
phytosterol-enriched foods on lowering plasma fat soluble vitamins and 
carotenoids has been a concern to regulatory bodies in some other 
countries. The European Commission (EC) Scientific Committee on Food 
(SCF) recommended that the beta-carotene lowering effect of 
phytosterol-enriched foods be communicated to the consumer, together 
with appropriate dietary advice regarding the regular consumption of 
fruits and vegetables (Refs. 76 and 77). As a result, EC regulations 
for the labeling of foods with added phytosterols require a label 
statement stating that: (1) Phytosterol-enriched foods may not be 
nutritionally appropriate for pregnant or breastfeeding women and 
children under the age of 5 years; and (2) phytosterol-enriched foods 
should be used as part of a balanced and varied diet, including regular 
consumption of fruit and vegetables to help maintain carotenoid levels 
(Refs. 78 and 79). Similarly, Food Standards Australia New Zealand 
(FSANZ) requires that phytosterol-enriched foods have a label statement 
advising that the product should be consumed in moderation as part of a 
diet low in saturated fat and high in fruits and vegetables, and that 
the product is not recommended for infants, children, or pregnant or 
lactating women unless under medical supervision (Ref. 80).
    FDA reviewed 19 intervention studies that evaluated the effect of 
phytosterol intake on the intestinal absorption of fat soluble vitamin 
and carotenoid, by measuring plasma levels (Refs. 24, 26, 35, 37, 39, 
41, 51, 55, 59, 81, 82, 83, 84, 85, 86, 87, 88, 89, and 90). 
Collectively, these studies provided phystosterols ranging from 0.8 to 
9 g per day. After adjusting for plasma total or LDL cholesterol 
levels, only one study showed that vitamin E levels were significantly 
reduced with phytosterol intake (3 g per day) (Ref. 88). Vitamin E 
levels were not altered at higher phytosterol intake levels (3.2 to 9 g 
per day) (Refs. 51, 55, 88, and 89). There was no effect of phytosterol 
intake on adjusted levels of other fat soluble vitamins (i.e., vitamin 
A, vitamin D, vitamin K).
    While phytosterol intake was shown in some studies to reduce 
adjusted levels of beta-carotene (the major pro-vitamin A carotenoid) 
to a statistically significant degree at phytosterol intake levels 
ranging from 3 to 9 g per day (Refs. 51, 55, 87, 88, 89, and 90) there 
was no effect on serum retinol levels (a biomarker of vitamin A 
status). Some studies also showed a reduction in carotenoids such as 
lutein and lycopene, but these food components likewise do not have an 
established health benefit at a particular level. Thus, FDA has no 
basis for concluding that any reduction in the intestinal absorption of 
these nutrients caused by consuming phytosterols amounts to an adverse 
health consequence.
    FDA has determined that available scientific evidence does not 
demonstrate that consuming phytosterols has an effect on intestinal 
absorption of fat soluble vitamins. Furthermore, although there is some 
evidence that consuming phytosterols reduces plasma levels of 
carotenoids such as beta-carotene, lutein, and lycopene, those 
carotenoids have no established health benefits at particular levels. 
Therefore, the agency is not proposing that Sec.  101.83 require a 
cautionary statement regarding a potential effect on fat soluble 
vitamins or carotenoids.
    In conclusion, the agency finds that the failure of a food bearing 
the health claim to include any of the foregoing cautionary statements 
would not render the food's labeling misleading under section 403(a)(1) 
of the act. We are therefore not proposing that Sec.  101.83 require 
any of the foregoing cautionary statements. Furthermore, the available 
science does not persuade FDA that the use of phytosterols at the 
levels necessary to justify the claim render the food unsafe or 
unlawful under the relevant safety provisions of the act, even in the 
absence of such cautionary statements. But FDA again notes that 
authorization of a health claim for a substance should not be 
interpreted as an affirmation that the substance is safe and lawful for 
all uses.

F. Status Under Section 301(ll) of Foods Containing Nonesterified and 
Esterified Phytosterols

    Section 301(ll) of the act (21 U.S.C. 331(ll)) prohibits the 
introduction or delivery for introduction into interstate commerce of 
any food that contains a drug approved under section 505 of the act (21 
U.S.C. 355), a biological product licensed under section 351 of the 
Public Health Service Act (42 U.S.C. 262), or a drug or a biological 
product for which substantial clinical investigations have been 
instituted and their existence made public, unless one of the 
exemptions in section 301(ll)(1)-(4) applies. In this proposal to amend 
the regulation authorizing a health claim on the relationship between 
plant sterol esters and plant stanol esters and reduced risk of CHD for 
use on food labels and in food labeling, FDA did not consider whether 
section 301(ll) of the act or any of its exemptions would apply to 
foods containing nonesterified or esterified phytosterols. Accordingly, 
this proposed rule should not be construed to be a statement that foods 
that contain nonesterified or esterified phytosterols, if introduced or 
delivered for introduction into interstate commerce, would not violate 
section 301(ll) of the act. Furthermore, this language is included in 
all health claim proposed

[[Page 76546]]

and final rules and should not be construed to be a statement of the 
likelihood that section 301(ll) of the act applies.

VI. Enforcement Discretion

    Pending issuance of a final rule, FDA intends to consider the 
exercise of its enforcement discretion on a case-by-case basis when a 
health claim regarding phytosterols is made in a manner that is 
consistent with the proposed rule. Beginning 75 days from the date the 
proposed rule publishes, FDA does not intend to exercise its 
enforcement discretion based on the letter issued in 2003 (Ref. 1). The 
act's enforcement provisions commit complete discretion to the 
Secretary of Health and Human Services (and by delegation to FDA) to 
decide how and when they should be exercised (see Heckler v. Chaney, 
470 U.S. 821 at 835 (1985); see also Shering Corp. v. Heckler, 779 F.2d 
683 at 685-86 (DC Cir. 1985) (stating that the provisions of the act 
``authorize, but do not compel the FDA to undertake enforcement 
activity'')). Until the agency issues a final rule amending the 
requirements of Sec.  101.83, the agency believes that its exercise of 
enforcement with respect to claims that do not comply with current 
Sec.  101.83 but do comply with the proposed rule is appropriate. Food 
bearing the health claim would be required to comply with any revised 
requirements established in the final rule when the final rule becomes 
effective.

VII. Environmental Impact

    FDA has determined under 21 CFR 25.32(p) that this action is of a 
type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VIII. Analysis of Economic Impacts

Preliminary Regulatory Impact Analysis

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this proposed rule is not a significant regulatory action as defined by 
the Executive order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because the costs to all businesses would be low and 
will not likely have a significant economic impact on a substantial 
number of small businesses, the agency believes that the proposed rule 
will not have a significant economic impact on a substantial number of 
small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and Tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $135 million, using the most current (2009) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
proposed rule to result in any 1-year expenditure that would meet or 
exceed this amount and has determined that this proposed rule does not 
constitute a significant rule under the Unfunded Mandates Reform Act.

A. Need for the Rule

    The scientific evidence relating to phytosterols and the risk of 
CHD has developed to warrant proposing to amend the existing health 
claim for plant sterol/stanol esters and CHD. If finalized, this rule 
would allow manufacturers of products that meet certain conditions to 
provide the most scientifically reliable, up-to-date information on the 
relationship between diets that include phytosterols and the risk of 
CHD. In addition, this rule would allow an increased number of foods to 
be eligible to make this health claim, by including foods other than 
the limited number in the current regulation, and increasing the 
variety of composition of the phytosterol ingredients included under 
the regulation, i.e., inclusion of plant sterol and plant stanol 
mixtures, inclusion of forms of phytosterols in conventional foods 
other than those esterified with fatty acids, and inclusion of 
additional forms of dietary supplements. The greater availability of 
foods containing the required minimum amounts of phytosterols and with 
up-to-date information on their labels would provide additional health 
benefits for consumers that are consistent with the current state of 
scientific evidence. FDA announced, in February 2003, its decision to 
consider exercise of enforcement discretion, within certain parameters, 
in regards to the use of the phytosterol/CHD health claim in order to 
provide greater flexibility in the application of the claim than that 
allowed under the IFR. The proposed rule would reduce any uncertainty 
that may arise on the part of manufacturers from the real and perceived 
lack of permanency inherent in the policy of enforcement discretion.

B. An Overview of the Changes in Behavior From the Regulatory Options

    FDA's benefit-cost analysis assumes the existing regulatory 
requirements of Sec.  101.83, rather than upon the 2003 enforcement 
discretion criteria, as the baseline upon which to measure the impact 
of this proposed rule. The regulatory options considered are as 
follows:
     Option 1--Take no new regulatory action,
     Option 2--Implement the proposed rule,
     Option 3--Restrict coverage of the proposed option to only 
conventional foods and not allow dietary supplements to make a 
phytosterols/CHD health claim, and
     Option 4--Restrict the proposed option to require 
manufacturers of any product claiming reduced risk of CHD from 
phytosterols consumption, for which the analytical method for 
determining the quantity of phytosterols is different than either the 
McNeil or Unilever methods, to provide FDA with access to documentation 
substantiating the amount of phytosterols contained in the food 
product.
    There would be no changes from current behavior by consumers and 
manufacturers for option 1. No products would need to be re-labeled or 
reformulated, and consumer information on the relationship between 
diets containing phytosterols and the risk of CHD currently found on 
food labels would remain unchanged.
    For option 2, the proposed rule, manufacturers of vegetable 
spreads, salad dressings, snack bars, and dietary supplements in 
softgel form that currently use the plant sterol/stanol esters health 
claim would be required to re-label their products to conform to the 
claim language required under the proposed rule. Manufacturers of plant 
sterol ester-enriched products would also be required to reformulate 
these products if they contain no more than the minimum 0.65 g sterol 
ester/RACC (equivalent to 0.4 g nonesterified plant sterol) required 
under the IFR for plant

[[Page 76547]]

sterol esters, and if they want to continue to make the claim. The IFR 
requires a minimum of 1.7 g/RACC of plant stanol esters (equivalent to 
1 g of nonesterified plant stanol), so manufacturers of plant stanol 
ester-enriched products, including dietary supplements in softgel form 
that currently make a phytosterols/CHD health claim, would not be 
required to reformulate to continue to make the claim. Consumers would 
benefit from more up-to-date information on food labels, the increase 
in the intake of phytosterols, and the wider range of foods and dietary 
supplements that would likely contain phytosterols, which may 
contribute to an increase in the intake of phytosterols and a reduction 
in the risk from CHD.
    For ensuring compliance with the labeling requirements for 
vegetable spreads, salad dressings, snack bars, and dietary supplements 
in softgel form, the protocol for sampling and testing the products 
directly for phytosterols content would be changed to the Sorenson and 
Sullivan method from the McNeil or Unilever methods. The Sorenson and 
Sullivan method would also be used to ensure compliance with the 
labeling requirements for the variety of products newly allowed to 
claim a relationship between diets containing phytosterols and the 
reduction in risk from CHD.
    Option 3 would restrict coverage of the proposed requirements to 
only conventional foods, so that manufacturers of some plant stanol 
ester-containing dietary supplements in softgel form that currently 
claim reduced risk of CHD from plant sterol/stanol esters consumption 
would no longer be allowed to make that claim. These manufacturers are 
assumed to re-label their products to either make no claim or to make a 
structure/function claim. Benefits from the consumption of dietary 
supplements in softgel form may be reduced.
    For option 4, the behavioral changes by manufacturers and consumers 
are assumed to be the same as those from the proposed option. To ensure 
compliance with the labeling requirements for vegetable spreads, salad 
dressings, snack bars, and dietary supplements, sampling and testing 
the products directly for phytosterols content using either the McNeil 
or Unilever methods would be used. Ensuring compliance with the 
labeling requirements for the variety of food products and dietary 
supplements that would be newly allowed to claim benefits from the 
relationship between phytosterols consumption and the risk of CHD, for 
which the analytical method for making this determination is different 
than either the McNeil or Unilever methods would require FDA access to, 
and analyses of, documents that substantiate the amount of phytosterols 
contained in these products.

C. Costs of Option 2 (the Proposed Rule)

    The costs of the proposed rule are from the re-labeling required of 
products that currently make the plant sterol/stanol esters-CHD health 
claim to conform to the claim language required under the proposed 
rule. Manufacturers of plant sterol ester-enriched products may also 
incur reformulation costs associated with the increase in the 
phytosterols content required to make the health claim under the 
proposed rule.
    Vegetable spreads, salad dressings, snack bars, and dietary 
supplements that currently make a plant sterol/stanol esters and CHD 
health claim would have to be re-labeled because of this rule. All 
current manufacturers of these products would bear the costs of unused 
label inventory as well as the costs of designing and printing new 
labels to comply with the updated health claim requirements. Some 
manufacturers of plant sterol ester-enriched vegetable spreads and 
salad dressings will decide to reformulate their products in order to 
meet the higher minimum amounts of phytosterols per serving required 
for plant sterol esters to make a phytosterols-CHD health claim under 
the proposed rule. Moreover, some manufacturers of plant stanol ester-
enriched snack bars may decide not to make a phytosterols-CHD health 
claim due to the required new language that specifies that the daily 
dietary intake of phytosterols should be consumed with meals; snack 
bars may be less likely than vegetable spreads or salad dressings to be 
consumed with meals.
    FDA does not have any information on how many labels would have to 
be redesigned, or the number of products that would be reformulated 
because of the proposed rule. Many existing products would not need to 
reformulate because the qualifying amount of plant stanol content in 
the IFR--1.7 g plant stanol esters per RACC, or the equivalent of 1 g 
of nonesterified stanols--is higher than the qualifying amount of 
phytosterols (plant sterols/stanols) per RACC in this proposed rule 
(0.5 g per RACC). Some products that currently enrich with plant sterol 
esters in order to make the plant sterol/stanol esters and CHD health 
claim may need slight reformulation since the qualifying amount in the 
IFR--0.65 g plant sterol esters per RACC, or the equivalent of 0.4 g of 
nonesterified sterols--is slightly lower than the qualifying amount of 
phytosterols per RACC required in this proposed rule. However, there is 
evidence suggesting that some food products now enriching with plant 
sterol esters are formulated with more than 0.5 g phytosterol per RACC. 
For example, the phytosterol content of the sterol ester-enriched 
product Benecol spread (Ref. 111) exceeds the 0.5 g per RACC and would 
not need to reformulate.
    The agency uses the FDA Labeling Cost Model to estimate the costs 
of redesigning the labels and the costs of lost label inventory for 
estimated small fractions of the vegetable spreads, salad dressings, 
snack bars and dietary supplements sectors (Ref. 112). In order to use 
the FDA Labeling Costs Model to estimate the re-labeling costs, FDA 
estimates the percentage of each of the sectors that would incur costs 
from the proposed rule. These percentages are then applied to the 
sector-wide results obtained by the Labeling Cost Model.
    For estimating the percentage of the dietary supplements sector 
that currently make a plant sterol/stanol esters and CHD health claim, 
FDA uses information from the 1999 report by Research Triangle 
Institute for FDA entitled ``Dietary Supplements Sales Information'' 
(Ref. 113). Research for that report found that of the approximately 20 
categories of claims made by dietary supplements, approximately 20 
percent make a claim regarding circulatory system benefits. FDA assumes 
that 67 percent of the claims regarding circulatory system benefits are 
either structure/function claims or nutrient content claims, and 50 
percent of the remaining 33 percent address the risk of CHD, then about 
3.3 percent of all dietary supplements address the risk of CHD (i.e., 
20 percent x 33 percent x 50 percent).
    FDA uses representative scanner data on sales and forms that 
dietary supplements take over the period 2001-2005, to estimate that 2 
percent of all dietary supplement sales are in softgel form. Consistent 
with the estimated percent for dietary supplements overall, FDA assumes 
that 3.3 percent of all dietary supplements in softgel form may have a 
health claim that addresses the risk of CHD, and that no more than 10 
percent of those with health claims that address the risk of CHD may 
make a phytosterols health claim. Consequently, FDA estimates that 
between 0 and 0.007 percent of dietary supplements sold may currently 
make a plant sterol/stanol esters and CHD health claim and would be re-
labeled (2 percent of all dietary supplements x 3.3

[[Page 76548]]

percent that make a claim that addresses CHD x 0 to 10 percent that may 
make a phytosterols-CHD health claim).
    To estimate the percent market shares of conventional food products 
to apply to the Labeling Cost Model, the agency uses results from FDA's 
2001 Food Label and Package Survey (FLAPS), from which LeGault, et al. 
report that 4.4 percent of all food products sold make at least one of 
the FDA-approved health claims (Ref. 114). In order to estimate the 
market share of foods that may make a plant sterol/stanol esters and 
CHD health claim, FDA takes the estimated percentage of total sales of 
products that make any claim (4.4 percent) and multiply it by the 
percentage of health claims that were found to address the risk of CHD 
(41.7 percent). FDA assumes that 10 percent of all packaged food sales 
with claims that address the risk of CHD may make a phytosterols-CHD 
health claim. Consequently, FDA estimates that approximately 0.2 
percent of all food sales in the vegetable spreads and salad dressings 
sectors may make a plant sterol/stanol esters and CHD health claim 
(i.e., 4.4 percent x 41.7 percent x 10 percent, rounded to the nearest 
tenth of a percent).
    To account for the smaller likelihood that manufacturers of snack 
bars that currently make a plant sterol/stanol esters and CHD health 
claim will continue to do so under the proposed rule, FDA divides the 
estimate for vegetable spreads by 2 to obtain the market share for the 
snack bar sector that would incur re-labeling costs.
    While the names of most of the sectors used by both the Labeling 
Cost Model and Reformulation Cost Model correspond closely with those 
that are currently identified in the IFR, there is no snack bar sector 
identified in the models. Consequently, FDA uses the labeling costs for 
the ``Salty Snacks--Other'' category to approximate those for the snack 
bar category. FDA assumes that firms will have 1 year to come into 
compliance. The estimated low, medium, and high costs of re-labeling 
generated by the labeling cost model for these sectors made assuming a 
12-month compliance period are provided in table 4 of this document. 
Because 12 months represents a compliance period likely to be shorter 
than the actual period, actual costs may be lower.

                        Table 4--Re-Labeling Costs Assuming a 12-Month Compliance Period
----------------------------------------------------------------------------------------------------------------
                          Product group                                 Low           Medium           High
----------------------------------------------------------------------------------------------------------------
Salty Snacks--Other.............................................         $27,000         $38,000         $52,000
Margarines......................................................           3,000           4,000           8,000
Fats and Oils...................................................          25,000          35,000          57,000
Salad Dressings and Toppings....................................          30,000          42,000          67,000
Dietary Supplements--Liquid.....................................             900           1,000           2,000
                                                                 -----------------------------------------------
    Total.......................................................          86,000         121,000         186,000
----------------------------------------------------------------------------------------------------------------

    FDA uses the Reformulation Cost Model to estimate the costs of 
reformulating products for estimated fractions of the vegetable 
spreads, salad dressings, snack bar, and dietary supplement sectors in 
which it is likely that firms currently make a plant sterol/stanol 
esters and CHD health claim (Ref. 115). FDA assumes that most 
conventional food products that currently make a plant sterol/stanol 
esters and CHD health claim currently meet the minimum per-serving 
requirements in the proposed rule. FDA assumes that some conventional 
food products that enrich with plant sterol esters will have to be 
reformulated in order to meet the minimum per-serving requirements. FDA 
assumes that 25 percent of conventional food products that currently 
make a plant sterol/stanol esters and CHD health claim will reformulate 
to keep the claim. FDA assumes that no dietary supplements in softgel 
form that currently make a plant sterol/stanol esters and CHD health 
claim would have to reformulate in order to meet the minimum per-
serving requirements in the proposed rule.
    FDA assumes that any reformulation costs incurred by manufacturers 
of these products will involve minor changes to recipes and 
ingredients. The estimated costs of reformulating generated by the 
reformulation cost model for sectors that correspond closely with those 
identified in the IFR used to compute labeling costs are made assuming 
a 12-month compliance period and are provided in Table 5 of this 
document. Discarded inventories are the primary cost of reformulation 
when the model is computed under these assumptions. FDA requests 
comments on the magnitude of the reformulation cost generated by the 
model, as well as the assumption that discarded inventories would be 
the primary source of reformulation costs.
    To characterize uncertainty about the total reformulation costs, 
FDA assumes that the estimated total reformulation costs is distributed 
normally with a mean equal to the addition of all of the costs 
estimated for the individual sectors ($5,200), and a standard deviation 
equal to that for the data across sectors ($650). FDA requests comments 
on these estimates. The confidence interval that contains the true 
amount of total reformulation costs with 95 percent probability under 
the stated assumptions is reported in the bottom row of Table 5.

   Table 5--Reformulation Costs Assuming a 12-Month Compliance Period
------------------------------------------------------------------------
              Product group                     Reformulation costs
------------------------------------------------------------------------
Salty Snacks--Other......................  $500.
Vegetable oils...........................  $1,500.
Margarines...............................  $1,500.
Salad Dressings--Refrigerated............  $150.
Salad Dressings--Bottled, Unrefrigerated.  $1,500.
                                          ------------------------------
    Total................................  Between $700 and $9,000.
------------------------------------------------------------------------

D. Benefits of Option 2 (the Proposed Rule)

1. The Importance of the Health Risk Addressed by the Claim
    CHD is the leading cause of death and permanent disability in the 
United States (Ref. 116). The National Center for Health Statistics in 
the Centers for Disease Control and Prevention (CDC) reports that in 
2002 there were approximately 23 million non-institutionalized adults 
diagnosed with CHD, resulting in approximately 700,000 deaths. 
According to the same source, CHD patients made approximately 20.8 
million office-based

[[Page 76549]]

physician visits and approximately 1.1 million hospital outpatient 
visits in that year. In addition, there were approximately 4.4 million 
hospital discharges of CHD patients, with average lengths of stay of 
approximately 4.4 days. As an indication of the extent to which this 
disease is disabling, CDC reports that approximately 66 percent of 
heart patients fail to fully recover (Refs. 116 and 117).
2. The Benefits Model
    The benefit of the proposed rule relative to the IFR is the reduced 
risk of CHD that may result from consumers substituting a greater 
number of foods containing phytosterols for currently consumed 
alternatives that do not reduce the risk of CHD. The proposed rule 
would increase the number of food products eligible to use the 
phytosterols-CHD health claim from only foods enriched with esterified 
sterols and stanols, to include conventional foods enriched with 
nonesterified and esterified phytosterols, as well as mixtures of 
sterols and stanols, and additional forms of dietary supplements. 
Consequently, a wide variety of low and non-fat foods that are 
currently not authorized to make the plant sterol/stanol esters-CHD 
health claim may do so under the proposed rule.
    FDA anticipates that foods for which GRAS notifications for 
phytosterols use have been submitted may be qualified to make a 
phytosterols-CHD health claim under this proposed rule. Phytosterol 
GRAS notifications to which FDA has no objections include, but are not 
limited to, the use of phytosterols as ingredients in: Margarine and 
vegetable oil spreads, salad dressings, mayonnaise, edible vegetable 
oils, snack bars, dairy and dairy-like substitutes (including those for 
yogurt, ice cream, cream cheese, and milk and milk based beverages), 
baked foods, ready-to-eat breakfast cereals, pasta and noodles, sauces, 
salty snacks, processed soups, puddings, confections, white breads and 
white bread products, vegetable meat analogues, fruit and vegetable 
juices, and coffee. The increase in the number of conventional foods in 
which phytosterol-enrichment has been self-determined to be GRAS and 
that may be qualified to make a health claim under the proposed rule, 
suggests an increase in consumption of conventional foods with 
phytosterols-CHD health claims.
    The higher effective daily intake of phytosterols required to be 
communicated on the health claim may also increase the dietary intake 
of phytosterols. The effective daily intake of phytosterols that must 
be stated in the health claim has been increased to 2 g per day of 
phytosterols (expressed as weight of nonesterified phytosterols) for 
both plant sterols and plant stanols in the proposed rule. The IFR 
specified effective daily intake levels of 1.3 g per day of plant 
sterol esters (equivalent to 0.8 g of nonesterified plant sterols) and 
3.4 g per day of plant stanol esters (equivalent to 2 g of 
nonesterified plant stanols).
    FDA assumes that the proposed change in the minimum amount of 
phytosterols required for eligible foods to 0.5 g of phytosterols per 
RACC would have no impact on the number of plant stanol-enriched foods 
that make the claim because the 0.5 g of phytosterols per RACC required 
minimum in this proposed rule is less than the qualifying amount of 
plant stanol esters required under the IFR (1 g/RACC as nonesterified 
stanol). FDA also assumes that the proposed change in the minimum 
amount of phytosterols required for eligible foods would have no impact 
on the number of plant sterol-enriched foods that make the claim 
because the 0.5 g of phytosterols per RACC required minimum in this 
proposed rule is only slightly higher than the qualifying amount 
required under the IFR for plant sterol esters (0.4 g/RACC as 
nonesterified sterol). Finally, the proposed new claim language 
specifying that phytosterols should be consumed with meals, rather than 
specifying that phytosterols should be consumed in two servings eaten 
at different times of day with other foods, may result in fewer snack 
foods making the health claim.
3. The Increase in Dietary Intake of Phytosterols
    FDA estimates the increase in the market share of newly labeled 
products that may make a phytosterols-CHD health claim as a first step 
to model the increase in dietary intake of phytosterols. The agency 
refines this estimate of the increase in dietary intake to account for 
the possibility that increased consumption of foods newly permitted to 
make a health claim under this proposed rule contain the same levels of 
phytosterols as foods currently consumed but not allowed to make a 
claim. FDA further refines its estimate of the increase in dietary 
intake of phytosterols from this proposed rule to account for the 
consumption of meals away from home that are not subject to packaged 
food labeling regulations; the portion of dietary intake of 
phytosterols from meals away from home is assumed to not be affected by 
the proposed rule.
    The increase in dietary intake of phytosterols will be less than 
the increase in the market share of packaged food products that may 
make a health claim if meals are consumed away from home and 
consequently not subject to packaged food labeling regulations, or if 
consumption of foods newly permitted to make a health claim under this 
proposed rule contain the same levels of phytosterols as foods 
currently consumed that are not allowed to make a claim. FDA uses data 
from the U.S. Department of Agriculture (USDA) to estimate the fraction 
of total food consumption (both in-home as well as away-from-home 
consumption) that is subject to packaged food labeling requirements. 
Food consumed at home accounts for about 57 percent of all food 
expenditures (Ref. 118). FDA assumes that half of the remaining sales 
of newly labeled foods that may make a phytosterols-CHD health claim 
will reflect purchases of existing products that contain threshold 
levels of phytosterols but are not currently allowed to make a 
phytosterols-CHD health claim. If FDA applies these estimates to the 
0.2 percent for the market share of packaged food products that may 
make the health claim permitted by this proposed rule, FDA estimates 
that the percent increase in dietary intake of phytosterols as a result 
of this proposed rule may be 0.06 percent (i.e., (0.2 percent x 57 
percent)/2) of current levels.
    Finally, the increase in dietary intake of phytosterols does not 
necessarily lead to health benefits for all consumers. Healthful 
characteristics, including the phytosterols content, are just some of 
several considerations consumers use when making food purchases. 
Consumers who choose newly formulated foods that make the phytosterols-
CHD health benefits over foods that do not contain phytosterols may 
include both those at risk of CHD as well as those who are not at risk. 
If a substantial number of those who are at risk of CHD will increase 
their intake of phytosterols because of the phytosterols-CHD health 
claims permitted by this proposed rule, then FDA can expect some 
positive effects on public health.

E. Costs and Benefits of Option 3

    Option 3 would restrict coverage of the proposed requirements to 
only conventional foods, so that manufacturers of some plant stanol 
ester-containing dietary supplements in softgel form that currently 
claim reduced risk of CHD from plant sterol/stanol esters consumption 
would no longer be allowed to make that claim. These manufacturers 
would need to re-label their products to either make no

[[Page 76550]]

claim or to make a structure/function claim. Benefits from the 
consumption of dietary supplements in softgel form may be reduced.
    There would be re-labeling costs for some dietary supplements in 
softgel form that currently make the plant stanol esters-CHD health 
claim based on the current regulation, but are no longer permitted to 
make that claim in the proposed rule. The re-labeling costs incurred 
for the dietary supplements under option 3 will be larger than those 
incurred by dietary supplement manufacturers under the proposed option; 
all dietary supplements that currently make a plant sterol/stanol 
esters and CHD health claim would have to be re-labeled to either make 
no claim or to make a structure/function claim--either of which implies 
larger changes to the label. FDA assumes the costs of a full label 
redesign will be incurred by manufacturers of dietary supplements that 
currently make a plant sterol/stanol esters and CHD health claim. 
Because dietary supplements would no longer be permitted to make the 
plant sterol/stanol esters and CHD health claim, there may also be 
reformulation costs incurred by manufacturers of some dietary 
supplements that choose to reduce current levels of phytosterols 
contained as an ingredient in the final product. However, these costs 
are considered to be a voluntary reallocation of resources rather than 
compliance costs.

F. Costs and Benefits of Option 4

    FDA assumes that manufacturers of any product making the 
phytosterols-CHD health claim, for which the analytical method for 
determining the quantity of phytosterols is different than either the 
Unilever or McNeil methods, may incur costs from the requirement to 
provide access to documentation that substantiates the amount of 
phytosterols in a food product. FDA considers the costs incurred for 
requiring FDA to have access to these documents for an estimated small 
number of firms to be a reallocation of resources rather than 
compliance costs, since claiming the health benefits from phytosterols 
is strictly voluntary; any product for which a testing method different 
than either the Unilever or McNeil methods is required would be 
different than a vegetable spread, salad dressing, or snack bar and 
would have voluntarily chosen to make a phytosterols-CHD health claim 
following passage of this proposed rule. The costs of ensuring 
compliance with phytosterols-content requirements in products for which 
the analytical method for making this determination is different than 
either the McNeil or Unilever methods would be higher than for the 
proposed rule if the FDA inspection resources required to access and 
analyze documents that substantiate the amount of phytosterols 
contained in products were greater than those required to sample and 
test the products directly with the Sorenson and Sullivan method.

IX. Small Entity Analysis (or Initial Regulatory Flexibility Analysis)

    FDA has examined the economic implications of this proposed rule as 
required by the Regulatory Flexibility Act (5 U.S.C. 601-612). If a 
rule has a significant economic impact on a substantial number of small 
entities, the Regulatory Flexibility Act requires the agency to analyze 
regulatory options that would minimize the economic impact of the rule 
on small entities.
    Small businesses that are currently making a plant sterol/stanol 
esters and CHD health claim may incur re-labeling costs to satisfy the 
change in the language required on the health claim, and reformulation 
costs to satisfy the increased minimum per-serving quantity of 
phytosterols required for a product to make a health claim. FDA uses 
the 2002 Economic Census to estimate the number of small businesses in 
the vegetable spreads, salad dressings, snack bars, and dietary 
supplements sectors that may incur costs from this proposed rule as 
well as the costs that they would incur. Based on the Economic Census 
there are approximately 3,065 firms in the sectors described by North 
American Industry Classification System (NAICS) codes 311225 (Fats and 
oils refining and blending), 311941 (Mayonnaise, dressing, and other 
prepared sauce manufacturing, 311942 (Spice and extract manufacturing), 
311919 (Other snack food manufacturing), 311999 (All other 
miscellaneous food manufacturing), and 325412 (Pharmaceutical 
preparation manufacturing). Approximately 95 percent of these firms 
have fewer than 500 employees and are considered small (Ref. 119). 
Moreover, FDA estimates from this data that firms with fewer than 500 
employees account for approximately 75 percent of the sales revenues 
from these sectors.
    In order to estimate the number of food manufacturers that may make 
a plant sterol/stanol esters and CHD health claim, FDA assumes that 
half of the small firms from the sectors described in the previous 
paragraph manufacture a product that is eligible to make a health 
claim. Consistent with FDA's 2001 FLAPS (Ref. 114), FDA multiplies 
those making a health claim by the percentage of health claims that 
were found to address the risk of CHD (41.7 percent). FDA assumes that 
10 percent of all packaged food sales with claims that address the risk 
of CHD may make a phytosterols-CHD health claim.
    Consequently, FDA estimates that 128 firms with fewer than 500 
employees would manufacture one product that makes the plant sterol/
stanol esters and CHD health claim and would incur compliance costs 
from this proposed rule (i.e., 95 percent of 3,065 food and dietary 
supplements manufacturers, multiplied by 50 percent for only those that 
manufacture products making a health claim, multiplied by 41.7 percent 
for manufacturing products that make a health claim addressing the risk 
of CHD, and multiplying by 10 percent for making the plant sterol/
stanol esters and CHD health claim. Because each individual food 
product currently making the plant sterol/stanol esters and CHD health 
claim would need to be re-labeled, fewer labels would need to be 
redesigned or discarded for a small manufacturer than for a large 
manufacturer. FDA uses data from the 2002 Economic Census indicating 
that 75 percent of total sales revenue--and by extension re-labeling 
costs--for the entire sector can be attributed to small manufacturers. 
FDA multiplies the re-labeling cost estimates for the entire sector of 
between $86,000 and $186,000 obtained in the cost-benefit analysis by 
75 percent, and then divides by the number of small firms to obtain the 
cost per small firm. Consequently, FDA estimates that the average one-
time re-labeling cost per small business would be between approximately 
$700 and $1,500.
    FDA assumes that only some manufacturers that currently enrich 
conventional food products with plant sterol esters will incur 
reformulation costs. FDA assumes that 25 percent of small manufacturers 
of conventional food products that make a plant sterol/stanol esters 
and CHD health claim would need to reformulate a product as a result of 
this proposed rule. Consistent with the earlier discussion in this 
document, FDA estimates that 95 percent of the reformulation costs, or 
approximately $5,000, would be incurred by approximately 30 small 
manufacturers with fewer than 500 employees. FDA obtains an estimate of 
the reformulation costs per small manufacturer of approximately $160. 
FDA requests comments on the estimate of reformulation costs per 
manufacturer. Small businesses that currently are not making a plant 
sterol/stanol esters and CHD health claim will incur labeling and 
reformulation costs only if they

[[Page 76551]]

choose to take advantage of the marketing opportunity presented by this 
proposed rule.

X. Paperwork Reduction Act of 1995

    FDA concludes that the labeling provisions of this proposed rule 
are not subject to review by the Office of Management and Budget 
because they do not constitute a ``collection of information'' under 
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). Rather, the 
food labeling health claim on the association between consumption of 
phytosterols and CHD risk is a ``public disclosure of information 
originally supplied by the Federal Government to the recipient for the 
purpose of disclosure to the public'' (see 5 CFR 1320.3(c)(2)).

XI. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. Section 4(a) of the 
Executive order requires agencies to ``construe * * * a Federal statute 
to preempt State law only where the statute contains an express 
preemption provision or there is some other clear evidence that the 
Congress intended preemption of State law, or where the exercise of 
State law conflicts with the exercise of Federal authority under the 
Federal statute.'' Federal law includes an express preemption provision 
that preempts ``any requirement respecting any claims of the type 
described in [21 U.S.C. 343(r)(1)] made in the label or labeling of 
food that is not identical to the requirement of [21 U.S.C. 343(r)] * * 
*.'' 21 U.S.C. 343-1(a)(5). However, the statutory provision does not 
preempt any State requirement respecting a statement in the labeling of 
food that provides for a warning concerning the safety of the food or 
component of the food (Pub. L. 101-535, section 6, 104 Stat. 2353 
(1990)). If this proposed rule is made final, the final rule would 
create requirements for various health claims for phytosterols in the 
label or labeling of food under 21 U.S.C. 343(r).

XII. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) either electronic or written comments regarding this 
document. It is only necessary to send one set of comments. It is no 
longer necessary to send two copies of mailed comments. Identify 
comments with the docket number found in brackets in the heading of 
this document. Received comments may be seen in the Division of Dockets 
Management between 9 a.m. and 4 p.m., Monday through Friday.

XIII. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES) and may be seen between 
9 a.m. and 4 p.m., Monday through Friday, except on Federal Government 
holidays. (FDA has verified the Web site addresses, but is not 
responsible for any subsequent changes to the Web sites after this 
document publishes in the Federal Register.)

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[[Page 76552]]

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List of Subjects in 21 CFR Part 101

    Food labeling, Incorporation by reference, Nutrition, Reporting and 
recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 101 be amended as follows:

PART 101--FOOD LABELING

    1. The authority citation for 21 CFR part 101 continues to read as 
follows:

    Authority: 15 U.S.C. 1453, 1454, 1455; 21 U.S.C. 321, 331, 342, 
343, 348, 371; 42 U.S.C. 243, 264, 271.

    2. Section 101.83 is revised to read as follows:


Sec.  101.83  Health claims: phytosterols and risk of coronary heart 
disease (CHD).

    (a) Relationship between diets that include phytosterols and the 
risk of CHD. (1) Cardiovascular disease means diseases of the heart and 
circulatory system. Coronary heart disease (CHD) is one of the most 
common and serious forms of cardiovascular disease and

[[Page 76555]]

refers to diseases of the heart muscle and supporting blood vessels. 
High blood total cholesterol and low density lipoprotein (LDL) 
cholesterol levels are associated with increased risk of developing 
CHD. Lowering of blood total and/or LDL cholesterol has been shown 
conclusively to lower risk for CHD, and thus is the primary target of 
cholesterol-lowering therapy. The relationship between total and LDL 
cholesterol levels and CHD risk is continuous over a broad range of LDL 
cholesterol levels from low to high. High CHD rates occur among people 
with high total cholesterol levels of 240 milligrams per deciliter (mg/
dL) (6.21 millimole per liter (mmol/L)) or above. Borderline high risk 
blood cholesterol levels range from 200 to 239 mg/dL (5.17 to 6.18 
mmol/L). An optimal blood LDL cholesterol level is less than 100 mg/dL 
(2.6 mg/L); borderline high LDL levels range from 130 to 160 mg/dL (3.4 
to 4.1 mmol/L); and a high LDL cholesterol level is above 160 mg/dL.
    (2) Populations with a low incidence of CHD tend to have relatively 
low blood total cholesterol and LDL cholesterol levels. These 
populations also tend to have dietary patterns that are not only low in 
total fat, especially saturated fat and cholesterol, but are also 
relatively high in plant foods that contain dietary fiber and other 
components.
    (3) Phytosterols (plant sterols) are structurally similar to 
cholesterol. Although there are many different phytosterols found in 
plants, the phytosterols most abundant in the diet are beta ([beta])-
sitosterol, campesterol, and stigmasterol. Phytosterols usually have a 
double bond at the 5 position of the core ring structure. Phytosterols 
that have been saturated to remove the double bond in the ring 
structure are sometimes referred to as ``stanols.'' This regulation 
uses the term phytosterol as inclusive of both sterol and stanol forms.
    (4) Scientific evidence demonstrates that diets that include 
phytosterols may reduce the risk of CHD.
    (b) Significance of the relationship between diets that include 
phytosterols and the risk of CHD. (1) CHD is a major public health 
concern in the United States. It accounts for more deaths than any 
other disease or group of diseases. Early management of risk factors 
for CHD is a major public health goal that can assist in reducing risk 
of CHD. High blood total and LDL cholesterol are major modifiable risk 
factors in the development of CHD.
    (2) The scientific evidence establishes that including phytosterols 
in the diet helps to lower blood total and LDL cholesterol levels.
    (c) Requirements--(1) General. All requirements set forth in Sec.  
101.14 shall be met, except Sec.  101.14(a)(4), as specified in 
paragraph (c)(2)(iii)(C) of this section, for disqualifying levels of 
total fat in vegetable oil spreads resembling margarine, dressings for 
salad, and liquid vegetable oils and Sec.  101.14(e)(6), as specified 
in paragraph (c)(2)(iii)(D) of this section, for minimum nutrient 
contribution requirements with respect to vegetable oil spreads 
resembling margarine, dressings for salad, and liquid vegetable oils.
    (2) Specific requirements--(i) Nature of the claim. A health claim 
associating diets that include phytosterols with reduced risk of heart 
disease may be made on the label or labeling of a food described in 
paragraph (c)(2)(iii) of this section provided that:
    (A) The claim states that phytosterols should be consumed as part 
of a diet low in saturated fat and cholesterol;
    (B) The claim states that diets that include phytosterols ``may'' 
or ``might'' reduce the risk of heart disease;
    (C) In specifying the disease, the claim uses the following terms: 
``heart disease'' or ``coronary heart disease'';
    (D) In specifying the substance, the claim accurately uses the term 
``phytosterols,'' ``plant sterols,'' ``plant stanols,'' or ``plant 
sterols and stanols,'' except that if the sole source of the plant 
sterols or stanols is vegetable oil, the claim may so specify, e.g., 
``vegetable oil phytosterols'' or ``vegetable oil sterols and 
stanols'';
    (E) The claim does not attribute any degree of risk reduction for 
CHD to diets that include phytosterols;
    (F) The claim does not imply that consumption of diets that include 
phytosterols is the only recognized means of achieving a reduced risk 
of CHD;
    (G) The claim specifies the daily dietary intake of phytosterols 
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. The daily dietary intake level of phytosterols that has been 
associated with reduced risk of CHD is 2 grams (g) per day, based on 
the nonesterified weight of phytosterols; and
    (H) The claim specifies that the daily dietary intake of 
phytosterols should be consumed with meals or snacks.
    (ii) Nature of the substance. (A) The substance may be derived from 
either vegetable oils or from tall oils and shall contain at least 80 
percent beta-sitosterol, campesterol, stigmasterol, sitostanol, and/or 
campestanol (combined weight). For conventional foods, the substance 
may be esterified with food-grade fatty acids; for dietary supplements, 
the substance must be esterified with food-grade fatty acids.
    (B) The Food and Drug Administration (FDA) will measure 
phytosterols by the Association of Official Analytical Chemists (AOAC) 
Official Method 994.10, ``Cholesterol in Foods,'' as modified for 
assaying phytosterols by Sorenson and Sullivan (Journal of AOAC 
International, Vol. 89, No. 1, 2006). These methods are incorporated by 
reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies 
may be obtained from the Center for Food Safety and Applied Nutrition, 
Food and Drug Administration, 5100 Paint Branch Pkwy., College Park, MD 
20740, or at the National Archives and Records Administration (NARA). 
For information on the availability of this material at NARA, call 202-
741-6030, or go to http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html.
    (iii) Nature of the food eligible to bear the claim. (A) The food 
product shall contain at least 0.5 g of phytosterols, based on the 
nonesterified weight of phytosterols that comply with paragraph 
(c)(2)(ii) of this section per reference amount customarily consumed;
    (B) If the food product is a dietary supplement, the phytosterols 
shall be esterified with food-grade fatty acids;
    (C) If the food product is a conventional food, the use of the 
phytosterols in such food has been submitted to FDA in a generally 
recognized as safe (GRAS) notification, to which the agency had no 
further questions, and the conditions of use are consistent with the 
eligibility requirements for the health claim;
    (D) The food shall meet the nutrient content requirements in Sec.  
101.62 for a ``low saturated fat'' and ``low cholesterol'' food;
    (E) The food shall meet the limit for total fat in Sec.  
101.14(a)(4), except that, if the label of the food bears a disclosure 
statement that complies with Sec.  101.13(h), vegetable oil spreads 
resembling margarine and dressings for salad are not required to meet 
the limit for total fat per 50 g and liquid vegetable oils are not 
required to meet the limit for total fat per reference amount 
customarily consumed, per label serving size, and per 50 g; and
    (F) The food shall meet the minimum nutrient contribution 
requirement in Sec.  101.14(e)(6) unless it is a liquid vegetable oil 
or dressing for salad. The minimum nutrient contribution requirement 
for vegetable oil spreads

[[Page 76556]]

resembling margarine may be met by added vitamin A.
    (d) Optional information. (1) The claim may state that the 
development of heart disease depends on many factors and may identify 
one or more of the following risk factors for heart disease about which 
there is general scientific agreement: A family history of CHD, 
elevated blood total and LDL cholesterol, excess body weight, high 
blood pressure, cigarette smoking, diabetes, and physical inactivity. 
The claim may also provide additional information about the benefits of 
exercise and management of body weight to help lower the risk of heart 
disease.
    (2) The claim may state that the relationship between intake of 
diets that include phytosterols and reduced risk of heart disease is 
through the intermediate link of ``blood cholesterol'' or ``blood total 
and LDL cholesterol.''
    (3) The claim may include information from paragraphs (a) and (b) 
of this section, which summarize the relationship between diets that 
include phytosterols and the risk of CHD and the significance of the 
relationship.
    (4) The claim may include information from the following paragraph 
on the relationship between saturated fat and cholesterol in the diet 
and the risk of CHD: The scientific evidence establishes that diets 
high in saturated fat and cholesterol are associated with increased 
levels of blood total and LDL cholesterol and, thus, with increased 
risk of CHD. Intakes of saturated fat exceed recommended levels in the 
diets of many people in the United States. One of the major public 
health recommendations relative to CHD risk is to consume less than 10 
percent of calories from saturated fat and keep total fat intake 
between 20 to 35 percent of calories. Recommended daily cholesterol 
intakes are 300 mg or less per day. Scientific evidence demonstrates 
that diets low in saturated fat and cholesterol are associated with 
lower blood total and LDL cholesterol levels.
    (5) The claim may state that diets that include phytosterols and 
are low in saturated fat and cholesterol are consistent with ``Dietary 
Guidelines for Americans.'' U.S. Department of Agriculture (USDA) and 
Department of Health and Human Services (DHHS), Government Printing 
Office (GPO).
    (6) The claim may state that individuals with elevated blood total 
and LDL cholesterol should consult their physicians for medical advice 
and treatment. If the claim defines high or normal blood total and LDL 
cholesterol levels, then the claim shall state that individuals with 
high blood cholesterol should consult their physicians for medical 
advice and treatment.
    (7) The claim may include information on the number of people in 
the United States who have heart disease. The sources of this 
information shall be identified, and it shall be current information 
from the National Center for Health Statistics, the National Institutes 
for Health, or ``Dietary Guidelines for Americans,'' U.S. Department of 
Agriculture (USDA) and Department of Health and Human Services (DHHS), 
Government Printing Office (GPO).
    (e) Model health claims. The following model health claims may be 
used in food labeling to describe the relationship between diets that 
include phytosterols and reduced risk of heart disease:
    (1) Foods containing at least 0.5 g per serving of phytosterols 
[plant sterols, plant stanols, or plant sterols and stanols] eaten with 
meals or snacks for a daily total intake of 2 g as part of a diet low 
in saturated fat and cholesterol, may reduce the risk of heart disease. 
A serving of [name of the food] supplies----g of phytosterols [plant 
sterols, plant stanols, or plant sterols and stanols].
    (2) Diets low in saturated fat and cholesterol that include 2 g per 
day of phytosterols [plant sterols, plant stanols, or plant sterols and 
stanols] eaten with meals or snacks may reduce the risk of heart 
disease. A serving of [name of food] supplies----g of [phytosterols 
plant sterols, plant stanols, or plant sterols and stanols].

    Dated: November 24, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.

Tables 1 and 2 to Preamble

    Note: These tables will not appear in the Code of Federal 
Regulations.


                  Table 1--Randomized Clinical Trials of Phytosterols in Conventional Foods and Total and LDL Cholesterol Concentration
--------------------------------------------------------------------------------------------------------------------------------------------------------
               Study                         Design                Population             Intervention               Diet                 Results
--------------------------------------------------------------------------------------------------------------------------------------------------------
AbuMweis et al., 2006 (Ref. 38)      Randomized single-      Healthy adults 38       One serving/d test     Controlled diet; all   Total-C (mg/dL)
                                      blind, placebo-         enrolled, 30            margarine, eaten       food and beverage      Baseline: 228
                                      controlled, crossover   completed               with breakfast. PS     prepared/provided by  After 4-wk test
                                      trial; five 29-d test  Mean age     dose: 22 mg/kg body    study; American diet   period:
                                      periods, separated by   sd.                     wgt (about 1.7 g PS/   w/30% energy from     C 222
                                      2-4 wk washout         59  10 y..   d) \1\                 fat                   I1 219
                                      periods                n = 30/phase..........  C = margarine w/o                             I2 220
                                                             Inclusion criteria:      added PS.                                    I3 224
                                                              LDL-C >100 mg/dL, BMI  I1 = ~1.7 g PS/d as                           I4 223
                                                              22-34, age 40-85 y,     nonesterified plant                          LDL-C (mg/dL)
                                                              no chronic disease or   sterols in PS-                                Baseline: 147
                                                              lipid-lowering RX.      enriched margarine.                          After 4-wk test
                                                             USA...................  I2 = ~1.7 g PS/d as                            period:
                                                                                      plant sterol esters                          C 141
                                                                                      (sunflower oil fatty                         I1 139
                                                                                      acids) in PS-                                I2 139
                                                                                      enriched margarine.                          I3 145
                                                                                     I3 = ~1.7 g PS/d as                           I4 143
                                                                                      plant sterol esters                          No significant
                                                                                      (fish oil n-3 LC                              changes of Total-C
                                                                                      PUFA) in PS-enriched                          or LDL-C compared to
                                                                                      margarine.                                    control
                                                                                     I4 = ~1.7 g PS/d as
                                                                                      nonesterified plant
                                                                                      sterols fish oil.
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 76557]]

 
Doornbos et al., 2006 (Ref. 43)      Randomized double-      Mildly                  Single serving         Habitual diet........  Total-C (mg/dL)
                                      blind, placebo-         hypercholesterolemic    bottled yogurt drink                          Baseline: 234
                                      controlled, parallel    adults                  (100 g) consumed                             Total-C % change
                                      trial with 5 groups;   191 randomized, 184      with a meal, or                               compared to control:
                                      4-wk run-in followed    Included in analysis.   while fasting                                I1 [darr] 7.0%*
                                      by 4-wk test period    Mean age    C = drink w/o added                           I2 [darr] 4.1%*
                                                              sd.                     PS.                                          I3 [darr] 6.5%*
                                                             57  2 y...  I1 = 3.2 g PS/d in                            I4 [darr] 4.7%*
                                                             n = 33(C).............   low-fat yogurt (0.1                          *p < 0.05
                                                             n = 38 (I1)...........   g dairy fat, 2.2 g                           LDL-C (mg/dL)
                                                             n = 38 (I2)...........   fat in the stanol/                            Baseline: 155
                                                             n = 39 (I3)...........   sterol ester) w/meal.                        LDL-C % change
                                                             n = 36 (I4)...........  I2 = 3.2 g PS/d in                             compared to control:
                                                             Inclusion criteria:      low-fat yogurt (0.1                          I1 [darr] 9.5%*
                                                              BMI 18-32 kg/m\2\;      g dairy fat, 2.2 g                           I2 [darr] 5.1%*
                                                              total-C 193-309 mg/dL   fat in the stanol/                           I3 [darr] 9.3%*
                                                              TG < 355 mg/dL.         sterol ester) w/o                            I4 [darr] 6.9%*
                                                             The Netherlands.......   meal.                                        *p < 0.05
                                                                                     I3 = 2.8 g tall oil
                                                                                      PS/d in regular-fat
                                                                                      yogurt (1.5 g dairy
                                                                                      fat, 2.1 g fat in
                                                                                      the stanol/sterol
                                                                                      ester) w/meal.
                                                                                     I4 = 2.8 g PS/d in
                                                                                      regular-fat yogurt
                                                                                      (1.5 g dairy fat,
                                                                                      2.1 g fat in the
                                                                                      stanol/sterol ester)
                                                                                      w/o meal.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Jauhiainen et al., 2006 (Ref. 89)..  Randomized double-      Mildly                  50 g/d hard cheese     Habitual diets.......  Total-C (mg/dL)
                                      blind, placebo-         hypercholesterolemic    divided into 2                                Baseline:
                                      controlled parallel     adults                  portions consumed                            C 224
                                      trial, 1-wk run-in, 5- 67 enrolled, 67          with two major meals                         I 218
                                      wk test period          completed.             C = cheese w/o added                          Total-C % change
                                                             n = 34 (C)............   phytosterols.                                 compared to placebo:
                                                             n = 33 (I)............  I = 2.0 g PS/d as                             I [darr] 5.7% (p <
                                                             Age range 25-65 y.....   plant stanol ester                            0.05)
                                                             Inclusion criteria:...   in PS-enriched hard                          LDL-C (mg/dL)
                                                             Total-C 193-251.......   cheese.                                       Baseline:
                                                             mg/dL, TG < 266.......                                                C 139
                                                             mg/dL.................                                                I 138
                                                             Finland...............                                                LDL-C % change
                                                                                                                                    compared to control:
                                                                                                                                    I [darr] 10.1% (p <
                                                                                                                                    0.05)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Korpela et al., 2006 (Ref. 37).....  Randomized double-      Mildly                  150 g low-fat yogurt,  Habitual diets plus    Total-C (mg/dL)
                                      blind, placebo-         hypercholesterolemic    50 g low-fat hard      low-fat yogurt and     Baseline:
                                      controlled, parallel    adults. 170 enrolled,   cheese, and 50 g low-  low-fat hard/fresh    C 247
                                      trial; 3-wk run-in, 6-  164 completed           fat fresh cheese       cheese                I 247
                                      wk test period         n = 82/group..........  C = yogurt and cheese                         % change compared to
                                                             Mean age     w/out added PS.                               control: I [darr]
                                                              sd.                    I= 1.65-2.0 g PS/d as                          6.5% (p < 0.05)
                                                             57  8 y      nonesterified sterol/                        LDL-C (mg/dL)
                                                              (C).                    stanol in enriched                            Baseline:
                                                             58  9 y      yogurt and cheeses.                          C 155
                                                              (I).                                                                 I 159
                                                             Inclusion criteria:                                                   % change compared to
                                                              Total-C 193-329 mg/                                                   control: I [darr]
                                                              dL, TG < 354 mg/dL.                                                   11.0% (p < 0.05)
                                                             Finland...............
--------------------------------------------------------------------------------------------------------------------------------------------------------
Jakulj et al., 2005 (Ref. 90)......  Randomized double-      Healthy moderately      25 g/d test margarine  Habitual diets.......  Total-C (mg/dL)
                                      blind, crossover        hypercholesterolemic    on sandwiches or                              Baseline: 261
                                      design for PS           adults 40 enrolled,     mixed with food in a                         At end of 4 wk test
                                      component, and open-    39 Included in          hot meal                                      period:
                                      label RX tmt; 2x2       analyses               C = spread w/o added                          C 249
                                      factorial trial. 2-wk  Mean age     PS.                                          I1 235
                                      run-in followed by      sd.                    I1 = 2.0 g PS/d as                            I2 208
                                      four consecutive 4-wk  55.5  7.9    plant sterol on PS-                          I3 204
                                      test periods            y.                      enriched spread.                             Total-C % change
                                                             n = 39................   Information not                               compared to control:
                                                             Inclusion criteria:      provided as to                               I1 [darr] 5.2%*
                                                              plasma LDL-C 135-193    whether                                      I2 [darr] 15.7%*
                                                              mg/dL; TG < 355 mg/dL.  nonesterified or                             I3 [darr] 17.2%*
                                                             The Netherlands.......   esterified.                                  *p < 0.05
                                                                                     I2 = Ezetimibe.......                         LDL-C (mg/dL)
                                                                                     I3 = Ezetimibe + PS-                           Baseline: 174
                                                                                      enriched spread.                             At end of 4-wk:
                                                                                                                                   C 157
                                                                                                                                   I1 148
                                                                                                                                   I2 121
                                                                                                                                   I3 116
                                                                                                                                   % change compared to
                                                                                                                                    control:
                                                                                                                                   I1 [darr] 5.1%*
                                                                                                                                   I2 [darr] 20.9%*
                                                                                                                                   I3 [darr] 23.8%*
                                                                                                                                   *p < 0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 76558]]

 
Clifton et al. 2004 (Ref. 88)......  Randomized single-      Mildly                  One serving/d each 4   Habitual diets         Total-C (mg/dL)
                                      blind, placebo-         hypercholesterolemic    of test foods          supplemented by one    Baseline: 241
                                      controlled,             adults 63 enrolled,     (bread, milk,          serving daily of      % change compared to
                                      incomplete crossover    58 completed            cereal, and yoghurt)   yoghurt, low-fat       placebo:
                                      trial; four            n = 58 (C)............   consumed with meals    milk, bread, and      I1 [darr] 5.6%*
                                      consecutive 3-wk test  n = 36 (I1)...........  C = test foods w/o      muesli-type cereal.   I2 [darr] 8.5%*
                                      periods, no washout    n = 40 (I2)...........   added PS.              No changes in         I3 [darr] 3.2%*
                                      periods                n = 58 (I3)...........  I1 = 1.6 g/d PS as      reported intakes of   I4 [darr] 6.3%*
                                                             n = 40 (I4)...........   soy sterol esters in   energy, fat, CHO, or  *p < 0.05
                                                             Mean age 54 y.........   2 slices of PS-        protein across        LDL-C (mg/dL)
                                                             Inclusion criteria:      enriched bread.        treatment periods or   Baseline: 156
                                                              BMI < 31, no RX that   I2 = 1.6 g/d PS as      between centers       % change compared to
                                                              affect lipids, total-   soy sterol esters in                          control:
                                                              C 193-290 mg/dL.        500 ml of 2% PS-                             I1 [darr] 10.4%*
                                                             Australia.............   enriched milk.                               I2 [darr] 13.2%*
                                                                                     I3 = 1.6 g/d PS as                            I3 [darr] 6.0%*
                                                                                      soy sterol esters in                         I4 [darr] 10.4%*
                                                                                      45 g of PS-enriched                          *p < 0.05
                                                                                      cereal.
                                                                                     I4 = 1.6 g/d PS as
                                                                                      soy sterol esters
                                                                                      200g of PS-enriched
                                                                                      yogurt.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Devaraj et al., 2004 (Ref. 33).....  Randomized double-      Healthy mildly          2 servings/d of test   Habitual diets. No     Total-C (mg/dL)
                                      blind, parallel trial   hypercholesterolemic    orange juice, with     other orange juice,    Baseline:
                                      with 2 groups; 2-wk     adults                  meals.                 citrus fruit, or PS-  C 209
                                      run-in period          75 enrolled; 72         C = orange juice w/o    enriched margarine    I 207
                                      followed by 8-wk test   completed.              added PS.              allowed. 3-day diet   Total-C % change
                                      period                 Mean age    I=2 g PS/d as           records at beginning   compared to control:
                                                              sd.                     nonesterified sterol   and end of study      I [darr] 5.3% (p <
                                                             44  13 y     in PS-enriched                                0.05)
                                                              (C).                    orange juice.                                LDL-C (mg/dL)
                                                             41  13 y                                                   Baseline:
                                                              (I).                                                                 C 140
                                                             n = 36/group..........                                                I 137
                                                             Inclusion criteria:                                                   LDL-C % change
                                                              LDL-C >100 mg/dL; no                                                  compared to control:
                                                              Rx that affect                                                        I [darr] 7.3% (p <
                                                              lipids, no smoking,                                                   0.05)
                                                              no HX of CVD.
                                                             USA...................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Thomsen et al., 2004 (Ref. 26).....  Randomized double-      Mildly                  2 servings/d of 1.2%-  Habitual Danish diet   Total-C (mg/dL)
                                      blind, crossover        hypercholesterolemic    fat test milk w/       with limits on         Baseline: 271
                                      trial, with three       adults                  meals                  certain fatty foods;  Total-C % change
                                      consecutive 4-wk       81 subjects Randomized  C = milk w/o added PS   e.g., 20 g/d cheese,   relative to control:
                                      periods; no run-in or   69 completed.          I1 = 1.2 g PS/day as    2 portions of         I1 [darr] 4.73%*
                                      wash-our periods       Mean age     nonesterified plant    crustaceans and       I2 [darr] 7.05%*
                                                              sd.                     sterols in PS-         mollusks per wk       * p < 0.0001
                                                             60  5 y...   enriched milk.                               LDL-C (mg/dL)
                                                             n = 69................  I2 = 1.6 g PS/day as                           Baseline: 169
                                                             Inclusion criteria: no   nonesterified plant                          LDL-C % change
                                                              RX that affect          sterols in PS-                                relative to control:
                                                              lipids, total-C 217-    enriched milk.                               I1 [darr] 7.1%*
                                                              325 mg/dL, TG < 310                                                  I2 [darr] 9.6%*
                                                              mg/dL.                                                               * p < 0.0001
                                                             Denmark...............
--------------------------------------------------------------------------------------------------------------------------------------------------------
Cleghorn et al., 2003 (Ref. 91)....  Randomized double-      Mildly                  Test butter (20 g/d)   Self-selected low-fat  Total-C (mg/dL)
                                      blind, placebo-         hypercholesterolemic    or test margarine      diets. Test           At end of 3 wk test
                                      controlled, crossover   adults;                 (25 g/d)               substance (butter or   period:
                                      trial; 3-wk run-in     58 subjects enrolled,   B = Butter w/o added    margarine) added to   B 235
                                      period, 3-wk test       53 completed.           PS.                    low-fat diet          M 227
                                      period                 Mean age    M = margarine w/o                             I 215
                                                              sd.                     added PS.                                    Total-C % change
                                                             46.7  10.5  I = 2 g PS/d PS as                             relative to control:
                                                              y.                      plant sterol esters                           I [darr] 5.45% (p <
                                                             n = 53................   in PS-enriched                                0.05)
                                                             Inclusion criteria:      margarine.                                   LDL-C (mg/dL)
                                                              total-C 193-290 mg/                                                  At end of 3 wk test
                                                              dL, TG < 266 mg/dL;                                                   period:
                                                              no cholesterol-lowing                                                B 154
                                                              RX.                                                                  M 145
                                                             New Zealand...........                                                I 135
                                                                                                                                   LDL-C % change
                                                                                                                                    compared to control:
                                                                                                                                    I [darr] 7.2% (p <
                                                                                                                                    0.01)
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 76559]]

 
Homma et al., 2003 (Ref. 82).......  Randomized double-      Healthy adult Japanese  2 or 3 servings/d of   Habitual Japanese      Total-C (mg/dL)
                                      blind, placebo-        105 enrolled, 104        low-fat test spread,   diet. Diets were       Baseline:
                                      controlled, parallel    completed.              eaten w/meals.         assessed with 2 day   C 238
                                      trial, 4-wk test       Mean age    C = spread w/o added    diet analysis at      I1 235
                                      period, and 4-wk post-  sd.                     PS, 3 servings/d.      start and end of      I2 232
                                      trial follow-up        46  14 y    I1 = 2 g PS/d as        trial                 Total-C % change
                                      period                  (P).                    plant stanol esters                           compared to control:
                                                             47  13 y     in PS-enriched                               I1 [darr] 5.7%*
                                                              (I1).                   spread, 2 servings/d.                        I2 [darr] 4.9%*
                                                             49  12 y    I2 = 3 g PS/d as                              *p < 0.001
                                                              (I2).                   stanol esters in PS-                         LDL-C (mg/dL)
                                                             n = 33-34/group.......   enriched spread, 3                            Baseline:
                                                             Inclusion criteria:      servings/d.                                  C 157
                                                              age >20 y, total-C                                                   I1 153
                                                              209-278 mg/dL, TG <                                                  I2 153
                                                              345 mg/dL.                                                           LDL-C % change
                                                             Japan.................                                                 compared to control:
                                                                                                                                   I1 [darr] 8.9%*
                                                                                                                                   I2 [darr] 6.6%*
                                                                                                                                   *p < 0.001
--------------------------------------------------------------------------------------------------------------------------------------------------------
Ishiwata et al., 2002 (Same          Randomized double-      See Homma et al. 2003   2 or 3 servings/d of   Habitual Japanese      Total-C (mg/dL)
 subjects as Homma et al., 2003)      blind, placebo-        n = 30-31/group.......   low-fat test spread,   diet                   Baseline:
 (Ref. 92).                           controlled, parallel   Analysis stratified by   eaten w/meals                                C ApoE3 236
                                      trial, 4-wk test        apolipoprotein E       C = spread w/o added                          C ApoE4 241
                                      period, and 4-wk post-  phenotype.              PS, 3 servings/d.                            I1 ApoE3 237
                                      trial follow-up                                I1 = 2 g PS/d as                              I1 ApoE4 231
                                      period                                          plant stanol esters                          I2 ApoE3 234
                                                                                      in PS-enriched                               I2 ApoE4 233
                                                                                      spread, 2 servings/d.                        Total-C % change
                                                                                     I2 = 3 g PS/d as                               compared to control:
                                                                                      stanol esters in PS-                         I1 ApoE3 [darr] 7.1%*
                                                                                      enriched spread, 3                           I1 ApoE4 [darr] 6.3%*
                                                                                      servings/d.                                  I2 ApoE3 [darr] 5.9%*
                                                                                                                                   I2 ApoE4 [darr] 4.7%
                                                                                                                                   * p < 0.05
                                                                                                                                   LDL-C (mg/dL)
                                                                                                                                    Baseline:
                                                                                                                                   C ApoE3 153
                                                                                                                                   C ApoE4 161
                                                                                                                                   I1 ApoE3 155
                                                                                                                                   I1 ApoE4 148
                                                                                                                                   I2 ApoE3 155
                                                                                                                                   I2 ApoE4 151
                                                                                                                                   LDL-C % change
                                                                                                                                    compared to control:
                                                                                                                                   I1 ApoE3 [darr] 9.2%*
                                                                                                                                   I1 ApoE4 [darr]
                                                                                                                                    11.0%*
                                                                                                                                   I2 ApoE3 [darr] 8.7%*
                                                                                                                                   I2 ApoE4 [darr] 6.4%
                                                                                                                                   * p < 0.01
--------------------------------------------------------------------------------------------------------------------------------------------------------
Jones et al., 2003 (Ref. 34).......  Randomized double-      Mildly                  3 servings/d of        Typical American       Total-C (mg/dL)
                                      blind, crossover        hypercholesterolemic    nonfat or low fat      diet. Controlled       Baseline:
                                      trial; three 3-wk       adults                  test beverage          intake; all food/     C 237
                                      controlled feeding     15 enrolled, 15          consumed w/meals       beverage prepared/    I1 242
                                      test periods            completed.             C = nonfat beverage w/  provided by study     I2 229
                                      separated by 4-wk      age range 22-68 y.....   o added PS.                                  Total-C % change at 3
                                      washout periods        n = 15................  I1 = 1.8 g PS/d as                             wk:
                                                             Inclusion criteria:      nonesterified plant                          C [darr] 8.5%
                                                              BMI 22-32 kg/m\2\,      tall oil sterol/                             I1 [darr] 11.6%
                                                              LDL-C 126-232 mg/dL,    stanol in PS-                                I2 [darr] 10.1%
                                                              HDL < 31 mg/dL, TG <    enriched nonfat                              no significant
                                                              355 mg/dL.              beverage.                                     differences between
                                                             Canada................  I2 = 1.8 g PS/d as                             control and PS
                                                                                      nonesterified plant                           periods
                                                                                      tall oil sterol/                             LDL-C (mg/dL)
                                                                                      stanol in PS-                                 Baseline:
                                                                                      enriched low fat                             C 155
                                                                                      beverage.                                    I1 160
                                                                                                                                   I2 150
                                                                                                                                   LDL-C % change at 3
                                                                                                                                    wk:
                                                                                                                                   C [darr] 5.0%
                                                                                                                                   I1 [darr] 10.4%
                                                                                                                                   I2 [darr] 8.5%
                                                                                                                                   no significant
                                                                                                                                    differences between
                                                                                                                                    P and PS periods
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 76560]]

 
Naumann et al., 2003 (Ref. 42).....  Randomized double-      Healthy adults, 44      1 serving/d of test    Habitual diets; food   Total-C (mg/dL) At
                                      blind, placebo-         enrolled, 42            margarine              frequency              end of 3 wk:
                                      controlled, crossover   completed              C = margarine w/o       questionnaires        C 173
                                      trial; three           Mean age     added PS.              assessed diet at end  I1 167
                                      consecutive 3-wk test   sd.                    I1 = 2 g PS/d as        of each period. No    I2 168
                                      periods                32  14 y F   phytosterol ester,     margarine was         Total-C % difference
                                                             37  16 y M   1:1 sterol/stanol      allowed other than     compared to control:
                                                             n = 42................   ester ratio in PS-     the provided test     I1 [darr] 3.4%*
                                                             Inclusion criteria: BP   enriched margarine.    margarine. Study      I2 [darr] 2.7%*
                                                              < 160/95, BMI < 30,    I2 = 2 g PS/d as        provided sunflower    *p < 0.05
                                                              stable body wgt, age    phytosterol ester,     oil shortening (w/o   LDL-C (mg/dL)
                                                              18-65 y, Total-C <      3:1 sterol/stanol      added plant sterols   At end of 3 wk
                                                              309 mg/dL, TG < 355     ester ratio in PS-     and stanols) to       C 109
                                                              mg/dL.                  enriched margarine.    control unintended    I1 102
                                                             The Netherlands.......                          plant sterol and      I2 102
                                                                                                             stanol intake         LDL-C % difference
                                                                                                                                    compared to control
                                                                                                                                    3 wk:
                                                                                                                                   I1 [darr] 6.0%*
                                                                                                                                   I2 [darr] 6.7%*
                                                                                                                                   *p < 0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------
Qu[iacute]lez et al., 2003 (Ref.     Randomized double-      Healthy subjects, 61    2 test bakery          Habitual diets with    Total-C (mg/dL)
 93).                                 blind, placebo-         enrolled, 57 competed   products/d (1          test foods replacing   Baseline:
                                      controlled, parallel   Mean age     muffin, 1 croissant)   usual bakery product  C 162
                                      trial; 2 groups, 8 wk   sd.                     eaten at any time of   consumption           I 167
                                      test period            30.9  7.2    day                                          Total-C % change
                                                              y (C).                 C = bakery products w/                         compared to control:
                                                             31.0  6.7    o added PS.                                   I [darr] 8.9% (p <
                                                              y (I).                 I = 3.2 g PS/d as soy                          0.001)
                                                             n = 29 (C)............   sterol esters;                               Total-C (mg/dL)
                                                             n = 28 (I)............   divided between PS-                           Baseline:
                                                             Inclusion criteria:      enriched croissant                           C 93
                                                              BMI < 40, no RX or      and muffin.                                  I 97
                                                              diet that affect                                                     Total-C % change
                                                              blood lipids, total-C                                                 compared to control:
                                                              < 240 mg/dL, global                                                   I [darr] 14.6% (p <
                                                              CV risk < 20% (Eur                                                    0.001)
                                                              Soc for
                                                              Atherosclerosis
                                                              criteria), TG < 200
                                                              mg/dL, consumers of
                                                              bakery products.
                                                             Spain.................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Seki et al., 2003 (Ref. 54)........  Randomized double-      Healthy mildly          3 slices test bread/d  Habitual diets; diets  Total-C (mg/dL)
                                      blind, parallel trial   hypercholesterolemic   C = bread made with     assessed with three    Baseline:
                                      with 2 groups; 2-wk     males                   veg oil w/o added PS.  3-d diet records      C 190
                                      run-in period          61 enrolled, 60         I = 0.45 g PS/d as                            I 194
                                      followed by 12-wk       completed.              plant sterol esters                          Total-C % change
                                      test period            Mean age     in PS-enriched veg                            compared to control:
                                                              sd.                     oil baked into bread.                         I [darr] 3%
                                                             39.4  1.4                                                 LDL-C (mg/dL)
                                                              y.                                                                    Baseline:
                                                             n = 28 (C)............                                                C 115
                                                             n = 32 (I)............                                                I 116
                                                             Inclusion criteria:                                                   LDL-C % change
                                                              healthy; total-C <                                                    compared to control:
                                                              280 mg/dL, TG < 400                                                   I [darr] 2.1%
                                                              mg/dL.                                                               No significant
                                                             Japan.................                                                 treatment effects
--------------------------------------------------------------------------------------------------------------------------------------------------------
Spilburg et al., 2003 (Ref. 27)....  Randomized double-      Moderately              Powdered lemonade-     American Heart         Total-C (mg/dL)
                                      blind, parallel         hypercholesterolemic    flavored fat-free      Association Step I     Baseline:
                                      trial, with 6-wk run-   adults                  test beverage, 3       diet; diet            C 200
                                      in period followed by  26 randomized, 24        servings/d             counseling to         I 224
                                      4-wk test period        completed.             P = beverage w/added    maintain weight if    % change compared to
                                                             Mean age     lecithin, w/o added    needed                 control: I [darr]
                                                              sd.                     PS.                                           10.1% (p < 0.05)
                                                             50.6  10 y  I = 1.9 g PS/d as                             LDL-C (mg/dL)
                                                             Inclusion criteria:      lecithin emulsified                          C 128
                                                              LDL-C 80-210 mg/dL,     soy nonesterified                            I 148
                                                              TG < 300; no illness;   stanol in PS-                                % change compared to
                                                              no RX except for oral   enriched beverage.                            control: I [darr]
                                                              contraceptives,                                                       14.3% (p < 0.05)
                                                              hormone replacement,
                                                              anti-hypertensives,
                                                              anti-depressants &
                                                              analgesics.
                                                             USA...................
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 76561]]

 
De Graaf et al., 2002 (Ref. 32)....  Randomized double-      Mildly                  3 servings/d of test   Self-selected Step I   Total-C (mg/dL)
                                      blind, parallel         hypercholesterolemic    chocolate/d (10.5 g    diet; supplemented w/ C 257
                                      trial; 4 wk run-in      adults                  each), eaten with      three servings/d of   I 261
                                      period; 4-wk test      70 randomized, 62        meals                  chocolate             Total-C% change
                                      period                  completed.             C = chocolate w/o                              compared to control:
                                                             Mean age..............   added PS.                                     I [darr] 6.4% (p <
                                                             57.8 y (C)............  I = 1.8 g PS/day as                            0.05)
                                                             56.2 y (I)............   nonesterified tall                           LDL-C (mg/dL)
                                                             n = 31/group..........   oil sterols/stanols                          C 177
                                                             Inclusion criteria:      in PS-enriched                               I 182
                                                              age 21-75 y; total-C    chocolate.                                   LDL-C% change
                                                              213-310 mg/dL, LDL-C                                                  compared to control:
                                                              >=135 mg/dL; TG < 354                                                 I [darr] 11.1 (p <
                                                              mg/dL; BMI < 35.                                                      0.05)
                                                             The Netherlands.......
--------------------------------------------------------------------------------------------------------------------------------------------------------
Geelen et al., 2002 (Ref. 94)......  Randomized double-      Healthy adults with     One tub (35 g) test    Habitual diets;        Total-C (mg/dL)
                                      blind, crossover        known apolipoprotein    margarine/d consumed   random 24-h recall     Baseline:
                                      trial, with 2           E phenotype 31 ApoE4    in place of usual      diet surveys          E3/4 & E4/4 201
                                      consecutive 3-wk test   subjects; 57 ApoE3      margarine              conducted during      E3/3 178
                                      periods                 subjects n = 88; Mean  C = margarine w/o       test                  Total-C% change
                                                              age 25.4 y              added PS.                                     compared to control:
                                                             Inclusion criteria:     I = 3.2 g PS/d as                              I [darr] 7% (p <
                                                              age >=18 y; no          vegetable oil sterol                          0.05)
                                                              prescribed diets; no    esters in PS-                                LDL-C% change
                                                              lipid-lowering RX;      enriched margarine.                           compared to control:
                                                              total-C <=310 mg/dL;                                                  I [darr] 11%
                                                              TG < 266 mg/dL.                                                       (P<0.05)
                                                             The Netherlands.......
--------------------------------------------------------------------------------------------------------------------------------------------------------
Judd et al., 2002 (Ref. 95)........  Randomized double-      Healthy adults, normal  Two servings/d of      Typical American       Type of salad
                                      blind, crossover        or slightly elevated    test salad dressing    diet; Controlled       dressing did not
                                      trial; two              total-C                 (Ranch or Italian),    diet provided by       affect plasma lipids
                                      consecutive 3-wk       58 enrolled, 53          eaten w/meals          study and eaten on     so data was combined
                                      intervention periods,   completed.             C1 = Ranch dressing w/  site                  Total-C (mg/dL)
                                      no wash out            Mean age     o added PS.                                   baseline: 214
                                                              sd.                    I1 = 2.2 g PS/d as                            Total-C% change
                                                             47.1  1.5    soy sterol esters in                          compared to control:
                                                              y.                      PS-enriched Ranch                             I [darr] 7.0% (p <
                                                             n = 53................   dressing.                                     0.0001)
                                                             Inclusion criteria:     C2 = Italian dressing                         LDL-C (mg/dL)
                                                              age 25-65 y; HDL >25    w/o added PS.                                 Baseline: 141
                                                              mg/dl (men) or >35 mg/ I2 = 2.2 g PS/d as                            LDL-C% change
                                                              dL (women), TG < 300    soy sterol esters in                          compared to control:
                                                              mg/dL.                  PS-enriched Italian                           I [darr] 9.2% (p <
                                                             USA...................   dressing.                                     0.0001)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Matvienko et al, 2002 (Ref. 60)....  Randomized double-      Hypercholesterolemic    One serving/d (112 g)  Habitual diets w/      Total-C (mg/dL)
                                      blind, placebo-         white males. 50% of     of cooked lean         limits on eggs (2-3    Baseline:
                                      controlled, parallel    subjects w/family HX    ground beef eaten at   eggs/wk), and no red  C 224
                                      trial; single 4-wk      of premature CVD &      lunch                  meat other than that  I 228
                                      test period             hyperlipidemia         C = ground beef......   in the test meal.     Total-C% change
                                                             36 enrolled, 34          w/o added PS........   Diets assessed by      compared to control:
                                                              completed.             I = 2.7 g PS/d as soy   interviewer            I [darr] 8.4% (p <
                                                             Mean age     sterols, partially     administered           0.001)
                                                              sd.                     esterified, in PS-     questionnaires        LDL-C (mg/dL)
                                                             22.23.9 y    enriched beef.                                Baseline:
                                                              (C).                                                                 C 153
                                                             23.63.9 y                                                 I 159
                                                              (I).                                                                 LDL-C% change
                                                             n = 17/group..........                                                 compared to control:
                                                             Inclusion criteria:                                                    I [darr] 13.3% (p <
                                                              total-C >197 mg/dL,                                                   0.001)
                                                              LDL-total-C >130 mg/
                                                              dL.
                                                             USA...................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Mensink et al., 2002 (Ref. 86).....  Randomized double-      Mildly                  3 servings/d of test   Habitual diets         Total-C (mg/dL)
                                      blind, placebo-         hypercholesterolemic    yogurt, eaten w/       supplemented with 3    Baseline:
                                      controlled, parallel    adults                  meals                  servings/day test     C 184
                                      trial; 3-wk run-in     69 randomized, 60       C = yogurt w/o added    yogurt. Low erucic    I 193
                                      followed by 4-wk test   completed.              PS.                    acid rapeseed oil     % change compared to
                                      period                 Mean age    I = 3 g PS/d as plant   margarine and          control: I [darr]
                                                              sd.                     stanol esters in PS-   shortening provided    8.7% (p < 0.001)
                                                             36  14 y..   enriched yogurt.       to standardize fatty  LDL-C (mg/dL)
                                                             n = 30/group..........                          acid intake. Diet      Baseline:
                                                             Inclusion criteria: no                          questionnaires to     C 111
                                                              diets that affects                             assess diet           I 113
                                                              lipids, no CAD HX,                                                   % change compared to
                                                              BMI < 30, total-C <                                                   control: I [darr]
                                                              251 mg/dL.                                                            13.7% (p < 0.001)
                                                             The Netherlands.......
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 76562]]

 
Mussner et al., 2002 (Ref. 96).....  Randomized double-      Mildly                  Two servings/d (10 g   Habitual diets; 3-day  Total-C (mg/dL)
                                      blind, crossover        hypercholesterolemic    each) of test          dietary recalls (at    Baseline: 233
                                      trial, with 2           adults                  margarine, consumed    beginning and end of  Total-C% change
                                      consecutive 3-wk test  63 enrolled, 62          in morning and         study) to assess       compared to control:
                                      periods                 completed.              evening, replacing     diets                  I [darr] 3.8% (p <
                                                             Mean age     usual margarine                               0.05)
                                                              sd.                    C = margarine w/o                             LDL-C (mg/dL)
                                                             42  11 y..   added PS.                                     Baseline: 152
                                                             n = 62................  I = 1.82 g PS/d as                            LDL-C% change
                                                             Inclusion criteria:      plant sterol esters                           compared to control:
                                                              BMI < 30, total-C 200-  in PS-enriched                                I [darr] 6.5% (p <
                                                              300 mg/dL, LDL-C 130-   margarine.                                    0.05)
                                                              200 mg/dL; TG < 160
                                                              mg/dL.
                                                             Germany...............
--------------------------------------------------------------------------------------------------------------------------------------------------------
Noakes et al., 2002 (Ref. 41)......  Randomized double-      Hypercholesterolemic    3 servings/d of        Usual low saturated    Total-C (mg/dL) After
                                      blind, crossover        adults                  reduced fat test       fat diet; w/>=5        3-wk intervention:
                                      trial; three           52 enrolled, 46          spread replacing       servings/d of fruit   C 244
                                      consecutive 3-wk test   completed.              usual margarine,       and vegetables, >=1   I1 229
                                      periods, no washout    Mean age     consumed w/meals       of which was high in  I2 226
                                      period; 1-wk run-in     sd.                    C = spread w/o added    carotenoids           Total-C% change
                                     Study 1...............  55  9.7 y    PS.                                           compared to control:
                                                              M.                     I1 = 2.3 g PS/d as                            I1 [darr] 6.0%*
                                                             58  7.3 y    plant sterol esters                          I2 [darr] 7.3%*
                                                              F.                      in PS-enriched                               *p < 0.001
                                                             n = 46................   spread.                                      LDL-C (mg/dL) After 3-
                                                             Inclusion criteria:     I2 = 2.5 g PS/d as                             wk intervention:
                                                              age 20-75 y; BMI <      plant stanol esters                          C 166
                                                              31, no RX that affect   in PS-enriched                               I1 153
                                                              lipids, total-C 209-    spread.                                      I2 150
                                                              329 mg/dL, TG < 400                                                  LDL-C% change
                                                              mg/dL.                                                                compared to control:
                                                             The Netherlands.......                                                I1 [darr] 7.7%*
                                                                                                                                   I2 [darr] 9.5%*
                                                                                                                                   *p < 0.001
                                                                                                                                   No significant
                                                                                                                                    difference between
                                                                                                                                    I1 and I2
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                     Randomized double-      Hypercholesterolemic    3 servings/d of        Diet same as in Study  Total-C (mg/dL) After
                                      blind, crossover        adults                  reduced fat test       1             3-wk intervention:
                                      trial; two             40 enrolled, 35          spread replacing                             C 233
                                      consecutive 3-wk test   completed.              usual margarine,                             I3 218
                                      periods, no washout    n = 35................   consumed w/meals                             Total-C% change
                                      period; 1-wk run-in    Inclusion criteria:     C = spread w/o added                           compared to control:
                                     Study 2...............   BMI < 31, no RX that    PS.                                           I3 [darr] 6.6%*
                                                              affect lipids, total-  I3 = 2 g PS/d as                              LDL-C (mg/dL) After 3-
                                                              C 209-329 mg/dL, TG <   plant sterol esters                           wk intervention:
                                                              400 mg/dL.              in PS-enriched                               C 161
                                                             The Netherlands.......   spread.                                      I3 145
                                                                                                                                   LDL-C% change
                                                                                                                                    compared to control:
                                                                                                                                    I3 [darr] 9.6%*
                                                                                                                                   *p < 0.001
--------------------------------------------------------------------------------------------------------------------------------------------------------
Ntanios et al., 2002 (Ref. 97).....  Double-blind, placebo-  Healthy adult           Two servings/d low-    Habitual Japanese      Total-C (mg/dL) After
                                      controlled, crossover   Japanese, 53            fat test spread        diet. Diets assessed   3 wks of
                                      trial. 1-wk run-in;     enrolled, 53            consumed w/meals       with food frequency    intervention:
                                      Two consecutive 3-wk    completed              C = spread w/o added    questionnaire during  C 213
                                      test periods w/o wash- Mean age     PS.                    run-in period         I 201
                                      out period              sd.                    I = 1.8 g PS/d as                             Total-C% change
                                                             45.1  10.4   plant sterol esters                           compared to control:
                                                              y.                      in PS-enriched                                I [darr] 5.8% (p <
                                                             n = 53................   spread.                                       0.01)
                                                             Inclusion criteria:                                                   LDL-C (mg/dL) After 3
                                                              age 24-67 y; BMI 19-                                                  wks of intervention
                                                              30, healthy, normal                                                  C 119
                                                              diet, no HX of CVD or                                                I 109
                                                              [uarr] total-C.                                                      LDL-C% change
                                                             Japan.................                                                 compared to control:
                                                                                                                                    I [darr] 9.1% (p <
                                                                                                                                    0.001)
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 76563]]

 
Simons et al., 2002 (Ref. 98)......  Multicenter,            Hypercholesterolemic    Two servings/d of      American Heart         Total-C (mg/dL)
                                      randomized double-      adults, some using      test margarine,        Association Step I     Baseline:
                                      blind, placebo-         statin drugs            consumed w/meals.      diet; closely         I1 295
                                      controlled, parallel   154 enrolled, 152        Drug intervention:     supervised by a       I2 297
                                      2 X 2 factorial trial   completed.              400 [mu]g/day          nutritionist          I3 282
                                      with 4-wk test period  Mean age     cerivastatin, or                             I4 298
                                                              sd.                     placebo tablet                               Total-C% change at 4
                                                             60  9 y     I1 = tablet +                                  wk relative to
                                                              (I1).                   margarine.                                    baseline:
                                                             58  10 y    I2 = placebo tablet +                         I1 [uarr]2.2%
                                                              (I2).                   2 g PS/d as plant                            I2 [darr] 5.3%
                                                             58  11 y     sterol esters in PS-                         I3 [darr] 23.2%
                                                              (I3).                   enriched margarine.                          I4 [darr] 28.9%
                                                             62  11 y    I3 = statin + placebo                         Main effect of PS-
                                                              (I4).                   margarine.                                    enriched margarine:
                                                             n = 37-29/group.......  I4 = statin + 2 g PS/                          [darr] 6.7% (p <
                                                             Inclusion criteria:      d as plant sterol                             0.0001)
                                                              LDL-C >=97 mg/dL, TG    esters in PS-                                LDL-C (mg/dL)
                                                              < 400 mg/dL, age >18    enriched margarine.                           Baseline:
                                                              y.                                                                   I1 210
                                                             Australia.............                                                I2 209
                                                                                                                                   I3 195
                                                                                                                                   I4 209
                                                                                                                                   LDL-C% change at 4 wk
                                                                                                                                    compared to
                                                                                                                                    baseline:
                                                                                                                                   I1 [uarr]2%
                                                                                                                                   I2 [darr] 8.2%
                                                                                                                                   I3 [darr] 32.4%
                                                                                                                                   I4 [darr] 38.5%
                                                                                                                                   Main effect of PS-
                                                                                                                                    enriched margarine:
                                                                                                                                    [darr] 8.1% (p <
                                                                                                                                    0.0001)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Tammi et al., 2002 (Ref. 99).......  Randomized double-      Healthy children (age   20 g/d test margarine  Continuation of STRIP  Total-C (mg/dL)
                                      blind, crossover        6 y) enrolled in        replaced similar       study diet (low sat    Baseline:
                                      trial, with two 3       Finnish STRIP* study    amount of usual        fat, low              158 (boys)
                                      month test periods     81 enrolled, 79          dietary fat            cholesterol) that     176 (girls)
                                      separated by a 6-wk     completed.             C = margarine w/o       the subjects had      Total-C% change at 3-
                                      wash out period        n = 35 F..............   added PS.              followed for several   mo compared to
                                                             n = 44 M..............  I = 1.6 g PS/d as       years                  control
                                                             *Special Turku           plant stanol esters                          Iboys [darr] 6.4%*
                                                              Coronary Risk Factor    in PS-enriched                               Igirls [darr] 4.4%*
                                                              Project; subjects       margarine.                                   *p < 0.05
                                                              enrolled as infants;                                                 LDL-C (mg/dL)
                                                              study diet aim was                                                    Baseline:
                                                              1:1:1 ratio of                                                       98 (boys)
                                                              PUFA:MUFA:sat fats,                                                  123 (girls)
                                                              cholesterol < 200 mg/                                                LDL-C% change at 3-mo
                                                              d.                                                                    compared to control:
                                                                                                                                   Iboys [darr] 9.1%*
                                                                                                                                   Igirls [darr] 5.8%*
                                                                                                                                   *p < 0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------
Temme et al., 2002 (Ref. 100)......  Randomized double-      Healthy adults, 42      3 portions/d of test   Habitual diet........  Total-C (mg/dL) After
                                      blind, crossover        enrolled, 42            margarine eaten w/                            4 wk test period:
                                      trial; no run-in        completed               meals replaced                               C 248
                                      period; two            Mean age     habitual margarine                           I 231
                                      consecutive 4-wk test   sd.                     use                                          Total-C% change
                                      periods                55  9 y...  C = spread w/o added                           compared to control:
                                                             n = 42................   PS.                                           I [darr] 6.9%*
                                                             Inclusion criteria:     I = 2.1 g PS/d as                             LDL-C (mg/dL) After 4
                                                              BMI < 30, no RX or      plant sterol esters                           wk test period:
                                                              prescribed diet that    in PS-enriched                               C 166
                                                              affect lipids.          spread.                                      I 150
                                                             Report states 70% of                                                  LDL-C % change
                                                              Belgium adult                                                         compared to control:
                                                              population is mildly                                                  I [darr] 9.6%*
                                                              hypercholesterolemic.                                                *p < 0.05
                                                             Belgium...............
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 76564]]

 
Vanstone et al., 2002 (Ref. 22)....  Randomized double-      Primary familial        3 portions/d test      Controlled feeding of  Total-C (mg/dL) At
                                      blind, crossover        hyperlipidemia adults   butter eaten w/meals   typical American       end of 3 wk test
                                      trial; no run-in       16 enrolled, 15         C = butter w/           diet, all food and     period:
                                      period; four 3-wk       completed.              cornstarch added to    beverage prepared/    C 238
                                      controlled test        Mean age     mimic appearance of    provided by study, 2  I1 214
                                      periods separated by    sd.                     PS-enriched butter.    or more meals/d       I2 215
                                      4-wk washout periods   47.8  1.9   I1 =1.8 g PS/d as       eaten onsite          I3 216
                                                              y.                      nonesterified soy                            Total-C % change
                                                             n = 15................   sterols in PS-                                compared to control:
                                                             Inclusion criteria:      enriched butter.                             I1 [darr] 7.8%*
                                                              age 35-58 y; Total-C   I2 = 1.8 g PS/d as                            I2 [darr] 11.9%*
                                                              201-348 mg/dL, and TG   nonesterified soy                            I3 [darr] 13.1%*
                                                              < 310 mg/dL.            stanols in PS-                               LDL-C (mg/dL) At end
                                                             Canada................   enriched butter.                              of three wk test
                                                                                     I3 = 1.8 g PS/d as 50/                         period:
                                                                                      50 mix of                                    C 155
                                                                                      nonesterified soy                            I1 139
                                                                                      sterols/stanols in                           I2 139
                                                                                      PS-enriched butter.                          I3 137
                                                                                                                                   LDL-C % change at 3
                                                                                                                                    wk relative to
                                                                                                                                    placebo:
                                                                                                                                   I1[darr]11.3*
                                                                                                                                   I2[darr]13.4*
                                                                                                                                   I3[darr]16.0*
                                                                                                                                   *p < 0.05
                                                                                                                                   No significant
                                                                                                                                    difference between
                                                                                                                                    I1, I2 and I3
--------------------------------------------------------------------------------------------------------------------------------------------------------
Christiansen et al., 2001 (Ref. 24)  Randomized double-      Hypercholesterolemic    2 servings/d of test   Habitual Finnish       Total-C (mg/dL)
                                      blind, parallel         adults                  spread (rapeseed oil   diet; 7-day food       Baseline: 257
                                      design; three arm, 6-  155 enrolled, 134        margarine) in place    diaries ``were kept   Total-C % change
                                      wk run-in, 6-month      completed.              of usual dietary fat   by half of             compared to control:
                                      test period            Mean age 50.7 y.......  C = spread w/o added    subjects.''           I1 [darr] 9%*
                                                             n = about 45/group....   PS.                                          I2 [darr] 8.3%*
                                                             Inclusion criteria:     I1 = 1.5g PS/d as                             *p=0.001
                                                              total-C >= 227 mg/dL,   microcrystalline                             LDL-C (mg/dL)
                                                              TG < 266 mg/dL.         wood-derived (tall                            Baseline: 166
                                                             Finland...............   oil) nonesterified                           LDL-C % change
                                                                                      sterol/stanols in PS-                         compared to control:
                                                                                      enriched spread.                             I1 [darr] 11.3%*
                                                                                     I2 = 3 g PS/d as                              I2 [darr] 10.6%*
                                                                                      microcrystalline                             *p=0.002
                                                                                      wood-derived (tall
                                                                                      oil) nonesterified
                                                                                      sterol/stanols in PS-
                                                                                      enriched spread.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Davidson et al., 2001 (Ref. 55)....  Randomized double-      Healthy adults          2 servings/d of        Habitual diet          Total-C (mg/dL)
                                      blind, parallel        84 randomized 77         reduced- fat test      supplemented w/3       Baseline: 205
                                      trial; four arm, 8-wk   completed.              spread, and 1          servings/d of test    Total-C % change
                                      test period            Mean Age 46 y.........   serving/d of reduced-  foods. 3-day diet      compared to control:
                                                             n = 19 (C)............   fat test salad         records collected at  I1 [darr] 3.9%
                                                             n = 19 (I1)...........   dressing               wk 0, 4, and 8        I2 [darr] 0.9%
                                                             n = 18 (I2)...........  C = spread + salad                            I3 [darr] 4.6%
                                                             n = 21 (I3)...........   dressing.                                    LDL-C (mg/dL)
                                                             Inclusion criteria:     I1 = 3 g PS/d as                               Baseline: 130
                                                              total-C < 300 mg/dL,    sterol esters in PS-                         LDL-C % change
                                                              TG < 350 mg/dL, BMI <   enriched spread;                              compared to control:
                                                              35.                     placebo salad                                C [darr] 1.3%
                                                             USA...................   dressing.                                    I1 [darr] 3.7%
                                                                                     I2 = 6 g PS/d as                              I2 [darr] 1.5%
                                                                                      sterol esters in PS-                         I3 [darr] 7.7%
                                                                                      enriched salad                               No significant
                                                                                      dressing; placebo                             treatment effects on
                                                                                      spread.                                       total-C or LDL-C
                                                                                     I3 = 9 g PS/d as
                                                                                      sterol esters in PS-
                                                                                      enriched spread + PS-
                                                                                      enriched salad
                                                                                      dressing.
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 76565]]

 
Maki et al., 2001 (Ref. 101).......  Randomized double-      Hypercholesterolemic    2 servings/d of        National Cholesterol   Total-C (mg/dL)
                                      blind, placebo-         adults                  reduced-fat test       Education Program      Baseline: 238
                                      controlled, parallel   224 enrolled, 192        spread eaten w/meals   Step I, supplemented  Total-C % change
                                      trial, 4-wk run-in; 5-  included in analysis.  C = spread with w/o     w/reduced-fat test     compared to control:
                                      wk test period         n = 83 (C)............   added PS.              spread                I1 [darr] 5.2%*
                                                             n = 75 (I1)...........  I1 = 1.1 g PS/d as                            I2 - 6.6%*
                                                             n = 35 (I2)...........   soy sterol esters in                         *p < 0.001
                                                             Mean age     PS-enriched spread.                          LDL-C (mg/dL)
                                                              sd.                    I2 = 2.2 g PS/d as                             Baseline: 158
                                                             57.5  10.8   soy sterol esters in                         LDL-C % change
                                                              y (C).                  PS-enriched spread.                           compared to control:
                                                             58.7  10.6                                                I1 [darr] 7.6%*
                                                              y (I1).                                                              I2 [darr] 8.1%*
                                                             60.4  9.7                                                 *p < 0.001
                                                              y (I2).
                                                             Inclusion criteria: no
                                                              RX that affect
                                                              lipids, BMI < 35, LDL-
                                                              C 130-200 mg/dL, TG <
                                                              350 mg/dL, BMI < 35.
                                                             USA...................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Nestel et al., 2001 (Ref. 35)......  Randomized single-      Hypercholesterolemic    3 servings/d of test   Habitual low sat fat,  Median Total-C (mg/
                                      blinded, crossover      adults                  foods (low-fat wheat   low cholesterol diet   dL) at 4 wk:
                                      trial; 2-wk run-in,    22 enrolled, 22          cereal, low-fat        prescribed for        C 271
                                      three 4-wk test         completed.              bread, spread), one    cholesterol control;  I1 247*
                                      periods w/o wash-out   Mean age     serving eaten w/each   diet assessed by 3-   I2 261*
                                      period                  sd.                     meal                   day FFQ during run-   *p < 0.001 compared
                                     Study 1...............  60  9 y...  C = test foods, w/o     in phase               to control
                                                             n = 22................   added phytosterols.                          Median LDL-C (mg/dL)
                                                             Inclusion criteria:     I1 = 2.4 g PS/d as                             at 4 wk:
                                                              Total-C >213 mg/dL,     soy sterol esters in                         C 184
                                                              TG < 266 mg/dL.         PS-enriched foods.                           I1 159*
                                                             Australia.............  I2 = 2.4 g PS/d as                            I2 169*
                                                                                      nonesterified soy                            *p < 0.05 compared to
                                                                                      stanols in PS-                                control
                                                                                      enriched foods.                              I1 significantly
                                                                                                                                    lower than I2
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                     Randomized single-      Hypercholesterolemic    1 serving/d of test    Habitual low sat fat,  Total-C (mg/dL)
                                      blinded, crossover      adults (all Study 1     dairy spread (butter   low cholesterol diet   Baseline: 257
                                      trial; 2-wk run-in      participants)           + margarine blend)     prescribed for        Total-C % change
                                      followed by two 4-wk   15 enrolled, 15          eaten w/a meal         cholesterol control    compared to control:
                                      test periods w/o wash-  completed.             C = spread w/o added                           I3 [darr] 9.8%*
                                      out period             Australia.............   PS.                                          *p < 0.001
                                     Study 2...............                          I3 = 2.4 g PS/d as                            LDL-C (mg/dL)
                                                                                      soy sterol esters in                          Baseline: 178
                                                                                      PS-enriched dairy                            LDL-C % change
                                                                                      spread.                                       compared to control:
                                                                                                                                    I3 [darr] 13.0%*
                                                                                                                                   *p = 0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------
Tikkanen 2001 (Ref. 25)............  Double-blind, placebo-  Hypercholesterolemic    3 servings/d of test   Subjects received      Total-C (mg/dL)
                                      controlled, parallel    adults                  foods/d (bread,        individual dietary     Baseline:
                                      trial, two arms; 2-wk  78 enrolled, 71          meat, jam)             advice and kept 3-d   C 253
                                      run-in period w/        completed.             C = test foods w/o      food diaries 5 times  I 263
                                      placebo foods, 3       Mean age     added PS.              during the study      Total-C % change
                                      consecutive 5-wk        sd.                    I=1.25 g PS/d for 5                            compared to control:
                                      periods. PS dose       54  11 y     wk, then 2.5 g PS/d                          I wk5 [darr] 4.4%
                                      doubled w/each          (C).                    for wks 6-10, then 5                         I wk10 [darr] 6.2%
                                      successive test        57  8 y      g PS/d for wks 11-                           I wk15 [darr] 5.5%
                                      period                  (I).                    15. PS as                                    Significant
                                                             n = 35 (C)............   nonesterified wood-                           difference between P
                                                             n = 36 (I)............   derived sterol/                               and I by repeated
                                                             Inclusion criteria:      stanol mixture in PS-                         measures ANOVA p <
                                                              age 25-75 y; no         enriched bread,                               0.05
                                                              familial [uarr]total-   meats, and jam.                              LDL-C (mg/dL)
                                                              C, no HX of CAD                                                       Baseline:
                                                              previous 3 mos, no HX                                                C 166
                                                              of revascularization                                                 I 173
                                                              previous 4 mo, no RX                                                 LDL-C % change
                                                              that affect lipids,                                                   compared to control:
                                                              total-C 232-310 mg/                                                  I wk5 [darr] 5.4%
                                                              dL; TG < 355 mg/dL.                                                  I wk10 [darr] 7.9%
                                                             Finland...............                                                I wk15 [darr] 8.9%
                                                                                                                                   Significant
                                                                                                                                    difference between C
                                                                                                                                    and I by repeated
                                                                                                                                    measures ANOVA p <
                                                                                                                                    0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 76566]]

 
Blair et al., 2000 (Ref. 102)......  Randomized double-      Hypercholesterolemic    3 servings/d of test   Habitual diet. Diets   Total-C (mg/dL)
                                      blind, placebo-         adults on statin RX     margarine in place     assessed by 24-hr      Baseline: 231
                                      controlled, parallel   167 randomized, 141      of usual margarine     recalls               Total-C % change
                                      trial, two arms; 8-wk   completed.              consumptions                                  compared to control:
                                      test period with       Mean age    C = margarine w/o                              I [darr] 7% (p <
                                      additional 6-wk         sd.                     added PS.                                     0.0001)
                                      follow-up              56  10 y..  I = 3.0g PS/d as                              LDL-C (mg/dL)
                                                             n = 72 (C)............   stanol esters in PS-                          Baseline: 147
                                                             n = 69 (I)............   enriched margarine.                          LDL-C % change
                                                             Inclusion criteria:                                                    compared to control:
                                                              age >=20 y; LDL-C                                                     I [darr] 9.6% (p <
                                                              >=130 mg/dL, TG <=350                                                 0.0001)
                                                              mg/dL, stable statin
                                                              dose for >90d.
                                                             USA...................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Hallikainen et al., 2000B (Ref. 39)  Randomized double-      Mildly                  2-3 portions/d of      Step I diet. Diet was  Total-C (mg/dL) At
                                      blind, crossover        hypercholesterolemic    test margarines        assessed with 4-day    end of 4 wk:
                                      trial; 2-wk run-in      adults                  eaten with meals       food records at the   C 236
                                      period; three          42 enrolled, 34         C = margarine w/o       end of each period    I1 213
                                      consecutive 4-wk test   completed.              added PS.                                    I2 218
                                      periods                Mean age    I1 = 2 g PS/d as                              Total-C % change
                                                              sd.                     plant stanol ester                            compared to control:
                                                             48.8  8.1    in PS-enriched                               I1 [darr] 9.2%*
                                                              y.                      margarine.                                   I2 [darr] 7.3%*
                                                             n = 34................  I2 = 2 g PS/d as                              *p < 0.001
                                                             Inclusion criteria:      plant sterol ester                           LDL-C (mg/dL) At end
                                                              age 30-65 y, Total-C    in PS-enriched                                of 4 wk:
                                                              186-271 mg/dL, TG <     margarine.                                   C 162
                                                              220 mg/dL.                                                           I1 141
                                                             Finland...............                                                I2 145
                                                                                                                                   LDL-C % change
                                                                                                                                    compared to control:
                                                                                                                                   I1 [darr] 12.7%*
                                                                                                                                   I2 [darr] 10.4%*
                                                                                                                                   *p < 0.001
                                                                                                                                   I1 and I2 not
                                                                                                                                    significantly
                                                                                                                                    different
--------------------------------------------------------------------------------------------------------------------------------------------------------
Hallikainen et al., 2000a (Ref. 53)  Randomized single-      Hypercholsterolemic     2-3 portions of test   Subjects consumed a    Total-C (mg/dL)
                                      blind crossover         adults                  margarine w/meals      standardized           Baseline:
                                      trial; 1-wk run-in     22 entolled, 22         C = margarine w/out     background diet       266  50
                                      period, five 3-wk       completed.              added PS.                                     mg/dL0
                                      test periods           Mean age 50.5  11.7.            plant stanol esters.                          compared to control:
                                                             n = 22................  I2 = 1.6 g/d PS/d as                          I1 [darr] 2.8%
                                                             Inclusion criteria:      plant stanol esters.                         I2 [darr] 6.8%*
                                                              Total-C 194-329 mg/dL. I3 = 2.4 g PS/d as                            I3 [darr] 10.3%*
                                                             Finland...............   plant stanol esters.                         I4 [darr] 11.3%*
                                                                                     I4 = 3.2 g PD/d as                            LDL-C % change
                                                                                      plant stanol esters.                          compared to control:
                                                                                                                                   I1 [darr] 1.7%
                                                                                                                                   I2 [darr] 5.6%
                                                                                                                                   I3 [darr] 9.7%*
                                                                                                                                   I4 [darr] 10.4%*
                                                                                                                                   *p < 0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------
Jones et al., 2000 (Ref. 40).......  Randomized double-      Hyperlipidemic males    3 servings/d of test   Controlled diet        Total-C (mg/dL)
                                      blind, crossover       18 enrolled, 15          margarine, eaten       formulated to meet     Baseline:
                                      trial; no run-in        included in analyses.   with meals             Canadian Recommended  C 250
                                      period; three 3-wk     n = 15................  C = margarine w/o       Nutrient Intakes.     I1 247
                                      controlled feeding     Inclusion criteria:      added PS.              All food and          I2 246
                                      test periods            Age 37-61 y; Total-C   I1 = 1.84 g PS/d as     beverage prepared/    Total-C % change
                                      separated by 5-wk       232-387 mg/dL, TG <     plant sterol esters    provided by study;     compared to control:
                                      washout periods         266 mg/dL.              in PS-enriched         at least 2 meals/d    I1 [darr] 9.1%*
                                                             Canada................   margarine.             eaten onsite          I2 [darr] 5.5%
                                                                                     I2 = 1.84 g PS/d as                           *p < 0.02
                                                                                      plant stanol esters                          LDL-C (mg/dL)
                                                                                      in PS-enriched                                Baseline:
                                                                                      margarine.                                   C 172
                                                                                                                                   I1 166
                                                                                                                                   I2 168
                                                                                                                                   LDL-C % change
                                                                                                                                    compared to control:
                                                                                                                                   I1 [darr] 13.2%*
                                                                                                                                   I2 [darr] 6.4%* *
                                                                                                                                   *p < 0.02
                                                                                                                                   I1 significantly
                                                                                                                                    lower than I2
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 76567]]

 
Plat et al. 2000 (Ref. 87).........  Randomized double-      Healthy, normal or      One serving/d of test  Habitual diets         Total-C (mg/dL)
                                      blind, placebo-         mildly                  margarine and 3        supplemented w/test   At end of 4 wk:
                                      controlled, crossover   hypercholesterolemic    servings/d of test     margarine and test    C 194
                                      trial. Three            subjects                shortening (in         cookies/cake. PS-     I1 182
                                      consecutive 4-wk test  40 enrolled, 39          cookies/cakes) with    free shortening was   I2 181
                                      periods, no washout     completed.              each meals             provided to subjects  Total-C % change
                                      periods                Mean age    C = margarine &         for baking and         compared to control:
                                                              sd.                     shortening w/o added   cooking               I1 [darr] 6.4%*
                                                             31  14 y..   PS.                                          I2 [darr] 6.6%*
                                                             n = 39................  I1 = 2.5 g PS/d as                            *p < 0.001
                                                             Inclusion criteria:      stanol ester in PS-                          LDL-C (mg/dL) At end
                                                              age 18-65 y; Total-C    enriched margarine                            of 4 wk
                                                              < 250 mg/dL; TG <       eaten w/lunch.                               C 118
                                                              266; BMI < 30, BP <    I2 = 2.5 g PS/d as                            I1 106
                                                              160/95, no RX or diet   stanol ester in PS-                          I2 106
                                                              that affect lipids,     enriched margarine                           LDL-C % change
                                                              no HX of CVD.           and PS-enriched                               compared to control:
                                                             The Netherlands.......   shortening divided                           I1 [darr] 9.9%*
                                                                                      over 3 servings w/                           I2 [darr] 10.2%*
                                                                                      meals.                                       *p < 0.001
--------------------------------------------------------------------------------------------------------------------------------------------------------
Vissers et al., 2000 (Ref. 36).....  Double-blind,           Normal adults           Test margarine,        Habitual diets. Diet   Total-C (mg/dL) At
                                      crossover trial; no    60 enrolled, 60          divided over           assessed each period   end of 3 wks:
                                      run-in period; three    completed.              multiple portions,     with 24-h diet        C 164
                                      consecutive 3-wk test  age range=18-59 y.....   eaten with meals in    recall                I1 157
                                      periods                n = 60................   place of usual                               I2 162
                                                             Inclusion criteria:      margarine                                    Total-C % change
                                                              age >17 y; no RX or    C = margarine without                          compared to control:
                                                              prescribed diet that    added PS.                                    I1 [darr] 4.5%*
                                                              affect lipids, Total-  I1 = 2.1 g PS/d as                            I2 [darr] 1.2%
                                                              C < 290 mg/dL, TG <     rice bran                                    *p < 0.05
                                                              204 mg/dL.              nonesterified oil                            LDL-C (mg/dL) At end
                                                             The Netherlands.......   sterols in PS-                                of 3 wks:
                                                                                      enriched margarine                           C 91
                                                                                      (~1 g/d of 4-                                I1 84
                                                                                      desmethylsterols).                           I2 89
                                                                                     I2 = sheanut oil                              LDL-C % change
                                                                                      triterpenes in                                compared to control:
                                                                                      margarine.                                   I1 [darr] 8.5%*
                                                                                                                                   I2 [darr] 3.0%
                                                                                                                                   *p < 0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------
Andersson et al., 1999 (Ref. 103)..  Randomized double       Moderately              25 g/d margarine       Consumed a test diet.  Total-C % change
                                      blind controlled        hypercholesterolemic    provided as 3 single                          compared to baseline
                                      parallel trial; 4-wk    adults                  servings                                     C [darr] 8.0%
                                      run-in period, three   Age  sd...  C = margarine w/o                             I1 [darr] 15%*
                                      8-wk test periods      55.1  7.9    added PS.                                    *p = 0.0035
                                                              y.                     I1 = 2 g PS/d as                              LDL-C % change
                                                             n = 21 (C)............   plant stanol esters                           compared to baseline
                                                             n = 19 (I)............   in PS-enriched                               C [darr] 12%
                                                             Inclusion criteria:      margarine.                                   I1 [darr] 19%*
                                                              Total-C < 330 mg/dL,                                                 *p = 0.0158
                                                              BMI >30.
                                                             Sweden................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Ayesh et al., 1999 (Ref. 104)......  Randomized placebo-     Healthy adults          40 g/d margarine       Typical British diet,  Total-C % change
                                      controlled parallel    24 enrolled, 21          consumed at            breakfast and dinner   compared to control:
                                      trial; 21 to 28 d run-  completed.              breakfast and dinner   consumed under        I [darr] 18%*
                                      in, 21-28 d test       Age 30-40 y...........  C = margarine w/o       supervision           LDL-C % change
                                      period                 n = 11 (C)............   added PS.                                     compared to control:
                                                             n =10 (I).............  I = 8.6 g PS/d as                             I [darr] 23%*
                                                             Inclusion criteria:      plant sterol esters                          *p < 0.0001
                                                              Total-C 158-255 mg/dL.  in PS-enriched
                                                             United Kingdom........   margarine.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Gylling and Miettinen, 1999 (Ref.    Randomized double-      Moderately              25 g/d butter          Subjects were advised  Total-C % change
 105).                                blind crossover         hypercholesterolemic,  C = butter w/out        to replace 25 g of     compared to control:
                                      trial; 1-wk run-in      postmenopausal women;   added PS.              their normal dietary  I [darr] 8%*
                                      period; two 5 wk test   24 enrolled            I = 2.4 g PS/d as       fat with butter       LDL-C % change
                                      periods                Age 50-55 y...........   wood sitostanol                               compared to control:
                                                             n = 21 butter period..   ester in PS-enriched                         I [darr] 12%*
                                                             Inclusion criteria:      butter.                                      *p < 0.05
                                                              Total-C between 213
                                                              and 310 mg/dL.
                                                             Finland...............
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 76568]]

 
Hendriks et al., 1999 (Ref. 51)....  Randomized, double-     Normocholesterolemic    25 g/d butter or       Habitual diets.        Total-C (mg/dL)
                                      blind, crossover        and mildly              spread consumed at     Spreads replace an     Baseline:
                                      trial; no run-in        cholesterolemic         lunch or dinner        equivalent amount of  197 mg/dL
                                      period, four test       adults, 100 enrolled,  C1 = butter w/out       spreads habitually    Total-C % change
                                      periods of 3.5 wks      80 per test period      added PS.              used                   compared to C2
                                                             Age 19-58 y...........  C2 = spread w/out                             I1 [darr] 4.9%*
                                                             n = 80................   added PS.                                    I2 [darr] 5.9%*
                                                             Inclusion criteria:     I1 = 0.8 g PS/d as                            I3 [darr] 6.8%*
                                                              Total-C < 290 mg/dL.    plant sterol esters                          LDL-C % change
                                                             The Netherlands.......   in PS-enriched                                compared to C2
                                                                                      spreads.                                     I1 [darr] 6.7%*
                                                                                     I2 = 1.6 g PS/d as                            I2 [darr] 8.5%*
                                                                                      plant sterol esters                          I3 [darr] 9.9%*
                                                                                      in PS-enriched                               *p < 0.0001
                                                                                      spreads.
                                                                                     I3 = 3.2 g PS/d as
                                                                                      plant sterol esters
                                                                                      in PS-enriched
                                                                                      spreads.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Jones et al., 1999 (Ref. 21).......  Randomized double-      Hypercholsterolemic     30 g/d test margarine  Controlled feeding     Total-C (mg/dL)
                                      blind, placebo-         adults, 32 enrolled,    consumed with 3        regimen; a prudent     Baseline:
                                      controlled, parallel    32 completed            meals                  fixed North American  C 263
                                      trial with 2 groups;   Age 25-60 y...........  C = margarine w/o       diet formulated to    I 260
                                      No run-in period; 30-  n = 16 (C)............   added PS.              meet Canadian         LDL-C % change
                                      d test period; 20-d    n = 16 (I)............  I = 1.7 g PS/d          recommended nutrient   compared to control:
                                      follow-up after test   Inclusion criteria:      sistostanol-           intakes                I [darr] 15.5% (p <
                                      period                  Total-C 252-387 mg/dL.  containing                                    0.05)
                                                             Canada................   phytosterols (20%
                                                                                      sitostanol,
                                                                                      remaining plant
                                                                                      sterols are
                                                                                      sitosterol,
                                                                                      campesterol) as
                                                                                      nonesterified tall
                                                                                      oil.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Nguyen et al., 1999 (Ref. 106).....  Multicenter             Mildly                  24 g/d U.S. vegetable  Usual dietary habits   Total-C % change
                                      randomized, double-     hypercholesterolemic    oil spread (three 8    maintained             compared to control:
                                      blind, placebo-         adults                  g servings/d)                                I1 [darr] 6.4*
                                      controlled parallel    Age  sd...  C = U.S. vegetable                            I2 [darr] 4.1*
                                      trial; 4-wk run-in     51.3  12.0   oil spread w/out                             *p < 0.001
                                      period, 8-wk test       to 54.5     added PS.                                    LDL-C % change
                                      period                  11.3 y.                I1 = 3 g PS/d as                               compared to control:
                                                             n = 76 (C)............   stanol esters in                             I1 [darr] 10.1*
                                                             n = 71 (I1)...........   U.S. vegetable oil                           I2 [darr] 4.1*
                                                             n = 77 (I2)...........   spread.                                      *p < 0.02
                                                             Inclusion criteria: 20  I2 = 2 g PS/d as
                                                              y, Total-C 200 and      stanol esters in
                                                              280 mg/dL.              U.S. vegetable oil
                                                             USA...................   spread.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Sierksma et al., 1999 (Ref. 29)....  Balanced, double-blind  Healthy adults, 78      25 g/d Flora spread,   Habitual diets.        Total-C (mg/dL)
                                      crossover trial; 1-wk   enrolled, 76            with meals             Phytosterol-           Baseline:
                                      run-in, 3-wk test       completed              C = Flora spread w/o    containing spread     310 mg/dL
                                      period                 Age 18-62 y...........   added PS.              replaced all or part  Total-C (mg/dL)
                                                             n = 75................  I1 = 0.8 g PS/d as      of habitual spread    C 196
                                                             Inclusion criteria: <    nonesterified          or butter used for    I1 188*
                                                              Total-C < 309 mg/dL.    sterols in PS-         spreading             I2 194
                                                             The Netherlands.......   enriched Flora                               LDL-C (mg/dL)
                                                                                      spread.                                      C 122
                                                                                     I2 = 3.3 g PS/d as                            I1 114*
                                                                                      esterified sterols                           I2 119
                                                                                      in PS-enriched Flora                         Total-C % change
                                                                                      spread.                                       compared to control:
                                                                                                                                   I1 [darr] 3.8%*
                                                                                                                                   LDL-C % change
                                                                                                                                    compared to control:
                                                                                                                                   I1 [darr] 6.0%*
                                                                                                                                   *p < 0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------
Westrate and Meijer, 1998 (Ref. 31)  Balanced, Randomized    Normocholesterolemic    30 g/d margarine       Test margarine         Total-C (mg/dL)
                                      double-blind            and mildly              consumed at lunch      replaced margarines    Baseline:
                                      crossover trial; 5-d    hypercholesterolemic    and dinner             habitually used       207
                                      run-in, four test       adults, 100 enrolled,  C = Flora spread w/o                          Total-C % change
                                      periods of 3.5 wks      95 completed            added PS.                                     compared to control:
                                                             Mean age    I1 = 2.7 g PS/d as                            I1 [darr] 7.3%*
                                                              sd.                     plant stanol esters                          I2 [darr] 8.3%*
                                                             45  12.8 y   (2.7 g/d.                                    I3 [darr] 1.1%
                                                             n = 95................  I2 = 3.0 g PS/d as                            I4 [darr] 0.7%
                                                             Inclusion criteria:      soybean sterol                               LDL-C % change
                                                              Total-C < 310 mg/dL.    esters.                                       compared to control:
                                                             The Netherlands.......  I3 = 1.6 g PS/d as                            I1 [darr] 13%*
                                                                                      rice bran                                    I2 [darr] 13%*
                                                                                      nonesterified                                I3 [darr] 1.5%
                                                                                      sterols.                                     I4 [darr] 0.9%
                                                                                     I4 = 2.9 g PS/day as                          *p < 0.05
                                                                                      sheanut
                                                                                      nonesterified
                                                                                      sterols.
                                                                                     Stanol source: wood..
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 76569]]

 
Niinikoski et al., 1997 (Ref. 107).  Randomized double-      Normocholesterolemic    24 g margarine         Habitual diet.         Total-C (mg/dL)
                                      blind, placebo-         adults, 24 enrolled     consumed in 3          Replace normal         Baseline:
                                      controlled parallel    Age 24-52 y...........   portions               dietary fat with      197
                                      trial; no run-in       n = 12 (C)............  C = margarine w/out     test rapeseed oil     Total C % compared to
                                      period, 5-wk test      n = 12 (I)............   added PS.              margarine              control
                                      period                 Inclusion criteria:     I = 3 g PS/day as                             C [darr] 11
                                                              not provided.           esterified                                   I [darr] 31*
                                                             Finland...............   sitostanol.                                  *p < 0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------
Pelletier et al., 1995 (Ref. 30)...  Randomized, crossover   Normolipidemic men      50 g/d butter as part  Controlled but normal  Total-C % change
                                      trial; 1-wk run-in,    Mean age     of a normal diet       diet                   compared to control:
                                      two test periods of 4   sd.                    C =butter w/out added                         I [darr] 10%*
                                      wks                    22.7  2.6    PS.                                          LDL-C % change
                                                              y.                     I = 0.74 g PS/d as                             compared to control:
                                                             n = 12................   soybean                                      I [darr] 15%*
                                                             Inclusion criteria:      nonesterified                                *p < 0.05
                                                              light smokers and       sterols.
                                                              normal physical
                                                              activity.
                                                             France................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Miettinen et al., 1994 (Ref. 28)...  Randomized double-      Hypercholesterolemic    50 g rapeseed oil      Habitual diets.        Total-C % change
                                      blind, placebo-         adults, 31 enrolled     mayonnaise, with       Advised to replace     compared to control:
                                      controlled parallel    Mean age     meals                  50 g of typical       I1 [darr] 7.7%
                                      trial; 6-wk run-in, 9-  sd.                    C = mayonnaise w/out    daily fat with        I2 [darr] 0.4%
                                      wk test period         45  3 y...   added PS.              mayonnaise            I3 [darr] 7.4%*
                                                             n = 31................  I1 = 0.7 g PS/d as      containing rapeseed   LDL-C % change
                                                             Inclusion criteria:      nonesterified          oil                    compared to control:
                                                              Total-C >232 mg/dL.     sitosterol in                                I1 [darr] 7.0%
                                                             Finland...............   mayonnaise.                                  I2 [darr] 1.2%
                                                                                     I2 = 0.7 g PS/d as                            I3 [darr] 7.7%*
                                                                                      nonesterified                                *p < 0.05
                                                                                      sitostanol in
                                                                                      mayonnaise.
                                                                                     I3 = 0.8 g PS/d as
                                                                                      sitostanol ester in
                                                                                      mayonnaise.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Blomqvist et al., 1993 Vanhanen et   Randomized double-      Hypercholesterolemic    50 g rapeseed oil      Habitual diets.        Total-C % change
 al., 1993 (Ref. 108).                blind placebo           adults, 37 enrolled     mayonnaise, with       Advised to replace     compared to control:
                                      controlled parallel    Mean age     meals                  50 g of daily fat     C [darr] 2.7
                                      trial; 4-wk run-in, 6-  sd.                    C = mayonnaise w/out    intake with 50 of     I [darr] 17.0*
                                      wk test period         43-48  2 y   added PS.              mayonnaise            LDL-C % change
                                                             n = 33 (C)............  I = 3.4 g PS/d as       containing rapeseed    compared to control:
                                                             n =34 (I).............   sitosterol ester in    oil                   C [darr] 1.5
                                                             Inclusion criteria:      mayonniase.                                  I [darr] 14.3*
                                                              Total-C >232 mg/dL.                                                  *p < 0.051
                                                             Finland...............
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Weight represents nonesterified sterols or stanols.


                     Table 2--Randomized Clinical Trials of Phytosterols in Supplements and Total and LDL Cholesterol Concentration
--------------------------------------------------------------------------------------------------------------------------------------------------------
               Study                         Design                Population             Intervention               Diet                 Results
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                               Nonesterified Phytosterols
--------------------------------------------------------------------------------------------------------------------------------------------------------
Denke 1995 (Ref. 65)...............  Non-random, non-        Moderately              (1) Gelatin capsules   Step I diet (control)  Total-C (mg/dL)
                                      blinded, 3 sequential   hypercholesterolemic    containing tall oil    during intervention    Baseline: 239
                                      3-mos trial periods     males.                  sitostanol suspended   and washout periods.  Total-C % change
                                      separated by 3-mos     33 enrolled, 33          in safflower oil; 3                           compared to Step I
                                      washout periods.        completed.              doses/d of 4                                  diet:
                                                             Age range 31-70 y.....   capsules (total 12                           I[ihel1] [darr] 0.5%
                                                             Subjects'                capsules/d) taken                            I[ihel2] [darr] 7.1%*
                                                              characteristics: mean   with meals. (2)                              I[ihel3] [darr] 8.9%*
                                                              LDL-C with Step I       Cholestyramine                               LDL-C (mg/dL)
                                                              diet 175 mg/dL, TG <    supplied in flavored                          Baseline: 175
                                                              250 mg/dL, mean BMI     bars.                                        LDL-C % change from
                                                              26.2.                  I[ihel1] = 3 g/d                               Sep 1 diet:
                                                             USA...................   sitostanol\1\.                               I[ihel1] [darr] 1.8%
                                                                                     I[ihel2] =                                    I[ihel2] [darr]
                                                                                      cholestyramine.                               12.6%*
                                                                                     I[ihel3] = sitostanol                         I[ihel3] [darr]
                                                                                      + cholestyramine.                             14.8%*
                                                                                                                                   *p < 0.001 compared
                                                                                                                                    to preceding and
                                                                                                                                    subsequent washout
                                                                                                                                    periods.
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 76570]]

 
McPherson et al., 2005 (Ref. 66)...  Randomized, double      Healthy adults 52       Dietary supplement of  AHA heart healthy      Total-C (mg/dL)
                                      blind, placebo-         enrolled, 52            rapidly                diet.                  Baseline:
                                      controlled, parallel    completed.              disintegrating                               CT 195
                                      design; four arms; 6-  Mean age     tablets or slowly                            IT 186
                                      wk trial period.        sd 46.5     disintegrating                               CC 198
                                                              8.1 y (tablets).        capsules, twice/d                            IC 203
                                                             50.7  12.5   with meals.                                  Total-C % change
                                                              y (capsules).          CT = lecithin-                                 compared to control:
                                                             tablet trial..........   containing tablets w/                        IT [darr] 4.8%
                                                             n = 13 (IT)...........   o PS.                                        IC [darr] 1.9%
                                                             n = 12 (PT)...........  CC = lecithin-                                No significant
                                                             n = 27 (capsule trial)   containing capsules                           differences between
                                                             Inclusion criteria:      w/o PS.                                       IT and IC and
                                                              LDL-C 70-190 mg/dL,    IT = 1.26 g PS/d as                            control
                                                              TG < 300 mg/dL.         spray-dried plant                            LDL-C (mg/dL)
                                                             USA...................   stanol/lecithin                               Baseline:
                                                                                      emulsion in tablets.                         CT 121
                                                                                     IC = 1.26 g PS/d as                           IT 117
                                                                                      spray-dried plant                            CC 123
                                                                                      stanol/lecithin                              IC 235
                                                                                      emulsion in gelatin                          LDL-C % change
                                                                                      capsules.                                     relative to placebo:
                                                                                                                                   IT [darr] 10.4%*
                                                                                                                                   IC [darr] 2.5%
                                                                                                                                   * p < 0.05 compared
                                                                                                                                    to placebo
--------------------------------------------------------------------------------------------------------------------------------------------------------
Goldberg et al., 2006 (Ref. 67)....  Randomized double-      Hyperlipidemic adults   Soy stanols as a       American Heart         Total-C (mg/dL)
                                      blind, placebo-         taking statins 26       tableted stanol/       Association Heart      Baseline:
                                      controlled, parallel    enrolled, 26            lecithin emulsion.     Healthy Diet.         C 197
                                      trial, 1-wk run-in, 6-  completed..             225 mg PS/tablet; 4                          I 193
                                      wk test period.        age range 40-78 y.....   tablets twice a day                          Total-C % change
                                                             n = 13/group..........   before meals. Starch                          compared to control:
                                                             Inclusion criteria:      replaced stanol/                             I [darr] 5.7% (p <
                                                              Stable statin dose,     lecithin complex in                           0.05)
                                                              LDL-C >100 mg/dL, TG    placebo tablets.                             LDL-C (mg/dL)
                                                              < 300 mg/dL.           C = placebo tablet...                          Baseline:
                                                             USA...................  I = 1.8 g PS/d as                             C 119
                                                                                      stanol/lecithin                              I 112
                                                                                      emulsion in tablets.                         LDL-C % change
                                                                                                                                    compared to placebo:
                                                                                                                                   I [darr] 9.1% (p <
                                                                                                                                    0.05)
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                 Esterified Phytosterols
--------------------------------------------------------------------------------------------------------------------------------------------------------
Woodgate et al., 2006 (Ref. 64)....  Randomized, double-     Hyperchoelsterolemic    Total of 6 softgel     Habitual diets         Total-C (mg/dL)
                                      blind, placebo-         adults, 30 enrolled,    (glyceron) capsules                           Baseline:
                                      controlled trial with   29 completed.           with breakfast and                           C 266
                                      2 groups; 4-wk test    Age 33-70 y...........   dinner.                                      I 267
                                      period.                Inclusion criteria: no  C = corn oil.........                         Total-C % change
                                                              diabetes, no           I = 1.6 g PS/d as                              compared to control
                                                              cholesterol lowering    stanol esters.                               I [darr] 8% (p <
                                                              Rx, no prior                                                          0.05)
                                                              myocardial infarction                                                LDL-C (mg/dL)
                                                              or heart surgery.                                                     Baseline:
                                                                                                                                   C 207
                                                                                                                                   I 201
                                                                                                                                   LDL-C % change
                                                                                                                                    compared to control
                                                                                                                                   I [darr] 9% (p <
                                                                                                                                    0.05)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Acuff et al., 2007 (Ref. 62).......  Randomized, double-     Hypercholesterolemic    2 dietary supplement   Habitual diets, diets  Total-C (mg/dL)
                                      blind, placebo-         adults, 20 enrolled,    capsules/d, one        not monitored.         Baseline: 256
                                      controlled,             16 completed.           capsule w/lunch,                             After 4 wk test
                                      sequential trial; two  Mean age     second capsule w/                             period:
                                      4-wk test periods       sd.                     dinner.                                      C 242
                                      separated by 2-wk      51  13 y..  C = soy oil capsules.                         I 230
                                      washout period.        Inclusion criteria:     I = 0.8 g PS/d as                             Total-C % change
                                                              hyperlipidemia, BMI <   plant sterol esters                           compared to control:
                                                              30, no lipid lowering   divided between 2                            I [darr] 4.7% (not
                                                              RX, no diseases         capsules.                                     significant)
                                                              requiring tmt, no                                                    LDL-C (mg/dL)
                                                              hypertension.                                                         Baseline: 177
                                                             USA...................                                                After 4 wk test
                                                                                                                                    period:
                                                                                                                                   C 169
                                                                                                                                   I 163
                                                                                                                                   LDL-C % change
                                                                                                                                    compared to control:
                                                                                                                                   I [darr] 3.5% (p <
                                                                                                                                    0.05)
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 76571]]

 
Earnest et al., 2007 (Ref. 63).....  Randomized double-      Mildly                  4 dietary supplement   Habitual diets, diets  Total-C (mg/dL)
                                      blind, placebo-         hypercholesterolemic    capsules/d; 2          not monitored.         Baseline:
                                      controlled, parallel    adults.                 capsules w/each of 2                         C 232
                                      trial with 2 groups;   54 enrolled, 54          meals.                                       I 243
                                      12-wk test period.      completed.             C = capsule w/o PS...                         After 4 wk test
                                                             Age 20-70 y...........  I = 2.6 g PS/d as                              period:
                                                             Inclusion criteria:      plant sterol esters                          C 237
                                                              LDL-C >=130 mg/dL.      divided among 4                              I 234
                                                             USA...................   capsules.                                    Total-C % change
                                                                                                                                    compared to control:
                                                                                                                                   I [darr] 6.0% (p <
                                                                                                                                    0.05)
                                                                                                                                   LDL-C (mg/dL)
                                                                                                                                    Baseline:
                                                                                                                                   P 155
                                                                                                                                   I 165
                                                                                                                                   After 4 wk test
                                                                                                                                    period:
                                                                                                                                   P 161
                                                                                                                                   I 157
                                                                                                                                   LDL-C % change
                                                                                                                                    compared to control:
                                                                                                                                   I [darr] 9.2% (p <
                                                                                                                                    0.05)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Rader and Nguyen, 2000 (Ref. 61)...  Randomized, double-     Hypercholesterolemic    3 dietary supplement   Habitual diets         Total-C (mg/dL)
                                      blind, placebo-         adults; 160 enrolled,   test capsules/d with                          Baseline:
                                      controlled, parallel    156 completed.          meals.                                       P 245
                                      trial, two arm. 3-wk   n = 156...............  C = placebo capsules                          I 248
                                      trial period.          Inclusion criteria:      w/o PS.                                      Total-C % change
                                                              Total-C 220-300 mg/    I = 1 g PS/d as plant                          compared to control:
                                                              dL; TG <=350 mg/dL;     stanol esters                                I [darr] 3.0% (p <
                                                              good health.            divided over 3                                0.05)
                                                             USA...................   capsules.                                    LDL-C (mg/dL)
                                                                                                                                    Baseline:
                                                                                                                                   C 154
                                                                                                                                   I 155
                                                                                                                                   LDL-C % change
                                                                                                                                    compared to control:
                                                                                                                                   I [darr] 5.2% (p <
                                                                                                                                    0.05)
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Weight represents nonesterified sterols or stanols.
Abbreviations Used in table:
C control group/period
I intervention group/period
BMI body mass index
Total-C serum total cholesterol
LDL-C serum low density lipoprotein cholesterol
wk week
y years
PS phytosterols (mixture of sterols and stanols)
mg/dL milligrams per deciliter
g gram
g/d grams per day
w/ with
w/o without
TG serum triglycerides
tmt treatment
mos months
CAD coronary artery disease
CVD cardiovascular disease
Rx prescription drugs
Hx history
Sd standard deviation
d day
RSO Rape seed oil


[FR Doc. 2010-30386 Filed 12-7-10; 8:45 am]
BILLING CODE 4160-01-P