Food Labeling; Health Claim; Phytosterols and Risk of Coronary Heart Disease, 76526-76571 [2010-30386]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 75, Number 235 (Wednesday, December 8, 2010)]
[Proposed Rules]
[Pages 76526-76571]
From the Federal Register Online via the Government Printing 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

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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: https://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 https://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 https://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