76526 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

1The 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. 

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. 

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. 

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 

§ 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 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 76527 

2The 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 

§ 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 § 169.150 does not include 

a number of common types of dressings for salad, 

such as Italian dressing. 

3A correction notice published in the Federal 

Register on November 24, 2000 (65 FR 70466). 

4Section 101.83(c)(2)(iii)(B)—The food must be 

‘‘low in saturated fat’’ and ‘‘low in cholesterol’’ as 

defined in § 101.62 (21 CFR 101.62); 

§ 101.83(c)(2)(iii)(C)—the food must meet the limits 

for total fat in § 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 

§ 101.13(h) (e.g., ‘‘See nutrition information for fat 

content’’); and § 101.83(c)(2)(iii)(D)—the food must 

meet the minimum nutrient contribution 

requirement in § 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. 

5The 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. 

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 substancedisease 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 §§ 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. 

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 

§ 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). 

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 § 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 

§ 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 

§ 101.83(c)(2)(i)(D) 5 in the health claim 

to describe the substance (e.g., ‘‘plant 

sterols’’ or ‘‘phytosterols’’); (5) the claim 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
76528 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

6E.g., ‘‘See nutrition information for fat content.’’ 

7Although 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. 

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 § 101.13(h) (21 CFR 

101.13(h)); 6 and (7) use of the claim 

otherwise complies with § 101.83. 

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 § 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 

§ 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 § 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 § 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. 

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 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 76529 

8As 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. 

9Weight 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. 

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 postintervention 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 phytosterolenriched 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). 

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 

(§ 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. (§ 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 (§ 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 § 101.14(b)(1) (65 FR 54686 at 

54687). Current § 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 foodgrade 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) (§ 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 (§ 101.83(c)(2)(i)(C)). 

For reasons discussed elsewhere in 

this preamble, FDA is proposing to 

amend § 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 § 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 

§ 101.14(b)(3)(i) is satisfied. 

Finally, under § 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 

§ 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 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
76530 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

10See, e.g., GRAS Notification Numbers (GRN) 

000039, GRN 000048, GRN 000176, GRN 000177, 

GRN 000112, GRN 000181, GRN 000053, and GRN 

000206). 

11Section 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. 

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 § 101.83. 

These submissions have included data 

to support the manufacturer’s selfdeterminations 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 

§ 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. 

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 

§ 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. 

V. Proposed Modifications to Current 

§ 101.83 

A. Nature of the Substance 

1. Esterification 

Current § 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 betasitosterol, 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) 

(§ 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, cholesterollowering 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 § 101.83 provides 

only for a claim about phytosterol 

esters, the evidence that was considered 

in the IFR included five intervention 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 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, lowfat 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 § 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 § 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 § 101.83 must 

be comprised of at least 80 percent 

(combined weight) of beta-sitosterol, 

campesterol, and stigmasterol 

(§ 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 

(§ 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) 

(§ 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) betasitosterol, 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 cholesterollowering 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 cholesterollowering effects of mixtures of plant 

sterols and plant stanols added to 

conventional foods (Refs. 21, 22, 24, 25, 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
76532 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

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 § 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 

§ 101.83(c)(2)(ii) would specify the 

eligible substance as ‘‘phytosterols.’’ The 

proposal would also add a new 

paragraph (§ 101.83(a)(3)) in the 

background section of amended § 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 (§ 101.83(c)(2)(i)(D)). 

3. Sources of Phytosterols 

Current § 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 

§ 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 

§ 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 woodderived 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 

§ 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 § 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 § 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 § 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 § 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 § 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 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 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 

(§ 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 

§ 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

Method Description Analytes, analytical ranges, 

other features 

Validation data available, 

matrices studied Comments 

1. McNeil—§ 101.83(c)(2)(ii)

(B)(2).

Direct saponification, silyl 

derivatization, GC.

Lipids are saponified at high 

temp with ethanolic KOH. 

The unsaponifiable fraction 

is extracted into hexane. 

Sterols are derivatized to 

trimethylsilyl (TMS) ethers 

and quantified by capillary 

GC with FID 

Analytes: sitosterol, sitostanol, 

campesterol, campestanol.

Ranges: 3–8 g/100 g dressing; 

6–18 g/100 g tub spread; 

2.5–7.5 g/100 g snack bars; 

464–696 mg/softgel capsules 

In-house validation data on linearity, accuracy, precision, 

and reproducibility.

Matrices: dressings, tub 

spreads, snack bars, softgel 

capsules 

Method is applicable to the determination of added 

phytosterols. 

Alkaline saponification 

hydrolyses sterol-ester 

bonds; analytes are 

nonesterified sterols. 

Internal standard: 5bcholestan-3a-ol System suitability standards: cholestanol 

+ stigmastanol.

Column: capillary, 30 m × 0.32 

mm × 0.25 μm film thickness; cross-linked 5% 

phenyl-methyl silicone or 

methyl silicone gum (HP–5).

2A. Unilever—§ 101.83(c)(2)(ii)

(A)(2).

Direct saponification, no 

derivatization, GC.


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
76534 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

TABLE 3—SUMMARY OF KEY FEATURES OF SEVERAL RECENT METHODS USED FOR QUANTITATION OF PHYTOSTEROLS— 

Continued 

Method Description Analytes, analytical ranges, 

other features 

Validation data available, 

matrices studied Comments 

Lipids are saponified at high 

temp with ethanolic KOH..

Unsaponifiable fraction is extracted into heptane. Quantitation by GC with FID 

Internal standard: b-cholestanol (CAS No. 80–97–7) 

Column: capillary, 10 m × 0.32 

mm × 0.12 μm film thickness; CP–Sil-5CB 

Analytes: total 4-desmethyl 

sterols.

Range: 7–60 g/100 g product 

Validation results for recovery, 

and repeatability.

Matrices: margarines, 

dressings, fats, fat blends, 

and phytosterol ester concentrates 

Method has been validated 

through a collaborative 

study; however, this method 

quantifies total 4-desmethyl 

sterol content only and is not 

recommended for identification of unknown sterols. 

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). Method validated only 

for measurement of plant 

sterols in vegetable oil 

blends and plant sterol concentrates. 

2B. Duchateau et al., 2002 

(Ref. 47).

Direct saponification, no 

derivatization, GC. 

Sample is saponified with 

ethanolic KOH at 70° C for 

50 min. Unsaponifiable fraction is extracted into 

heptane. Quantitation by GC 

with FID 

Internal standard: b-cholestanol (5a-cholestane-3b-ol) 

Reference standards: cholesterol, campesterol, stigmasterol, b-sitosterol 

Column: capillary, 10 m × 0.32 

mm × 0.12 μm film thickness; CP–Sil-5CB 

Analytes: cholesterol, 

brassicasterol, campesterol, 

stigmasterol, b-sitosterol, D5- 

avenasterol.

Ranges: 15–20 g/100 g vegetable oils; 8 g/100 g vegetable oil spreads; 60 g/100 g 

phytosterol ester concentrates 

International collaborative 

study performed with 8 samples from 4 different products and batches. Validation 

data for recovery, accuracy, 

and repeatability. Instrument 

details (GC brand, type; columns, injector type, temperature program) for all participants provided.

Method is that of Unilever (2A). 

Phytosterols analyzed as 

nonesterified sterols. 

3. AOAC Official Method 

994.10 ‘‘Cholesterol in 

Foods.’’ Direct saponification-gas chromatographic 

method (Ref. 45).

Direct saponification, silyl 

derivatization, GC.

Lipids are saponified at high 

temperature (not specified) 

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 

Analyte: cholesterol Test sample should contain ≤ 1 g fat 

or ≤ 5 g water. Suggested 

sample weights provided for 

pure oils, salad dressings, 

substances with high moisture content..

LOQ: 1.0 mg/100 g Calibration 

curve 2.5–200 μg/ml 

Collaborative study matrices: 

Butter cookies, vegetable 

bacon baby food, chicken 

vegetable baby food, skinless wieners, NIST egg powder (SRM 1845) commercial 

powdered eggs, Cheese 

Whiz.

The method is applicable to 

the determination of ≥ 1 mg 

cholesterol/100 g of foods, 

food products. 

Collaborative study reference: 

Journal of AOAC International, 78(6):1522–1525, 

1995. (Ref. 48). 

Internal standard: 5a-cholestane.

Column: capillary, 25 m × 0.32 

mm × 0.17 μm film thickness; cross-linked 5% 

phenyl-methyl silicone or 

methyl silicone gum (HP–5, 

Ultra 2 of HP–1).


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 76535 

TABLE 3—SUMMARY OF KEY FEATURES OF SEVERAL RECENT METHODS USED FOR QUANTITATION OF PHYTOSTEROLS— 

Continued 

Method Description Analytes, analytical ranges, 

other features 

Validation data available, 

matrices studied Comments 

4. Sorenson and Sullivan, 

2006 (Ref. 46).

Direct saponification, silyl 

derivatization, GC.

Modification of AOAC Official 

Method 994.10 (see item 3. 

of this table) to include determination of phytosterols 

Lipids are saponified at high 

temperature (not specified) 

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: 5a-cholestane 

Column: capillary, 25 m × 0.32 

mm × 0.17 μm film thickness; cross-linked 5% 

phenyl-methyl silicone or 

methyl silicone gum (HP–5, 

Ultra 2 of HP–1) 

Analytes: campesterol, stigmasterol, b-sitosterol.

LOQ: 1.0 mg/100 g Calibration 

curve: 2.5–200 μg/ml 

Single laboratory validation: 

precision, stability, accuracy, 

and ruggedness.

Matrices: powdered saw palmetto berry, saw palmetto 

dried fruit CO2 extracts, saw 

palmetto 45% powdered extract, dietary supplement 

samples 

Full collaborative study said to 

be in progress. 

5. Quaker Method #210 (Ref. 

49).

Direct extraction, silyl 

derivatization, GC.

Lipids are extracted from homogenized food sample into 

toluene. Sterols are 

derivatized to TMS ethers 

and quantified by capillary 

GC with FID 

Analytes: sitosterol, sitostanol, 

campesterol, campestanol..

Range: 0.7–2.25 g/100 g bars; 

0.13–0.38 g/100 g beverages; 3–9 g/100 g cereals 

In-house validation data for 

specificity, accuracy linearity, 

precision, and stability..

Matrices: food bars, beverages, ready-to-eat cereals 

Intended for use in only relatively low-fat foods enriched 

with nonesterified plant 

sterols/stanols. 

Applicable for determination of 

added nonesterified 

phytosterols. 

Internal standard: 5a-cholestane (CAS No. 481–21–0).

Reference standards: mixture 

of nonesterified sitosterol, 

sitostanol, campesterol, 

campestanol 

Column: capillary, 30 m × 0.25 

mm × 0.25 μm film thickness; (DB–5) 

6. Toivo, J. et al. 2001 (Ref. 

50).

Acid hydrolysis, saponification, 

silyl derivatization, GC.

First step uses HCL hydrolysis 

to liberate glycosylated 

phytosterols bound in food 

matrices. Lipids are extracted into hexane:ether, 

dried and the lipid extract is 

saponified at high temp with 

ethanolic KOH. Unsaponifiable fraction is extracted 

into cyclohexane. Sterols are 

derivatized to TMS ethers 

and quantified by capillary 

GC with FID.

Analytes: cholesterol, sitosterol, sitostanol, 

campersterol, campestanol, 

stigmasterol, D5-avenasterol.

Range: 0.5–800 mg/100 g for 

individual phytosterols.

Single laboratory validation includes method optimization, 

accuracy, and repeatability..

Matrices: flour, canola oil, corn 

meal, dried onion, sunflower 

seed, diet composite.

Intended for use in determining 

levels of endogenous 

phytosterols in foods. 

Acid hydrolysis step included 

to release conjugated forms 

of phytosterols. Important for 

grains, flours; not so for oils. 

Use of acid hydrolysis prior 

to or following lipid extraction 

discussed. 

Method has been used for 

analysis of hundreds of 

foods to create database of 

phytosterol in foods. 

Internal standard: 

dihydrocholesterol (cholestanol).

Reference standard: 

dihydrocholesterol (cholestanol), cholesterol, 

cholesteryl palmitate, and 

mixture of soybean steryl 

glucosides containing sitosterol, campesterol, and stigmasterol as their glucosides.

Column: capillary, 60 m × 0.25 

mm × 0.1 μm film thickness; 

cross-linked 5% diphenyl95% dimethyl polysiloxane.

ABREVIATIONS: GC—gas chromatography; TMS—trimethylsilyl; FID—flame ionization detector; KOH—potassium hydroxide; CAS—Chemical Abstract Service; 

LOQ—limit of quantitation. 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
76536 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

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., b-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 betasitosterol 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 § 101.83 (Unilever’s method in 

§ 101.83(c)(2)(ii)(A)(2) and McNeil’s 

methods in § 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 § 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 § 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 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 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 § 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 * * *’’ (§ 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 § 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 § 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 phytosterolenriched 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 § 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 § 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 phytosterolenriched 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, 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
76538 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

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 ‘‘onceper-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 § 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 § 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 § 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 phytosterolenriched 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 cholesterollowering 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 § 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 § 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 fatfree 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 

§ 101.83(c)(2)(i)(H) to require that the 

health claim specify that phytosterolenriched 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 § 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 § 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 

§ 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 § 101.83 would result in a 

greater variety of phytosterol-enriched 

foods eligible for the claim than now 

included in current § 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 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 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 § 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 § 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 § 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 § 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 (§ 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 (§ 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 

§ 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 cholesterollowering 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 § 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 longterm 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 estercontaining 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 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
76540 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

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 cholesterollowering 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 § 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 phytosterolester 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 estercontaining 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 estercontaining 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 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 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 § 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 § 101.83 and the general health claim 

requirements of § 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 cholesterollowering 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 

(§ 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 (§ 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 § 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 § 101.13(h) 

(i.e., ‘‘See nutrition information for fat 

content’’) (65 FR 54686 at 54706). 

Current § 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 § 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 

§ 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 fatdisqualifying 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 § 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 

§ 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 (§ 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 buttertype 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 

§ 101.83(c)(2)(iii)(D) that the spreads 

that are exempt from § 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, 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
76542 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

12Hydrogenation is the addition of a carboncarbon 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 byproduct of hydrogenation of vegetable oils (Ref. 75). 

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 

§ 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 

§ 101.83(c)(2)(iii)(B) requires foods that 

bear the health claim to meet the 

nutrient content requirements in 

§ 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 § 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). 

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 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 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 

§ 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 § 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 § 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 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
76544 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

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 hearthealthy 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 § 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 

§ 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 (§§ 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 § 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 § 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 § 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 

§ 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 

§ 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 

§ 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 § 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 § 101.83(c)(2)(i) prescribes 

specific requirements for health claims 

that link plant sterol/stanol esters to 

reduced risk of CHD. Current § 101.83(e) 

provides examples of model health 

claims that may be used to comply with 

the requirements in § 101.83(c)(2)(i). As 

discussed in previous sections of this 

document, we are proposing 

modifications to § 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 

§ 101.83(c)(2)(i) and (e) accordingly. 

E. Cautionary Statements 

Current § 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 [§ 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 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 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 hypersensitive 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 § 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 cholesterollowering 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 betacarotene lowering effect of phytosterolenriched 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) Phytosterolenriched 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 provitamin 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 § 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 § 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 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
76546 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

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-bycase 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 

§ 101.83, the agency believes that its 

exercise of enforcement with respect to 

claims that do not comply with current 

§ 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-todate 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 

§ 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 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 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 esterenriched 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 relabel 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 esterenriched 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 

× 33 percent × 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 × 3.3 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
76548 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

percent that make a claim that addresses 

CHD × 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 × 41.7 percent × 

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 noninstitutionalized adults diagnosed with 

CHD, resulting in approximately 

700,000 deaths. According to the same 

source, CHD patients made 

approximately 20.8 million office-based 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 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 selfdetermined 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 sterolenriched 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 × 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 relabel their products to either make no 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
76550 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

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 phytosterolsCHD 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 relabeled, 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 relabeling 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 relabeling 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 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 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.) 

1. Center for Food Safety and Applied 

Nutrition, Food and Drug Administration. 

Letter of Enforcement Discretion from FDA to 

Cargill Health & Food Technologies. Docket 

No. FDA–2000–P–0102, document ID 

DRAFT–0059 (formerly 2000P–1275/LET3) 

and Docket No. FDA–2000–P–0133, 

document ID DRAFT–0127 (formerly 2000P– 

1276/LET4). February 14, 2003. 

2. Center for Food Safety and Applied 

Nutrition, Food and Drug Administration. 

‘‘Guidance for Industry: Evidence-Based 

Review System for the Scientific Evaluation 

of Health Claims.’’ January 2009. Available at: 

http://www.fda.gov/Food/ 

GuidanceComplianceRegulatoryInformation/ 

GuidanceDocuments/FoodLabelingNutrition/ 

ucm073332.htm. 

3. National Heart, Lung, and Blood 

Institute, National Institutes of Health. Third 

Report of the National Cholesterol Education 

Program (NCEP) Expert Panel on Detection, 

Evaluation, and Treatment of High Blood 

Pressure in Adults (Adult Treatment Panel 

III) Executive Summary. National Institutes 

of Health, Bethesda, MD, 2001. Available at 

http://www.nhlbi.nih.gov/guidelines/ 

cholesterol/atp3xsum.pdf. 

4. Hallikainen, M., E. Sarkkinen, I. Wester, 

and M. Uusitupa. ‘‘Short-Term LDL 

Cholesterol-Lowering Efficacy on Plants 

Sterol Esters.’’ BioMed Central 

Cardiovascular Disorders, 2:14, 2002. 

5. Kozlowska-Wojciechowska, M., M. 

Jastrzebska, M. Naruszewicz, and A. 

Foltynska. Impact of Margarine Enriched 

With Plant Sterols on Blood Lipids, Platelet 

Function, and Fibrinogen Level in Young 

Men. Metabolism, 52:1373–1378, 2003. 

6. Vuorio, A.F., H. Gylling, K. Kantula, P. 

Ketonent, and T.A. Miettinen. ‘‘Stanol Ester 

Margarine Alone and With Simivastatin 

Lowers Serum Cholesterol in Families With 

Familial Hypercholesterolemia Caused by the 

FH–North Karelia Mutation.’’ 

Arteriosclerosis, Thrombosis, and Vascular 

Biology, 20:500–506, 2000. 

7. Miettinen, T.A., M. Vuoristo, M. 

Nissinen, H.J. Jarvinen, and H. Gylling. 

‘‘Serum, Bliliary, and Fecal Cholesterol and 

Plant Sterols in Cholectomized Patients 

Before and During Consumption of Stanol 

Ester Margarine.’’ American Journal of 

Clinical Nutrition, 71:1095–1102, 2000. 

8. Clifton, P.M., M. Noakes, D. Sullivan, N. 

Erichsen, D. Ross, G. Annison, C.M. 

Fassoulakis, and P. Nestel. ‘‘CholesterolLowering Effects of Plant Sterol Esters Differ 

in Milk, Yoghurt, Bread, and Cereal.’’ 

European Journal of Clinical Nutrition, 

58(3):503–509, 2004. 

9. Volpe, R., L. Niittynen, R. Korpela, C. 

Sirtori, A. Bucci, N. Fraone, and R. 

Pazzucconi. ‘‘Effects of Yoghurt Enriched 

With Plant Sterols on Serum Lipids in 

Patients With Moderate 

Hypercholesterolaemia.’’ British Journal of 

Nutrition, 86(2):233–239, 2001. 

10. Lau, V.W.Y., M. Journoud, and P.J.H 

Jones. ‘‘Plant Sterols are Effacious in 

Lowering Plasma LDL and Non-HDL 

Cholesterol in Hypercholesterolemic Type 2 

Diabetic and Nondiabetic Persons.’’ American 

Journal of Clinical Nutrition, 81:1351–1358, 

2005. 

11. Sudhop, T., D. Lutjohann, M. Agna, C. 

von Ameln, W. Prange, and K. von 

Bergmann. ‘‘Comparison of the Effects of 

Sitostanol, Sitostanol Acetate, and Sitostanol 

Oleate on the Inhibition of Cholesterol 

Absorption in Normolipmeic Healthy Male 

Volunteers. A Placebo Controlled 

Randomized Cross-Over Study.’’ 

Arzneimittel-Forschung, 53:708–713, 2003. 

12. O’Neill, F.H., A. Byrnes, R. Mandeno, 

N. Rendell, G. Taylor, M. Seed, and G.R. 

Thompson. ‘‘Comparison of the Effects of 

Dietary Plant Sterol and Stanol Esters on 

Lipid Metabolism.’’ Nutrition Metabolism 

and Cardiovascular Diseases, 14:133–142, 

2004. 

13. Cicero, A.F.G., A. Fiorito, M.P. 

Panourgia, Z. Sangiorgi, and A. Gaddi. 

‘‘Effects of a New Soy/Beta-Sitosterol 

Supplement on Plasma Lipids in Moderately 

Hypercholesterolemic Subjects.’’ Journal of 

the American Dietetic Association, 

102(12):1807–1811, 2002. 

14. St-Onge, M.P., B. Lamarche, J.F. 

Mauger, and P.J.H. Jones. ‘‘Consumption of a 

Functional Oil Rich in Phytosterols and 

Medium-Chain Triglyceride Oil Improves 

Plasma Lipid Profiles in Men.’’ Journal of 

Nutrition, 133:1815–1820, 2003. 

15. Maki, K.C., F. Shinnick, M.A. Seely, 

P.E. Veith, L.C. Quinn, P.J. Hallissey, A. 

Temer, and M.H. Davison. ‘‘Food Products 

Containing Free Tall Oil-Based Phytosterols 

and Oat Beta-Glucan Lower Serum Total and 

LDL Cholesterol in Hypercholesterolemic 

Adults.’’ Journal of Nutrition, 133:808–813, 

2003. 

16. Jenkins, D.J., C.W. Kendall, A. Marchie, 

D.A. Faulkner, G.M. Wong, R. de Souza, et 

al. ‘‘Effects of a Dietary Portfolio of 

Cholesterol-Lowering Foods vs Lovastatin on 

Serum Lipids and C-Reactive Protein.’’ 

Journal of the American Medical Association, 

260:502–510, 2003. 

17. Bourque, C., M.P. St-Onge, A.A. 

Papamandjaris, J.S. Cohn, and P.J.H. Jones. 

‘‘Consumption of an Oil Composed of 

Medium Chain Triacylglycerols, 

Phytosterols, and n-3 Fatty Acids Improves 

Cardiovascular Risk Profile in Overweight 

Women.’’ Metabolism, 52:771–777, 2003. 

18. Salo, P. and I. Wester. ‘‘Low-Fat 

Formulations of Plant Stanols and Sterols.’’ 

American Journal of Cardiology, 

96(suppl):51D–54D, 2005. 

19. Center for Food Safety and Applied 

Nutrition, Food and Drug Administration. 

‘‘New Dietary Ingredient Report 54. Plant 

Stanol Fatty Acid Esters.’’ Available at http:// 

www.fda.gov/ohrms/dockets/dockets/ 

95s0316/rpt0054_01.pdf. 

20. Center for Food Safety and Applied 

Nutrition, Food and Drug Administration. 

‘‘New Dietary Ingredient Report 77. Tall Oil 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
76552 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

Phytosterols (Ingredient of ReducolTM).’’ 

Available at http://www.fda.gov/ohrms/ 

dockets/dockets/95s0316/rpt0077.pdf. 

21. Jones, P.J., F.Y. Ntanios, M. RaeiniSarjaz, and C.A. Vanstone. ‘‘CholesterolLowering Efficacy of a Sitostanol-Containing 

Phytosterol Mixture With a Prudent Diet in 

Hyperlipidemic Men.’’ American Journal of 

Clinical Nutrition, 69(6):1144–1150, 1999. 

22. Vanstone, C.A., M. Raeini-Sarjaz, W.E. 

Parsons, and P.J.H. Jones. ‘‘Unesterified Plant 

Sterols and Stanols Lower LDL–Cholesterol 

Concentrations Equivalently in 

Hypercholesterolemic Persons.’’ American 

Journal of Clinical Nutrition, 76:1272–1278, 

2002. 

23. Hayes, K.C., A. Pronczuk, and D. 

Perlman. ‘‘Nonesterified Phytosterols 

Dissolved and Recrystallized in Oil Reduce 

Plasma Cholesterol in Gerbils and Humans.’’ 

Journal of Nutrition, 134:1395–1399, 2004. 

24. Christiansen, L.I., P.L. La ̈hteenma ̈ki, 

M.R. Mannelin, T.E. Seppa ̈nen-Laakso, 

R.V.K. Hiltunen, and J.K. Yliruusi. 

‘‘Cholesterol-Lowering Effect of Spreads 

Enriched With Microcrystalline Plant Sterols 

in Hypercholesterolemic Subjects.’’ European 

Journal of Nutrition, 40(2):66–73, 2001. 

25. Tikkanen, M.J., P. Ho ̈gstro ̈m, J. 

Tuomilehto, S. Keina ̈nen-Kiukaanniemi, J. 

Sundvall, and H. Karppanen. ‘‘Effect of a Diet 

Based on Low-Fat Foods Enriched With 

Nonesterified Plant Sterols and Mineral 

Nutrients on Serum Cholesterol.’’ American 

Journal of Cardiology, 88(10):1157–1162, 

2001. 

26. Thomsen, A.B., H.B. Hansen, C. 

Christiansen, H. Green, and A. Berger. ‘‘Effect 

of Free Plant Sterols in Low-Fat Milk on 

Serum Lipid Profile in Hypercholesterolemic 

Subjects.’’ European Journal of Clinical 

Nutrition, 58(6):860–870, 2004. 

27. Spilburg, C.A., A.C. Goldberg, J.B. 

McGill, W.F. Stenson, S.B. Racette, J. 

Bateman, T.B. McPherson, and R.E. Ostlund. 

‘‘Fat-Free Foods Supplemented With Soy 

Stanol-Lecithin Powder Reduce Cholesterol 

Absorption and LDL Cholesterol.’’ Journal of 

the American Dietetic Association, 

103(5):577–581, 2003. 

28. Miettinen, T.A. and H.T. Vanhanen. 

‘‘Dietary Sitostanol Related Absorption, 

Synthesis and Serum Level of Cholesterol in 

Different Apolipoprotein E Phenotypes.’’ 

Atheroscelrosis, 105:217–226, 1994. 

29. Sierksma, A., J.A. Weststrate, and G.W. 

Meijer. ‘‘Spreads Enriched With Plant Sterols, 

Either Esterified 4,4–Dimethylsterols or Free 

4–Desmethylsterols, and Plasma Total- and 

LDL–Cholesterol Concentrations.’’ British 

Journal of Nutrition, 82(4):273–282, 1999. 

30. Pelletier, X., S. Belbraouet, D. Mirabel, 

F. Mordet, J.L. Perrin, X. Pages, and G. Derby. 

‘‘A Diet Moderately Enriched in Phytosterols 

Lowers Plasma Cholesterol Concentrations in 

Normocholesterolemic Humans. Annals of 

Nutrition and Metabolism, 39:291–295, 1995. 

31. Weststrate, J.A. and G.W. Meijer. ‘‘Plant 

Sterol-Enriched Margarines and Reduction of 

Plasma Total- and LDL–Cholesterol 

Concentrations in Normocholesterolemic and 

Mildly Hypercholesterolemic Subjects.’’ 

European Journal of Clinical Nutrition, 

52:334–343, 1998. 

32. deGraaf, J., P.R.W. deSauvage Nolting, 

M. vanDam, E.M. Belsey, J.J.P. Kastelein, P.H. 

Pritchard, and A.T.H. Stalenhoef. 

‘‘Consumption of Tall Oil-Derived 

Phytosterols in a Chocolate Matrix 

Significantly Decreases Plasma Total and 

Low-Density Lipoprotein-Cholesterol 

Levels.’’ British Journal of Nutrition, 

88(5):479–488, 2002. 

33. Devaraj, S., I. Jialal, and S. Vega. ‘‘Plant 

Sterol-fortified Orange Juice Effectively 

Lowers Cholesterol Levels in Mildly 

Hypercholesterolemic Healthy Individuals.’’ 

Arteriosclerosis, Thrombosis, and Vascular 

Biology, 24:1–5, 2004. 

34. Jones, P.J.H., C.A. Vanstone, M. RaeiniSarjaz, and M.P. St-Onge. ‘‘Phytosterols in 

Low- and Nonfat Beverages as Part of a 

Controlled Diet Fail to Lower Plasma Lipid 

Levels.’’ Journal of Lipid Research, 44:1713– 

1719, 2003. 

35. Nestel, P., M. Cehun, S. Pomeroy, M. 

Abby, G. Weldon. ‘‘Cholesterol-Lowering 

Effects of Plant Sterol Esters and NonEsterified Stanols in Margarine, Butter and 

Low-Fat Foods.’’ European Journal of Clinical 

Nutrition, 55(12):1084–1090, 2001. 

36. Vissers, M.N., P.L. Zock, G.W. Meijer, 

and M.B. Katan. ‘‘Effect of Plant Sterols From 

Rice Bran Oil and Triterpene Alcohols From 

Sheanut Oil on Serum Lipoprotein 

Concentrations in Humans.’’ American 

Journal of Clinical Nutrition, 72(6):1510– 

1515, 2000. 

37. Korpela, R., J. Tuomilehto, P. 

Ho ̈gstro ̈m, L. Seppo, V. Piironen, P. SaloVa ̈a ̈na ̈nen, J. Toivo, et al. ‘‘Safety Aspects and 

Cholesterol-lowering Efficacy of Low Fat 

Dairy Products Containing Plant Sterols.’’ 

European Journal of Clinical Nutrition, 

60:633–642, 2006. 

38. AbuMweis, S.S., C.A. Vanstone, N. 

Ebine, A. Kassis, L.M. Ausman, P.J.H. Jones, 

and A.H. Lichtenstein. ‘‘Intake of a Single 

Morning Dose of Standard and Novel Plant 

Sterol Preparations for 4 Weeks Does Not 

Dramatically Affect Plasma Lipid 

Concentrations in Humans.’’ Journal of 

Nutrition, 136:1012–1016, 2006. 

39. Hallikainen, M.A., E.S. Sarkkinen, H. 

Gylling, A.T. Erkkila, and M.I.J. Uusitupa. 

‘‘Comparison of the Effects of Plant Sterol 

Ester and Plant Stanol Ester-Enriched 

Margarines in Lowering Serum Cholesterol 

Concentrations in Hypercholesterolaemic 

Subjects on a Low-Fat Diet.’’ European 

Journal of Clinical Nutrition, 54:715–725, 

2000. 

40. Jones, P.J., M. Raeini-Sarjaz, F.Y. 

Ntanios, C.A. Vanstone, J.Y. Feng, and W.E. 

Parsons. ‘‘Modulation of Plasma Lipid Levels 

and Cholesterol Kinetics by Phytosterol 

Versus Phytostanol Esters.’’ Journal of Lipid 

Research, 41:697–705, 2000. 

41. Noakes, M., P. Clifton, F. Ntanios, W. 

Shrapnel, I. Record, and J. McInerney. ‘‘An 

Increase in Dietary Carotenoids When 

Consuming Plant Sterols or Stanols is 

Effective in Maintaining Plasma Carotenoid 

Concentrations.’’ American Journal of 

Clinical Nutrition, 75(1):79–86, 2002. 

42. Naumann, E., J. Plat, and R.P. Mensink. 

‘‘Changes in Serum Concentrations of 

Noncholesterol Sterols and Lipoproteins in 

Healthy Subjects Do Not Depend on the Ratio 

of Plant Sterols to Stanols in the Diet.’’ 

Journal of Nutrition, 133(9):2741–2747, 2003. 

43. Doornbos, A.M.E., E.M. Meynen, 

G.S.M.J.E. Duchateau, H.C.M. van der Knaap, 

and E.A Trautwein. ‘‘Intake Occasion Affects 

the Serum Cholesterol Lowering of a Plant 

Sterol-Enriched Single-Dose Yoghurt Drink 

in Mildly Hypercholesterolaemic Subjects.’’ 

European Journal of Clinical Nutrition, 

60:325–333, 2006. 

44. Merck & Co, Inc. ‘‘Tall Oil; Monograph 

9130.’’ The Merck Index, An Encyclopedia of 

Chemicals, Drugs, and Biologicals, 13th 

Edition, Whitehouse Station, NJ, 2001. 

45. AOAC International. AOAC Official 

Method 994.10, ‘‘Cholesterol in Foods, Direct 

Saponification—Gas Chromatographic 

Method.’’ Official Methods of Analysis of 

AOAC International, 16th Edition, 

Gaithersburg, MD, 2000. 

46. Sorenson, W.R. and D. Sullivan. 

‘‘Determination of Campesterol, Stigmasterol 

and Beta-Sitosterol in Saw Palmetto Raw 

Materials and Dietary Supplements by Gas 

Chromatography: Single-Laboratory 

Validation.’’ Journal of the AOAC 

International, 89:22–34, 2006. 

47. Duchateau, G.S.M.J.E., C.G. BauerPlank, A.J. Louter, M. van der Ham, J.A. 

Boerma, J.J.M. van Rooijen, et al. ‘‘Fast and 

Accurate Method for Total 4–Desmethyl 

Sterol(s) Content in Spreads, Fat-Blends, and 

Raw Materials.’’ Journal of the American Oil 

Chemists Society, 79:273–278, 2002. 

48. Naeemi, E.D., N. Ahmad, T.K alSharrah, and M. Behbahani. ‘‘Rapid and 

Simple Method for Determination of 

Cholesterol in Processed Food.’’ Journal of 

AOAC International, 78(6):1522–1525, 

November and December 1995. 

49. Novartis Consumer Health and Altus 

Food Company. ‘‘Determination of Sterols 

and Stanols in Food Products, Method 

Validation Report, Quaker Oats Standard 

Validation Method 210, January 18, 2001.’’ 

Comment Submitted to Docket Nos. FDA– 

2000–P–0102 and FDA–2000–P–0133 

(formerly 2000P–1275 and 2000P–1276), 

February 13, 2001. 

50. Toivo, J., K. Phillips, A.M. Lampi, and 

V. Piironen. ‘‘Determination of Sterols in 

Foods: Recovery of Free, Esterified, and 

Glycosidic Sterols.’’ Journal of Food 

Composition and Analysis, 14:631–643, 

2001. 

51. Hendriks, H.F.J., J.A. Weststrate, T. van 

Vliet, and G.W. Meijer. ‘‘Spreads Enriched 

With Three Different Levels of Vegetable Oil 

Sterols and the Degree of Cholesterol 

Lowering in Normocholesterolaemic and 

Mildly Hypercholesterolaemic Subjects.’’ 

European Journal of Clinical Nutrition, 

53:319–327, 1999. 

52. Vanhanen, H.T. and T.A. Miettinen. 

‘‘Effects of Unsaturated and Saturated Dietary 

Plant Sterols on Their Serum Contents.’’ 

Clinica Chimica Acta; International Journal 

of Clinical Chemistry, 205:97–107, 1992. 

53. Hallikainen, M.A., E.S. Sarkkinen, and 

M.I.J. Uusitupa. ‘‘Plant Stanol Esters Affect 

Serum Cholesterol Concentrations of 

Hypercholesterolemic Men and Women in a 

Dose-Dependent Manner.’’ The Journal of 

Nutrition, 130:767–776, 2000a. 

54. Seki, S., I. Hidaka, K. Kojima, H. 

Yoshino, T. Aoyama, M. Okazaki, and K. 

Kondo. ‘‘Effects of Phytosterol Ester-Enriched 

Vegetable Oil on Plasma Lipoproteins in 

Healthy Men.’’ Asia Pacific Journal of 

Clinical Nutrition, 12(3):282–291, 2003. 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 76553 

55. Davidson, M.H., K. Maki, D.M. 

Umporowicz, K.A. Ingram, M.R. Dicklin, E.J. 

Schaefer, et al. ‘‘Safety and Tolerability of 

Esterified Phytosterols Administered in 

Reduced-Fat Spread and Salad Dressing to 

Healthy Adult Men and Women.’’ Journal of 

the American College of Nutrition, 20(4):307– 

319, 2001. 

56. Law, M. ‘‘Plant Sterol and Stanol 

Margarines and Health.’’ British Medical 

Journal, 25;320:861–864, 2000. 

57. Ostlund, R.E. ‘‘Phytosterols in Human 

Nutrition.’’ Annual Review of Nutrition, 

22:533–549, 2002. 

58. Katan, M.B., S.M. Grundy, P. Jones, M. 

Law, T. Miettinen, and R. Paoletti. ‘‘Efficacy 

and Safety of Plant Stanols and Sterols in the 

Management of Blood Cholesterol Levels.’’ 

Mayo Clinic Proceedings, 78:965–978, 2003. 

59. Plat, J., E.N.M. van Onselen, M.M.A. 

van Heugten, and R.P. Mensink. ‘‘Effects on 

Serum Lipids, Lipoproteins and Fat Soluble 

Antioxidant Concentrations of Consumption 

Frequency of Margarines and Shortenings 

Enriched With Plant Stanol Esters.’’ European 

Journal of Clinical Nutrition, 54(9):671–677, 

2000. 

60. Matvienko, O.A., D.S. Lewis, M. 

Swanson, B. Arndt, D.L. Rainwater, J. 

Stewart, et al. ‘‘A Single Daily Dose of 

Soybean Phytosterols in Ground Beef 

Decreases Serum Total Cholesterol and LDL 

Cholesterol in Young, Mildly 

Hypercholesterolemic Men.’’ American 

Journal of Clinical Nutrition, 76(1):57–64, 

2002. 

61. Rader, D. and T.T. Nguyen. ‘‘A PlaceboControlled Trial Evaluating the Efficacy and 

Safety of a Softgel Containing Plant Stanol 

Ester to Help Reduce Total and LDLCholesterol.’’ McNeil Consumer Healthcare 

Clinical Study Report—Protocol 99–080, 

Unpublished, December 14, 2000. 

62. Acuff, R.V., D.J. Cai, Z.P. Dong, and D. 

Bell. ‘‘The Lipid Lowering Effect of Plant 

Sterol Ester Capsules in 

Hypercholesterolemic Subjects.’’ Lipids in 

Health and Disease, 6:11, 2007. 

63. Earnest, C.P., C.R. Mikus, I. Lemieux, 

B.J. Arsenault, and T.S. Church. 

‘‘Examination of Encapsulated Phytosterol 

Ester Supplementation on Lipid Indices 

Associated With Cardiovascular Disease.’’ 

Nutrition, 23(9):625–633, 2007. 

64. Woodgate, D., C.H. Vhan, and J.A. 

Conquer. ‘‘Cholesterol-Lowering Ability of a 

Phytostanol Softgel Supplement in Adults 

with Mild to Moderate Hypercholesterolemia.’’ Lipids, 41:127–132, 2006. 

65. Denke, M.A. ‘‘Lack of Efficacy of LowDose Sitostanol Therapy as an Adjunct to a 

Cholesterol-Lowering Diet in Men With 

Moderate Hypercholesterolemia.’’ American 

Journal of Clinical Nutrition, 61(2):392–396, 

1995. 

66. McPherson, T.B., R.E. Ostlund, A.C. 

Goldberg, J.H. Bateman, L. Schimmoeller, 

and C.A. Spilburg. ‘‘Phytosterol Tablets 

Reduce Human LDL-Cholesterol.’’ Journal of 

Pharmacy and Pharmacology, 57:889–896, 

2005. 

67. Goldberg, A.C., R.E. Ostlund, J.H. 

Batemean, L. Schimmoeller, T.B. McPherson, 

and C.A. Spilburg. ‘‘Effect of Plant Stanol 

Tablets on Low-Density Lipoprotein 

Cholesterol Lowering in Patients on Statin 

Drugs.’’ American Journal of Cardiology, 

97:376–379, 2006. 

68. Pollak, O.J. ‘‘Reduction of Blood 

Cholesterol in Man.’’ Circulation, 7:702–706, 

1953. 

69. U.S. Department of Health and Human 

Services and U.S. Department of Agriculture. 

‘‘Dietary Guidelines for Americans, 2005.’’ 

6th Edition, Washington, DC: U.S. 

Government Printing Office, January 2005. 

70. Food and Drug Administration. 

‘‘Consumer Health Information for Better 

Nutrition Initiative, Task Force Final Report.’’ 

July 10, 2003. Available at http://

www.fda.gov/Food/LabelingNutrition/Label

Claims/QualifiedHealthClaims/Qualified

HealthClaimsPetitions/ucm096010.htm. 

71. Center for Food Safety and Applied 

Nutrition, Food and Drug Administration. 

‘‘Qualified Health Claim Letter of 

Enforcement Discretion Regarding Olive Oil 

From FDA to the North American Olive Oil 

Association.’’ Docket No. FDA–2003–Q–0080 

(formerly 2003Q–0559) November 1, 2004. 

Available at http://www.fda.gov/Food/

LabelingNutrition/LabelClaims/Qualified

HealthClaims/ucm072963.htm. 

72. Center for Food Safety and Applied 

Nutrition, Food and Drug Administration. 

‘‘Qualified Health Claim Letter of 

Enforcement Discretion Regarding Canola Oil 

From FDA to Johnson Nutrition Solutions 

LLC.’’ Docket No. FDA–2006–Q–0161 

(formerly 2006Q–0091) October 6, 2006. 

Available at http://www.fda.gov/Food/

LabelingNutrition/LabelClaims/Qualified

HealthClaims/ucm072958.htm. 

73. Center for Food Safety and Applied 

Nutrition, Food and Drug Administration. 

‘‘Qualified Health Claim Letter of 

Enforcement Discretion Regarding Corn Oil 

From FDA to the Wood-Burditt Group LLC.’’ 

Docket No. FDA–2006–P–0002 (formerly 

2006P–0243). Available at http://

www.fda.gov/Food/LabelingNutrition/Label

Claims/QualifiedHealthClaims/

ucm072956.htm. 

74. IOM (Institute of Medicine). 2005. Final 

Report, Dietary Reference Intakes for Energy, 

Carbohydrate, Fiber, Fat, Fatty Acids, 

Cholesterol, Protein, and Amino Acids. 

Washington, DC: The National Academies 

Press, 422–541. 

75. Wardlaw G.M. and Hampl J.S. 2007. 

Perspectives in Nutrition, Seventh Edition. 

New York, NY: McGraw-Hill, G–9. 

76. European Commission, Scientific 

Committee on Food. ‘‘Opinion of the 

Scientific Committee on Food on 

Applications for Approval of a Variety of 

Plant Sterol-Enriched Foods,’’ expressed on 5 

March 2003. Available at http://ec.europa.eu/ 

food/fs/sc/scf/out174_en.pdf. 

77. European Commission, Scientific 

Committee on Food. ‘‘Opinion of the 

Scientific Committee on Food on a Request 

for the Safety Assessment of the Use of 

Phytosterol Esters in Yellow Fat Spreads.’’ 

Available at http://ec.europa.eu/food/fs/sc/

scf/out56_en.pdf. 

78. European Commission Regulation (EC) 

No. 608/2004 of 31 March 2004 Concerning 

the Labeling of Foods and Food Ingredients 

with Added Phytosterols, Phytosterol Esters, 

Phytostanols and/or Phytostanol Esters. 

Available at http://eur-lex.europa.eu/

LexUriServ/LexUriServ.do?uri=CELEX:

32004R0608:EN:HTML. 

79. European Commission. 2000/500/EC: 

Commission Decision of 24 July 2000 on 

Authorising the Placing on the Market of 

‘‘Yellow Fat Spreads With Added Phytosterol 

Esters’’ as a Novel Food or Novel Food 

Ingredient Under Regulation (EC) No. 258/97 

of the European Parliament and of the 

Council. Available at http://eur-lex.

europa.eu/LexUriServ/LexUriServ.do?uri=

CELEX:32000D0500:EN:HTML. 

80. Food Standards Australia New Zealand 

(FSANZ). Australia New Zealand Food 

Standards Code, Chapter 1 General Food 

Standards, Part 1.5 Foods Requiring PreMarket Clearance, Standard 1.5.1 Novel 

Foods. Available at http://

www.foodstandards.gov.au/_srcfiles/

Standard_1_5_1_Novel_Foods_v115.pdf. 

81. Saito, S., K. Tomonobu, N. Kudo, D. 

Shiiba, T. Hase, and I. Tokimistu. ‘‘Serum 

Retinol, Alpha-Tocopherol, and BetaCarotene Levels Are Not Altered by Excess 

Ingestion of Diacylglycerol-Containing Plant 

Sterol Esters.’’ Annals of Nutrition and 

Metabolism, 50:372–379, 2006. 

82. Hendriks, H.F.J., E.J. Brink, G.W. 

Meijer, H.M.G. Princen, and F.Y. Ntanios. 

‘‘Safety of Long-Term Consumption of Plant 

Sterol Esters-Enriched Spread.’’ European 

Journal of Clinical Nutrition, 57:681–692, 

2003. 

83. Raeini-Sarjaz, M., F.Y. Ntanios, C.A. 

Vanstone, and P.J.H. Jones. ‘‘No Changes in 

Serum Fat-Soluble Vitamin and Carotenoid 

Concentrations With the Intake of Plant 

Sterol/Stanol Esters in the Context of a 

Controlled Diet.’’ Metabolism, 51:652–656, 

2002. 

84. Homma, Y., I. Ikeda, T. Ishikawa, M. 

Tateno, M. Sugano, and H. Nakamura. 

‘‘Decrease in Plasma Low-Density 

Lipoprotein Cholesterol, Apolipoprotein B, 

Cholesteryl Ester Transfer Protein, and 

Oxidized Low-Density Lipoprotein by Plant 

Stanol Ester-Containing Spread: A 

Randomized, Placebo-Controlled Trial.’’ 

Nutrition, 19(4):369–374, 2003. 

85. Hallikainen, M.A., E.S. Sarkkinen, and 

M.I. Uusitupa. ‘‘Effects of a Low-Fat Stanol 

Ester Enriched Margarines on Concentrations 

of Serum Carotenoids in Subjects With 

Elevated Serum Cholesterol Concentrations.’’ 

European Journal of Clinical Nutrition, 

53:966–999, 1999. 

86. Richelle, M., M. Enslen, C. Hagar, M. 

Groux, I. Tavazzi, J.P. Goden, et al. ‘‘Both 

Free and Esterified Plants Sterols Reduce 

Cholesterol Absorption and the 

Bioavailability of Beta-Carotene and AlphaTocopherol in Normochoelsterolemic Men.’’ 

American Journal of Clinical Nutrition, 

80:171–177, 2004. 

87. Gylling, H., P. Puska, E. Vartiainen, and 

T.A. Miettinen. ‘‘Retinol, Vitamin D, 

Carotenes and Alpha-Tocopherol in Serum of 

a Moderately Hypercholesterolemic 

Population Consuming Sitostanol Ester 

Margarine.’’ Atherosclerosis, 145:279–285, 

1999. 

88. Mensink, R.P., S. Ebbing, M. Lindhout, 

J. Plat, and M.M.A. van Heugten. ‘‘Effects of 

Plant Stanol Esters Supplied in Low-Fat 

Yoghurt on Serum Lipids and Lipoproteins, 

Non-Cholesterol Sterols and Fat Soluble 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
76554 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

Antioxidant Concentrations.’’ 

Atherosclerosis, 160(1):205–213, 2002. 

89. Plat, J. and R.P. Mensink. ‘‘Effects of 

Diets Enriched With Two Different Plant 

Stanol Ester Mixtures on Plasma Ubiquinol10 and Fat-Soluble Antioxidant Vitamins.’’ 

Metabolism, 50:520–529, 2001. 

90. Clifton, P.M., M. Noakes, D. Ross, A. 

Fassoulakis, M. Cehum, and P. Nestel. ‘‘High 

Dietary Intake of Phytosterol Esters Decreases 

Carotenoids and Increases Plasma Plant 

Sterol Levels With No Additional Cholesterol 

Lowering.’’ Journal of Lipid Research, 

45:1493–1499, 2004. 

91. Jauhianen, T., P. Salo, L. Niittynen, T. 

Poussa, and R. Korpela. ‘‘Effects of Low-Fat 

Hard Cheese Enriched With Plant Stanol 

Esters on Serum Lipids and Apolipoprotein 

B in Mildly Hypercholesterolaemic Subjects.’’ 

European Journal of Clinical Nutrition, 

60:1253–1257, 2006. 

92. Jakulj, L., M.D. Trip, T. Sudhop, K. von 

Bergmann, J.J.P. Kastelein, and M.N. Vissers. 

‘‘Inhibition of Cholesterol Absorption by the 

Combination of Dietary Plant Sterols and 

Ezetimibe: Effects on Plasma Lipid Levels.’’ 

Journal of Lipid Research, 46:2692–2698, 

2005. 

93. Cleghorn, C.L., C.M. Skeaff, J. Mann, 

and A. Chisholm. ‘‘Plant Sterol-Enriched 

Spread Enhances the Cholesterol-Lowering 

Potential of a Fat-Reduced Diet.’’ European 

Journal of Clinical Nutrition, 57(1):170–176, 

2003. 

94. Ishiwata, K., Y. Homma, T. Ishikawa, 

H. Nakamura, and S. Handa. ‘‘Influence of 

Apolipoprotein E Phenotype on Metabolism 

of Lipids and Apolipoproteins After Plant 

Stanol Ester Ingestion in Japanese Subjects.’’ 

Nutrition, 18(7–8):561–5, 2002. 

95. Quı ́lez. J., M. Rafecas, G. Brufau, P. 

Garcia-Lorda, I. Megias, M. Bullo ́, J.A. Ruiz, 

and J. Salas-Salvado ́. ‘‘Bakery Products 

Enriched With Phytosterol Esters, AlphaTocopherol and Beta-Carotene Decrease 

Plasma LDL-Cholesterol and Maintain 

Plasma Beta-Carotene Concentrations in 

Normocholesterolemic Men and Women.’’ 

Journal of Nutrition, 133(10):3103–3109, 

2003. 

96. Geelen, A., P.L. Zock, J.H.M. de Vries, 

and M.B. Katan. ‘‘Apolipoprotein E 

Polymorphism and Serum Lipid Response to 

Plant Sterols in Humans.’’ European Journal 

of Clinical Investigation, 32(10):738–42, 

2002. 

97. Judd, J.T., D.J. Baer, S.C. Chen, B.A. 

Clevidence, R.A. Muesing, M. Kramer, and 

G.W. Meijer. ‘‘Plant Sterol Esters Lower 

Plasma Lipids and Most Carotenoids in 

Mildly Hypercholesterolemic Adults.’’ Lipids, 

37:33–42, 2002. 

98. Mussner, M.J., K.G. Parhofer, K. von 

Bergmann, P. Schwant, U. Broedl, and C. 

Otto. ‘‘Effects of Phytosterol Ester-Enriched 

Margarine on Plasma Lipoproteins in Mild to 

Moderate Hypercholesterolemia are Related 

to Basal Cholesterol and Fat Intake.’’ 

Metabolism: Clinical & Experimental, 

51(2):189–194, 2002. 

99. Ntanios, F.Y., Y. Homma, and S. 

Ushiro. ‘‘A Spread Enriched With Plant 

Sterol-Esters Lowers Blood Cholesterol and 

Lipoproteins Without Affecting Vitamins A 

and E in Normal and Hypercholesterolemic 

Japanese Men and Women.’’ Journal of 

Nutrition, 132(12):3650–3655, 2002. 

100. Simons, L.A. ‘‘Additive Effect of Plant 

Sterol-Ester Margarine and Cerivastatin in 

Lowering Low-Density Lipoprotein 

Cholesterol in Primary 

Hypercholesterolemia.’’ American Journal of 

Cardiology, 90(7):737–740, 2002. 

101. Tammi, A., T. Ro ̈nnemaa, T.A. 

Miettinen, H. Gylling, L. Rask-Nissila ̈, J. 

Viikari, et al. ‘‘Effects of Gender, 

Apolipoprotein E Phenotype and CholesterolLowering by Plant Stanol Esters in Children: 

The STRIP Study.’’ Special Turku Coronary 

Risk Factor Intervention Project. Acta 

Paediatrica, 91(11):1155–1162, 2002. 

102. Temme, E.H., P.G. Van Hoydonck, 

E.G. Schouten, H. Kesteloot. ‘‘Effects of a 

Plant Sterol-Enriched Spread on Serum 

Lipids and Lipoproteins in Mildly 

Hypercholesterolaemic Subjects.’’ Acta 

Cardiologica, 57(2):111–5, 2002. 

103. Maki, K.C., M.H. Davidson, D.M. 

Umporowicz, E.J. Schaefer, M.R. Dicklin, 

K.A. Ingram, et al. ‘‘Lipid Responses to PlantSterol-Enriched Reduced-Fat Spreads 

Incorporated Into a National Cholesterol 

Education Program Step I Diet.’’ American 

Journal of Clinical Nutrition, 74(1):33–43, 

2001. 

104. Blair, S.N., D.M. Capuzzi, S.O. 

Gottlieb, T. Nguyen, J.M. Morgan, and N.B. 

Carter. ‘‘Incremental Reduction of Serum 

Total Cholesterol and Low-Density 

Lipoprotein Cholesterol With the Addition of 

Plant Stanol Ester-Containing Spread to 

Statin Therapy.’’ American Journal of 

Cardiology, 86:46, 2000. 

105. Andersson, A., B. Karlstrom, R. 

Mohsen, and B. Vessby. ‘‘CholesterolLowering Effects of a Stanol Ester-Containing 

Low-Fat Margarine Used in Conjunction 

With a Strict Lipid Lowering Diet.’’ European 

Heart Journal Supplements, 1:S80–S90, 1999. 

106. Ayesh, R., J.A. Weststrate, P.N. 

Drewitt, and P.A. Hepburn. ‘‘Safety 

Evaluation of Phytosterol Esters, Part 5, 

Faecal Short-Chain Fatty Acid and Microflora 

Content, Faecal Bacterial Enzyme Activity 

and Serum Female Sex Hormones in Healthy 

Normolipidaemic Volunteers Consuming a 

Controlled Diet Either With or Without a 

Phytosterol Ester-Enriched Margarine.’’ Food 

and Chemical Toxicology, 37:1127–1138, 

1999. 

107. Gylling, H. and T.A. Miettinen. 

‘‘Cholesterol Reduction by Different Plant 

Stanol Mixtures and With Variable Fat 

Intake.’’ Metabolism, 48:575–580, 1999. 

108. Nguyen, T.T., L.C. Dale, K. von 

Bergmann, and I.T. Croghan. ‘‘CholesterolLowering Effect of Stanol Ester in a U.S. 

Population of Mildly Hypercholesterolemic 

Men and Women: A Randomized Controlled 

Trial.’’ Mayo Clinic Proceedings, 74:1198– 

1206, 1999. 

109. Niinikoski, H., J. Viikari, and T. 

Palmu. ‘‘Cholesterol-Lowering Effect and 

Sensory Properties of Sitostanol Ester 

Margarine in Normocholesterolemic Adults.’’ 

Scandinavian Journal of Nutrition, 41:9–12, 

1997. 

110. Vanhanen, H.T., S. Blomqvist, C. 

Ehnholm, M. Hyvonen, M. Jauhiainen, I. 

Torstila, et al. ‘‘Serum Cholesterol, 

Cholesterol Precursors, and Plant Sterols in 

Hypercholesterolemic Subjects With 

Different apoE Phenotypes During Dietary 

Sitostanol Ester Treatment.’’ Journal of Lipid 

Research, 34:1535–1544, 1993. 

111. Benecol Spreads Web site. Available 

at http://www.benecolusa.com/products/

index.jhtml?id=benecol/products/pr_

spreads.inc. 

112. RTI International. ‘‘FDA Labeling Cost 

Mode.’’ Prepared for FDA, January 2003. 

113. RTI International. ‘‘Dietary 

Supplement Sales Information.’’ Prepared for 

FDA, October 1999. 

114. LeGault, L., M. Brandt, N. McCabe, C. 

Adler, A. Brown, and S. Brecher. ‘‘2000–2001 

Food Label and Package Survey: An Update 

on Prevalence of Nutrition Labeling and 

Claims on Processed, Packaged Foods.’’ 

Journal of the American Dietetic Association, 

104:952–958, 2004. 

115. RTI International. ‘‘Modeling the 

Decision to Reformulate Food and 

Cosmetics.’’ Prepared for FDA, October 2003. 

116. National Center for Health Statistics, 

Centers for Disease Control and Prevention. 

FASTATS. Available at http://www.cdc.gov/ 

nchs/fastats/deaths.htm. 

117. National Center for Chronic Disease 

Prevention and Health Promotion, Centers for 

Disease Control and Prevention. ‘‘Heart 

Disease Burden, Chronic Disease Notes and 

Reports’’ [serial on the Internet]. Vol. 17:1, 

Fall 2004. Available at http://www.cdc.gov/

nccdphp/burdenbook2004/preface.htm. 

118. Economic Research Service. ‘‘Food 

CPI, Prices, and Expenditures: CPI for Food 

Forecasts.’’ Available at http://www.ers.usda.

gov/briefing/cpifoodandexpenditures/data/

cpiforecasts.htm. 

119. U.S. Census Bureau. ‘‘2002 Economic 

Census.’’ Available at http://factfinder.

census.gov/servlet/EconSectorServlet?caller=

dataset&sv_name=*&_SectorId=31&ds

_name=EC0200A1&_lang=en&

_ts=170866291817. 

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: 

§ 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 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 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 (b)-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 § 101.14 shall 

be met, except § 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 

§ 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 betasitosterol, 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 § 101.62 for a 

‘‘low saturated fat’’ and ‘‘low cholesterol’’ 

food; 

(E) The food shall meet the limit for 

total fat in § 101.14(a)(4), except that, if 

the label of the food bears a disclosure 

statement that complies with 

§ 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 

§ 101.14(e)(6) unless it is a liquid 

vegetable oil or dressing for salad. The 

minimum nutrient contribution 

requirement for vegetable oil spreads 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
76556 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

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] 

suppliesllg 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] suppliesllg 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-blind, 

placebo-controlled, 

crossover trial; five 29– 

d test periods, separated by 2–4 wk washout periods 

Healthy adults 38 enrolled, 30 completed 

Mean age ± sd 

59 ± 10 y 

n = 30/phase 

Inclusion criteria: LDL–C 

>100 mg/dL, BMI 22– 

34, age 40–85 y, no 

chronic disease or 

lipid-lowering RX

USA 

One serving/d test margarine, eaten with 

breakfast. PS dose: 22 

mg/kg body wgt (about 

1.7 g PS/d) 1

C = margarine w/o added 

PS 

I1 = ∼1.7 g PS/d as 

nonesterified plant 

sterols in PS-enriched 

margarine 

I2 = ∼1.7 g PS/d as plant 

sterol esters (sunflower 

oil fatty acids) in PSenriched margarine 

I3 = ∼1.7 g PS/d as plant 

sterol esters (fish oil n– 

3 LC PUFA) in PS-enriched margarine 

I4 = ∼1.7 g PS/d as 

nonesterified plant 

sterols fish oil 

Controlled diet; all food 

and beverage prepared/provided by 

study; American diet w/ 

30% energy from fat 

Total-C (mg/dL) Baseline: 

228 

After 4-wk test period: 

C 222 

I1 219 

I2 220 

I3 224 

I4 223 

LDL–C (mg/dL) Baseline: 

147 

After 4-wk test period: 

C 141 

I1 139 

I2 139 

I3 145 

I4 143 

No significant changes of 

Total-C or LDL–C compared to control 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 76557 

TABLE 1—RANDOMIZED CLINICAL TRIALS OF PHYTOSTEROLS IN CONVENTIONAL FOODS AND TOTAL AND LDL 

CHOLESTEROL CONCENTRATION—Continued 

Study Design Population Intervention Diet Results 

Doornbos et al., 2006 

(Ref. 43) 

Randomized doubleblind, placebo-controlled, parallel trial 

with 5 groups; 4-wk 

run-in followed by 4-wk 

test period 

Mildly 

hypercholesterolemic 

adults 

191 randomized, 184 Included in analysis 

Mean age ± sd 

57 ± 2 y 

n = 33(C) 

n = 38 (I1) 

n = 38 (I2) 

n = 39 (I3) 

n = 36 (I4) 

Inclusion criteria: BMI 

18–32 kg/m2; total-C 

193–309 mg/dL TG < 

355 mg/dL 

The Netherlands 

Single serving bottled yogurt drink (100 g) consumed with a meal, or 

while fasting 

C = drink w/o added PS 

I1 = 3.2 g PS/d in low-fat 

yogurt (0.1 g dairy fat, 

2.2 g fat in the stanol/ 

sterol ester) w/meal 

I2 = 3.2 g PS/d in low-fat 

yogurt (0.1 g dairy fat, 

2.2 g fat in the stanol/ 

sterol ester) w/o meal 

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 

Habitual diet ................... Total-C (mg/dL) Baseline: 

234 

Total-C % change compared to control: 

I1 ↓ 7.0%* 

I2 ↓ 4.1%* 

I3 ↓ 6.5%* 

I4 ↓ 4.7%* 

*p < 0.05 

LDL–C (mg/dL) Baseline: 

155 

LDL–C % change compared to control: 

I1 ↓ 9.5%* 

I2 ↓ 5.1%* 

I3 ↓ 9.3%* 

I4 ↓ 6.9%* 

*p < 0.05 

Jauhiainen et al., 2006 

(Ref. 89).

Randomized doubleblind, placebo-controlled parallel trial, 1- 

wk run-in, 5-wk test 

period 

Mildly 

hypercholesterolemic 

adults 

67 enrolled, 67 completed 

n = 34 (C) 

n = 33 (I) 

Age range 25–65 y 

Inclusion criteria: 

Total-C 193–251 

mg/dL, TG < 266 

mg/dL 

Finland 

50 g/d hard cheese divided into 2 portions 

consumed with two 

major meals 

C = cheese w/o added 

phytosterols 

I = 2.0 g PS/d as plant 

stanol ester in PS-enriched hard cheese 

Habitual diets .................. Total-C (mg/dL) Baseline: 

C 224 

I 218 

Total-C % change compared to placebo: 

I ↓ 5.7% (p < 0.05) 

LDL–C (mg/dL) Baseline: 

C 139 

I 138 

LDL–C % change compared to control: I ↓ 

10.1% (p < 0.05) 

Korpela et al., 2006 (Ref. 

37).

Randomized doubleblind, placebo-controlled, parallel trial; 3- 

wk run-in, 6-wk test 

period 

Mildly 

hypercholesterolemic 

adults. 170 enrolled, 

164 completed 

n = 82/group 

Mean age ± sd 

57 ± 8 y (C) 

58 ± 9 y (I) 

Inclusion criteria: Total-C 

193–329 mg/dL, TG < 

354 mg/dL 

Finland 

150 g low-fat yogurt, 50 

g low-fat hard cheese, 

and 50 g low-fat fresh 

cheese 

C = yogurt and cheese 

w/out added PS 

I= 1.65–2.0 g PS/d as 

nonesterified sterol/ 

stanol in enriched yogurt and cheeses 

Habitual diets plus lowfat yogurt and low-fat 

hard/fresh cheese 

Total-C (mg/dL) Baseline: 

C 247 

I 247 

% change compared to 

control: I ↓ 6.5% (p < 

0.05) 

LDL–C (mg/dL) Baseline: 

C 155 

I 159 

% change compared to 

control: I ↓ 11.0% (p < 

0.05) 

Jakulj et al., 2005 (Ref. 

90).

Randomized doubleblind, crossover design 

for PS component, and 

open-label RX tmt; 2x2 

factorial trial. 2-wk runin followed by four consecutive 4-wk test periods 

Healthy moderately 

hypercholesterolemic 

adults 40 enrolled, 39 

Included in analyses 

Mean age ± sd 

55.5 ± 7.9 y 

n = 39 

Inclusion criteria: plasma 

LDL–C 135–193 mg/ 

dL; TG < 355 mg/dL 

The Netherlands 

25 g/d test margarine on 

sandwiches or mixed 

with food in a hot meal 

C = spread w/o added 

PS 

I1 = 2.0 g PS/d as plant 

sterol on PS-enriched 

spread. Information not 

provided as to whether 

nonesterified or 

esterified 

I2 = Ezetimibe 

I3 = Ezetimibe + PS-enriched spread 

Habitual diets .................. Total-C (mg/dL) Baseline: 

261 

At end of 4 wk test period: 

C 249 

I1 235 

I2 208 

I3 204 

Total-C % change compared to control: 

I1 ↓ 5.2%* 

I2 ↓ 15.7%* 

I3 ↓ 17.2%* 

*p < 0.05 

LDL–C (mg/dL) Baseline: 

174 

At end of 4-wk: 

C 157 

I1 148 

I2 121 

I3 116 

% change compared to 

control: 

I1 ↓ 5.1%* 

I2 ↓ 20.9%* 

I3 ↓ 23.8%* 

*p < 0.05 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
76558 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

TABLE 1—RANDOMIZED CLINICAL TRIALS OF PHYTOSTEROLS IN CONVENTIONAL FOODS AND TOTAL AND LDL 

CHOLESTEROL CONCENTRATION—Continued 

Study Design Population Intervention Diet Results 

Clifton et al. 2004 (Ref. 

88).

Randomized single-blind, 

placebo-controlled, incomplete crossover 

trial; four consecutive 

3-wk test periods, no 

washout periods 

Mildly 

hypercholesterolemic 

adults 63 enrolled, 58 

completed 

n = 58 (C) 

n = 36 (I1) 

n = 40 (I2) 

n = 58 (I3) 

n = 40 (I4) 

Mean age 54 y 

Inclusion criteria: BMI < 

31, no RX that affect 

lipids, total-C 193–290 

mg/dL 

Australia 

One serving/d each 4 of 

test foods (bread, milk, 

cereal, and yoghurt) 

consumed with meals 

C = test foods w/o added 

PS 

I1 = 1.6 g/d PS as soy 

sterol esters in 2 slices 

of PS-enriched bread 

I2 = 1.6 g/d PS as soy 

sterol esters in 500 ml 

of 2% PS-enriched 

milk 

I3 = 1.6 g/d PS as soy 

sterol esters in 45 g of 

PS-enriched cereal 

I4 = 1.6 g/d PS as soy 

sterol esters 200g of 

PS-enriched yogurt 

Habitual diets supplemented by one serving 

daily of yoghurt, low-fat 

milk, bread, and 

muesli-type cereal. No 

changes in reported intakes of energy, fat, 

CHO, or protein across 

treatment periods or 

between centers 

Total-C (mg/dL) Baseline: 

241 

% change compared to 

placebo: 

I1 ↓ 5.6%* 

I2 ↓ 8.5%* 

I3 ↓ 3.2%* 

I4 ↓ 6.3%* 

*p < 0.05 

LDL–C (mg/dL) Baseline: 

156 

% change compared to 

control: 

I1 ↓ 10.4%* 

I2 ↓ 13.2%* 

I3 ↓ 6.0%* 

I4 ↓ 10.4%* 

*p < 0.05 

Devaraj et al., 2004 (Ref. 

33).

Randomized doubleblind, parallel trial with 

2 groups; 2-wk run-in 

period followed by 8- 

wk test period 

Healthy mildly 

hypercholesterolemic 

adults 

75 enrolled; 72 completed 

Mean age ± sd 

44 ± 13 y (C) 

41 ± 13 y (I) 

n = 36/group 

Inclusion criteria: LDL–C 

>100 mg/dL; no Rx

that affect lipids, no 

smoking, no HX of 

CVD 

USA 

2 servings/d of test orange juice, with meals.

C = orange juice w/o 

added PS 

I=2 g PS/d as 

nonesterified sterol in 

PS-enriched orange 

juice 

Habitual diets. No other 

orange juice, citrus 

fruit, or PS-enriched 

margarine allowed. 3- 

day diet records at beginning and end of 

study 

Total-C (mg/dL) Baseline: 

C 209 

I 207 

Total-C % change compared to control: 

I ↓ 5.3% (p < 0.05) 

LDL–C (mg/dL) Baseline: 

C 140 

I 137 

LDL–C % change compared to control: I ↓ 

7.3% (p < 0.05) 

Thomsen et al., 2004 

(Ref. 26).

Randomized doubleblind, crossover trial, 

with three consecutive 

4-wk periods; no run-in 

or wash-our periods 

Mildly 

hypercholesterolemic 

adults 

81 subjects Randomized 

69 completed 

Mean age ± sd 

60 ± 5 y 

n = 69 

Inclusion criteria: no RX

that affect lipids, totalC 217–325 mg/dL, TG 

< 310 mg/dL 

Denmark 

2 servings/d of 1.2%-fat 

test milk w/meals 

C = milk w/o added PS 

I1 = 1.2 g PS/day as 

nonesterified plant 

sterols in PS-enriched 

milk 

I2 = 1.6 g PS/day as 

nonesterified plant 

sterols in PS-enriched 

milk 

Habitual Danish diet with 

limits on certain fatty 

foods; e.g., 20 g/d 

cheese, 2 portions of 

crustaceans and mollusks per wk 

Total-C (mg/dL) Baseline: 

271 

Total-C % change relative to control: 

I1 ↓ 4.73%* 

I2 ↓ 7.05%* 

* p < 0.0001 

LDL–C (mg/dL) Baseline: 

169 

LDL–C % change relative 

to control: 

I1 ↓ 7.1%* 

I2 ↓ 9.6%* 

* p < 0.0001 

Cleghorn et al., 2003 

(Ref. 91).

Randomized doubleblind, placebo-controlled, crossover trial; 

3-wk run-in period, 3- 

wk test period 

Mildly 

hypercholesterolemic 

adults; 

58 subjects enrolled, 53 

completed 

Mean age ± sd 

46.7 ± 10.5 y 

n = 53 

Inclusion criteria: total-C 

193–290 mg/dL, TG < 

266 mg/dL; no cholesterol-lowing RX

New Zealand 

Test butter (20 g/d) or 

test margarine (25 g/d) 

B = Butter w/o added PS 

M = margarine w/o 

added PS 

I = 2 g PS/d PS as plant 

sterol esters in PS-enriched margarine 

Self-selected low-fat 

diets. Test substance 

(butter or margarine) 

added to low-fat diet 

Total-C (mg/dL) 

At end of 3 wk test period: 

B 235 

M 227 

I 215 

Total-C % change relative to control: I ↓ 

5.45% (p < 0.05) 

LDL–C (mg/dL) 

At end of 3 wk test period: 

B 154 

M 145 

I 135 

LDL–C % change compared to control: I ↓ 

7.2% (p < 0.01) 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 76559 

TABLE 1—RANDOMIZED CLINICAL TRIALS OF PHYTOSTEROLS IN CONVENTIONAL FOODS AND TOTAL AND LDL 

CHOLESTEROL CONCENTRATION—Continued 

Study Design Population Intervention Diet Results 

Homma et al., 2003 (Ref. 

82).

Randomized doubleblind, placebo-controlled, parallel trial, 4- 

wk test period, and 4- 

wk post-trial follow-up 

period 

Healthy adult Japanese 

105 enrolled, 104 completed 

Mean age ± sd 

46 ± 14 y (P) 

47 ± 13 y (I1) 

49 ± 12 y (I2) 

n = 33–34/group 

Inclusion criteria: age 

>20 y, total-C 209–278 

mg/dL, TG < 345 mg/ 

dL 

Japan 

2 or 3 servings/d of lowfat test spread, eaten 

w/meals.

C = spread w/o added 

PS, 3 servings/d 

I1 = 2 g PS/d as plant 

stanol esters in PS-enriched spread, 2 

servings/d 

I2 = 3 g PS/d as stanol 

esters in PS-enriched 

spread, 3 servings/d 

Habitual Japanese diet. 

Diets were assessed 

with 2 day diet analysis 

at start and end of trial 

Total-C (mg/dL) Baseline: 

C 238 

I1 235 

I2 232 

Total-C % change compared to control: 

I1 ↓ 5.7%* 

I2 ↓ 4.9%* 

*p < 0.001 

LDL–C (mg/dL) Baseline: 

C 157 

I1 153 

I2 153 

LDL–C % change compared to control: 

I1 ↓ 8.9%* 

I2 ↓ 6.6%* 

*p < 0.001 

Ishiwata et al., 2002 

(Same subjects as 

Homma et al., 2003) 

(Ref. 92).

Randomized doubleblind, placebo-controlled, parallel trial, 4- 

wk test period, and 4- 

wk post-trial follow-up 

period 

See Homma et al. 2003 

n = 30–31/group 

Analysis stratified by 

apolipoprotein E phenotype 

2 or 3 servings/d of lowfat test spread, eaten 

w/meals 

C = spread w/o added 

PS, 3 servings/d 

I1 = 2 g PS/d as plant 

stanol esters in PS-enriched spread, 2 

servings/d 

I2 = 3 g PS/d as stanol 

esters in PS-enriched 

spread, 3 servings/d 

Habitual Japanese diet Total-C (mg/dL) Baseline: 

C ApoE3 236 

C ApoE4 241 

I1 ApoE3 237 

I1 ApoE4 231 

I2 ApoE3 234 

I2 ApoE4 233 

Total-C % change compared to control: 

I1 ApoE3 ↓ 7.1%* 

I1 ApoE4 ↓ 6.3%* 

I2 ApoE3 ↓ 5.9%* 

I2 ApoE4 ↓ 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 ↓ 9.2%* 

I1 ApoE4 ↓ 11.0%* 

I2 ApoE3 ↓ 8.7%* 

I2 ApoE4 ↓ 6.4% 

* p < 0.01 

Jones et al., 2003 (Ref. 

34).

Randomized doubleblind, crossover trial; 

three 3-wk controlled 

feeding test periods 

separated by 4-wk 

washout periods 

Mildly 

hypercholesterolemic 

adults 

15 enrolled, 15 completed 

age range 22–68 y 

n = 15 

Inclusion criteria: BMI 

22–32 kg/m2, LDL–C 

126–232 mg/dL, HDL 

< 31 mg/dL, TG < 355 

mg/dL 

Canada 

3 servings/d of nonfat or 

low fat test beverage 

consumed w/meals 

C = nonfat beverage w/o 

added PS 

I1 = 1.8 g PS/d as 

nonesterified plant tall 

oil sterol/stanol in PSenriched nonfat beverage 

I2 = 1.8 g PS/d as 

nonesterified plant tall 

oil sterol/stanol in PSenriched low fat beverage 

Typical American diet. 

Controlled intake; all 

food/beverage prepared/provided by 

study 

Total-C (mg/dL) Baseline: 

C 237 

I1 242 

I2 229 

Total-C % change at 3 

wk: 

C ↓ 8.5% 

I1 ↓ 11.6% 

I2 ↓ 10.1% 

no significant differences 

between control and 

PS periods 

LDL–C (mg/dL) Baseline: 

C 155 

I1 160 

I2 150 

LDL–C % change at 3 

wk: 

C ↓ 5.0% 

I1 ↓ 10.4% 

I2 ↓ 8.5% 

no significant differences 

between P and PS periods 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
76560 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

TABLE 1—RANDOMIZED CLINICAL TRIALS OF PHYTOSTEROLS IN CONVENTIONAL FOODS AND TOTAL AND LDL 

CHOLESTEROL CONCENTRATION—Continued 

Study Design Population Intervention Diet Results 

Naumann et al., 2003 

(Ref. 42).

Randomized doubleblind, placebo-controlled, crossover trial; 

three consecutive 3-wk 

test periods 

Healthy adults, 44 enrolled, 42 completed 

Mean age ± sd 

32 ± 14 y F 

37 ± 16 y M 

n = 42 

Inclusion criteria: BP < 

160/95, BMI < 30, stable body wgt, age 18– 

65 y, Total-C < 309 

mg/dL, TG < 355 mg/ 

dL 

The Netherlands 

1 serving/d of test margarine 

C = margarine w/o added 

PS 

I1 = 2 g PS/d as phytosterol ester, 1:1 sterol/ 

stanol ester ratio in 

PS-enriched margarine 

I2 = 2 g PS/d as phytosterol ester, 3:1 sterol/ 

stanol ester ratio in 

PS-enriched margarine 

Habitual diets; food frequency questionnaires 

assessed diet at end of 

each period. No margarine was allowed 

other than the provided 

test margarine. Study 

provided sunflower oil 

shortening (w/o added 

plant sterols and 

stanols) to control unintended plant sterol 

and stanol intake 

Total-C (mg/dL) At end of 

3 wk: 

C 173 

I1 167 

I2 168 

Total-C % difference 

compared to control: 

I1 ↓ 3.4%* 

I2 ↓ 2.7%* 

*p < 0.05 

LDL–C (mg/dL) 

At end of 3 wk 

C 109 

I1 102 

I2 102 

LDL–C % difference 

compared to control 3 

wk: 

I1 ↓ 6.0%* 

I2 ↓ 6.7%* 

*p < 0.05 

Quı ́lez et al., 2003 (Ref. 

93).

Randomized doubleblind, placebo-controlled, parallel trial; 2 

groups, 8 wk test period 

Healthy subjects, 61 enrolled, 57 competed 

Mean age ± sd 

30.9 ± 7.2 y (C) 

31.0 ± 6.7 y (I) 

n = 29 (C) 

n = 28 (I) 

Inclusion criteria: BMI < 

40, no RX or diet that 

affect blood lipids, 

total-C < 240 mg/dL, 

global CV risk < 20% 

(Eur Soc for Atherosclerosis criteria), TG < 

200 mg/dL, consumers 

of bakery products 

Spain 

2 test bakery products/d 

(1 muffin, 1 croissant) 

eaten at any time of 

day 

C = bakery products w/o 

added PS 

I = 3.2 g PS/d as soy 

sterol esters; divided 

between PS-enriched 

croissant and muffin 

Habitual diets with test 

foods replacing usual 

bakery product consumption 

Total-C (mg/dL) Baseline: 

C 162 

I 167 

Total-C % change compared to control: I ↓ 

8.9% (p < 0.001) 

Total-C (mg/dL) Baseline: 

C 93 

I 97 

Total-C % change compared to control: I ↓ 

14.6% (p < 0.001) 

Seki et al., 2003 (Ref. 54) Randomized doubleblind, parallel trial with 

2 groups; 2-wk run-in 

period followed by 12- 

wk test period 

Healthy mildly 

hypercholesterolemic 

males 

61 enrolled, 60 completed 

Mean age ± sd 

39.4 ± 1.4 y 

n = 28 (C) 

n = 32 (I) 

Inclusion criteria: healthy; 

total-C < 280 mg/dL, 

TG < 400 mg/dL 

Japan 

3 slices test bread/d 

C = bread made with veg 

oil w/o added PS 

I = 0.45 g PS/d as plant 

sterol esters in PS-enriched veg oil baked 

into bread 

Habitual diets; diets assessed with three 3-d 

diet records 

Total-C (mg/dL) Baseline: 

C 190 

I 194 

Total-C % change compared to control: I ↓ 

3% 

LDL–C (mg/dL) Baseline: 

C 115 

I 116 

LDL–C % change compared to control: I ↓ 

2.1% 

No significant treatment 

effects 

Spilburg et al., 2003 (Ref. 

27).

Randomized doubleblind, parallel trial, with 

6-wk run-in period followed by 4-wk test period 

Moderately 

hypercholesterolemic 

adults 

26 randomized, 24 completed 

Mean age ± sd 

50.6 ± 10 y 

Inclusion criteria: LDL–C 

80–210 mg/dL, TG < 

300; no illness; no RX

except for oral contraceptives, hormone replacement, antihypertensives, anti-depressants & analgesics 

USA 

Powdered lemonade-flavored fat-free test beverage, 3 servings/d 

P = beverage w/added 

lecithin, w/o added PS 

I = 1.9 g PS/d as lecithin 

emulsified soy 

nonesterified stanol in 

PS-enriched beverage 

American Heart Association Step I diet; diet 

counseling to maintain 

weight if needed 

Total-C (mg/dL) Baseline: 

C 200 

I 224 

% change compared to 

control: I ↓ 10.1% (p < 

0.05) 

LDL–C (mg/dL) 

C 128 

I 148 

% change compared to 

control: I ↓ 14.3% (p < 

0.05) 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 76561 

TABLE 1—RANDOMIZED CLINICAL TRIALS OF PHYTOSTEROLS IN CONVENTIONAL FOODS AND TOTAL AND LDL 

CHOLESTEROL CONCENTRATION—Continued 

Study Design Population Intervention Diet Results 

De Graaf et al., 2002 

(Ref. 32).

Randomized doubleblind, parallel trial; 4 

wk run-in period; 4-wk 

test period 

Mildly 

hypercholesterolemic 

adults 

70 randomized, 62 completed 

Mean age 

57.8 y (C) 

56.2 y (I) 

n = 31/group 

Inclusion criteria: age 

21–75 y; total-C 213– 

310 mg/dL, LDL–C 

≥135 mg/dL; TG < 354 

mg/dL; BMI < 35 

The Netherlands 

3 servings/d of test chocolate/d (10.5 g each), 

eaten with meals 

C = chocolate w/o added 

PS 

I = 1.8 g PS/day as 

nonesterified tall oil 

sterols/stanols in PSenriched chocolate 

Self-selected Step I diet; 

supplemented w/three 

servings/d of chocolate 

Total-C (mg/dL) 

C 257 

I 261 

Total-C% change compared to control: I ↓ 

6.4% (p < 0.05) 

LDL–C (mg/dL) 

C 177 

I 182 

LDL–C% change compared to control: I ↓ 

11.1 (p < 0.05) 

Geelen et al., 2002 (Ref. 

94).

Randomized doubleblind, crossover trial, 

with 2 consecutive 3- 

wk test periods 

Healthy adults with 

known apolipoprotein E 

phenotype 31 ApoE4

subjects; 57 ApoE3

subjects n = 88; Mean 

age 25.4 y 

Inclusion criteria: age 

≥18 y; no prescribed 

diets; no lipid-lowering 

RX; total-C ≤310 mg/ 

dL; TG < 266 mg/dL 

The Netherlands 

One tub (35 g) test margarine/d consumed in 

place of usual margarine 

C = margarine w/o added 

PS 

I = 3.2 g PS/d as vegetable oil sterol esters in 

PS-enriched margarine 

Habitual diets; random 

24-h recall diet surveys 

conducted during test 

Total-C (mg/dL) Baseline: 

E3/4 & E4/4 201 

E3/3 178 

Total-C% change compared to control: I ↓ 

7% (p < 0.05) 

LDL–C% change compared to control: I ↓ 

11% (P<0.05) 

Judd et al., 2002 (Ref. 

95).

Randomized doubleblind, crossover trial; 

two consecutive 3-wk 

intervention periods, no 

wash out 

Healthy adults, normal or 

slightly elevated total-C 

58 enrolled, 53 completed 

Mean age ± sd 

47.1 ± 1.5 y 

n = 53 

Inclusion criteria: age 

25–65 y; HDL >25 mg/ 

dl (men) or >35 mg/dL 

(women), TG < 300 

mg/dL 

USA 

Two servings/d of test 

salad dressing (Ranch 

or Italian), eaten w/ 

meals 

C1 = Ranch dressing w/o 

added PS 

I1 = 2.2 g PS/d as soy 

sterol esters in PS-enriched Ranch dressing 

C2 = Italian dressing w/o 

added PS 

I2 = 2.2 g PS/d as soy 

sterol esters in PS-enriched Italian dressing 

Typical American diet; 

Controlled diet provided by study and 

eaten on site 

Type of salad dressing 

did not affect plasma 

lipids so data was 

combined 

Total-C (mg/dL) baseline: 

214 

Total-C% change compared to control: I ↓ 

7.0% (p < 0.0001) 

LDL–C (mg/dL) Baseline: 

141 

LDL–C% change compared to control: I ↓ 

9.2% (p < 0.0001) 

Matvienko et al, 2002 

(Ref. 60).

Randomized doubleblind, placebo-controlled, parallel trial; 

single 4-wk test period 

Hypercholesterolemic 

white males. 50% of 

subjects w/family HX of 

premature CVD & 

hyperlipidemia 

36 enrolled, 34 completed 

Mean age ± sd 

22.2±3.9 y (C) 

23.6±3.9 y (I) 

n = 17/group 

Inclusion criteria: total-C 

>197 mg/dL, LDL-totalC >130 mg/dL 

USA 

One serving/d (112 g) of 

cooked lean ground 

beef eaten at lunch 

C = ground beef 

w/o added PS 

I = 2.7 g PS/d as soy 

sterols, partially 

esterified, in PS-enriched beef 

Habitual diets w/limits on 

eggs (2–3 eggs/wk), 

and no red meat other 

than that in the test 

meal. Diets assessed 

by interviewer administered questionnaires 

Total-C (mg/dL) Baseline: 

C 224 

I 228 

Total-C% change compared to control: I ↓ 

8.4% (p < 0.001) 

LDL–C (mg/dL) Baseline: 

C 153 

I 159 

LDL–C% change compared to control: I ↓ 

13.3% (p < 0.001) 

Mensink et al., 2002 (Ref. 

86).

Randomized doubleblind, placebo-controlled, parallel trial; 3- 

wk run-in followed by 

4-wk test period 

Mildly 

hypercholesterolemic 

adults 

69 randomized, 60 completed 

Mean age ± sd 

36 ± 14 y 

n = 30/group 

Inclusion criteria: no diets 

that affects lipids, no 

CAD HX, BMI < 30, 

total-C < 251 mg/dL 

The Netherlands 

3 servings/d of test yogurt, eaten w/meals 

C = yogurt w/o added PS 

I = 3 g PS/d as plant 

stanol esters in PS-enriched yogurt 

Habitual diets supplemented with 3 

servings/day test yogurt. Low erucic acid 

rapeseed oil margarine 

and shortening provided to standardize 

fatty acid intake. Diet 

questionnaires to assess diet 

Total-C (mg/dL) Baseline: 

C 184 

I 193 

% change compared to 

control: I ↓ 8.7% (p < 

0.001) 

LDL–C (mg/dL) Baseline: 

C 111 

I 113 

% change compared to 

control: I ↓ 13.7% (p < 

0.001) 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
76562 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

TABLE 1—RANDOMIZED CLINICAL TRIALS OF PHYTOSTEROLS IN CONVENTIONAL FOODS AND TOTAL AND LDL 

CHOLESTEROL CONCENTRATION—Continued 

Study Design Population Intervention Diet Results 

Mussner et al., 2002 (Ref. 

96).

Randomized doubleblind, crossover trial, 

with 2 consecutive 3- 

wk test periods 

Mildly 

hypercholesterolemic 

adults 

63 enrolled, 62 completed 

Mean age ± sd 

42 ± 11 y 

n = 62 

Inclusion criteria: BMI < 

30, total-C 200–300 

mg/dL, LDL–C 130– 

200 mg/dL; TG < 160 

mg/dL 

Germany 

Two servings/d (10 g 

each) of test margarine, consumed in 

morning and evening, 

replacing usual margarine 

C = margarine w/o added 

PS 

I = 1.82 g PS/d as plant 

sterol esters in PS-enriched margarine 

Habitual diets; 3-day dietary recalls (at beginning and end of study) 

to assess diets 

Total-C (mg/dL) Baseline: 

233 

Total-C% change compared to control: I ↓ 

3.8% (p < 0.05) 

LDL–C (mg/dL) Baseline: 

152 

LDL–C% change compared to control: I ↓ 

6.5% (p < 0.05) 

Noakes et al., 2002 (Ref. 

41).

Randomized doubleblind, crossover trial; 

three consecutive 3-wk 

test periods, no washout period; 1-wk run-in 

Study 1 

Hypercholesterolemic 

adults 

52 enrolled, 46 completed 

Mean age ± sd 

55 ± 9.7 y M 

58 ± 7.3 y F 

n = 46 

Inclusion criteria: age 

20–75 y; BMI < 31, no 

RX that affect lipids, 

total-C 209–329 mg/ 

dL, TG < 400 mg/dL 

The Netherlands 

3 servings/d of reduced 

fat test spread replacing usual margarine, 

consumed w/meals 

C = spread w/o added 

PS 

I1 = 2.3 g PS/d as plant 

sterol esters in PS-enriched spread 

I2 = 2.5 g PS/d as plant 

stanol esters in PS-enriched spread 

Usual low saturated fat 

diet; w/≥5 servings/d of 

fruit and vegetables, 

≥1 of which was high 

in carotenoids 

Total-C (mg/dL) After 3- 

wk intervention: 

C 244 

I1 229 

I2 226 

Total-C% change compared to control: 

I1 ↓ 6.0%* 

I2 ↓ 7.3%* 

*p < 0.001 

LDL–C (mg/dL) After 3- 

wk intervention: 

C 166 

I1 153 

I2 150 

LDL–C% change compared to control: 

I1 ↓ 7.7%* 

I2 ↓ 9.5%* 

*p < 0.001 

No significant difference 

between I1 and I2

Randomized doubleblind, crossover trial; 

two consecutive 3-wk 

test periods, no washout period; 1-wk run-in 

Study 2 

Hypercholesterolemic 

adults 

40 enrolled, 35 completed 

n = 35 

Inclusion criteria: BMI < 

31, no RX that affect 

lipids, total-C 209–329 

mg/dL, TG < 400 mg/ 

dL 

The Netherlands 

3 servings/d of reduced 

fat test spread replacing usual margarine, 

consumed w/meals 

C = spread w/o added 

PS 

I3 = 2 g PS/d as plant 

sterol esters in PS-enriched spread 

Diet same as in Study #1 Total-C (mg/dL) After 3- 

wk intervention: 

C 233 

I3 218 

Total-C% change compared to control: I3 ↓ 

6.6%* 

LDL–C (mg/dL) After 3- 

wk intervention: 

C 161 

I3 145 

LDL–C% change compared to control: I3 ↓ 

9.6%* 

*p < 0.001 

Ntanios et al., 2002 (Ref. 

97).

Double-blind, placebocontrolled, crossover 

trial. 1-wk run-in; Two 

consecutive 3-wk test 

periods w/o wash-out 

period 

Healthy adult Japanese, 

53 enrolled, 53 completed 

Mean age ± sd 

45.1 ± 10.4 y 

n = 53 

Inclusion criteria: age 

24–67 y; BMI 19–30, 

healthy, normal diet, 

no HX of CVD or ↑ 

total-C 

Japan 

Two servings/d low-fat 

test spread consumed 

w/meals 

C = spread w/o added 

PS 

I = 1.8 g PS/d as plant 

sterol esters in PS-enriched spread 

Habitual Japanese diet. 

Diets assessed with 

food frequency questionnaire during run-in 

period 

Total-C (mg/dL) After 3 

wks of intervention: 

C 213 

I 201 

Total-C% change compared to control: I ↓ 

5.8% (p < 0.01) 

LDL–C (mg/dL) After 3 

wks of intervention 

C 119 

I 109 

LDL–C% change compared to control: I ↓ 

9.1% (p < 0.001) 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 76563 

TABLE 1—RANDOMIZED CLINICAL TRIALS OF PHYTOSTEROLS IN CONVENTIONAL FOODS AND TOTAL AND LDL 

CHOLESTEROL CONCENTRATION—Continued 

Study Design Population Intervention Diet Results 

Simons et al., 2002 (Ref. 

98).

Multicenter, randomized 

double-blind, placebocontrolled, parallel 2 X 

2 factorial trial with 4- 

wk test period 

Hypercholesterolemic 

adults, some using 

statin drugs 

154 enrolled, 152 completed 

Mean age ± sd 

60 ± 9 y (I1) 

58 ± 10 y (I2) 

58 ± 11 y (I3) 

62 ± 11 y (I4) 

n = 37–29/group 

Inclusion criteria: LDL–C 

≥97 mg/dL, TG < 400 

mg/dL, age >18 y 

Australia 

Two servings/d of test 

margarine, consumed 

w/meals. Drug intervention: 400 μg/day 

cerivastatin, or placebo 

tablet 

I1 = tablet + margarine 

I2 = placebo tablet + 2 g 

PS/d as plant sterol 

esters in PS-enriched 

margarine 

I3 = statin + placebo margarine 

I4 = statin + 2 g PS/d as 

plant sterol esters in 

PS-enriched margarine 

American Heart Association Step I diet; closely 

supervised by a nutritionist 

Total-C (mg/dL) Baseline: 

I1 295 

I2 297 

I3 282 

I4 298 

Total-C% change at 4 wk 

relative to baseline: 

I1 ↑2.2% 

I2 ↓ 5.3% 

I3 ↓ 23.2% 

I4 ↓ 28.9% 

Main effect of PS-enriched margarine: ↓ 

6.7% (p < 0.0001) 

LDL–C (mg/dL) Baseline: 

I1 210 

I2 209 

I3 195 

I4 209 

LDL–C% change at 4 wk 

compared to baseline: 

I1 ↑2% 

I2 ↓ 8.2% 

I3 ↓ 32.4% 

I4 ↓ 38.5% 

Main effect of PS-enriched margarine: ↓ 

8.1% (p < 0.0001) 

Tammi et al., 2002 (Ref. 

99).

Randomized doubleblind, crossover trial, 

with two 3 month test 

periods separated by a 

6-wk wash out period 

Healthy children (age 6 

y) enrolled in Finnish 

STRIP* study 

81 enrolled, 79 completed 

n = 35 F 

n = 44 M 

*Special Turku Coronary 

Risk Factor Project; 

subjects enrolled as infants; study diet aim 

was 1:1:1 ratio of 

PUFA:MUFA:sat fats, 

cholesterol < 200 mg/d 

20 g/d test margarine replaced similar amount 

of usual dietary fat 

C = margarine w/o added 

PS 

I = 1.6 g PS/d as plant 

stanol esters in PS-enriched margarine 

Continuation of STRIP 

study diet (low sat fat, 

low cholesterol) that 

the subjects had followed for several years 

Total-C (mg/dL) Baseline: 

158 (boys) 

176 (girls) 

Total-C% change at 3- 

mo compared to control 

Iboys ↓ 6.4%* 

Igirls ↓ 4.4%* 

*p < 0.05 

LDL–C (mg/dL) Baseline: 

98 (boys) 

123 (girls) 

LDL–C% change at 3-mo 

compared to control: 

Iboys ↓ 9.1%* 

Igirls ↓ 5.8%* 

*p < 0.05 

Temme et al., 2002 (Ref. 

100).

Randomized doubleblind, crossover trial; 

no run-in period; two 

consecutive 4-wk test 

periods 

Healthy adults, 42 enrolled, 42 completed 

Mean age ± sd 

55 ± 9 y 

n = 42 

Inclusion criteria: BMI < 

30, no RX or prescribed diet that affect 

lipids 

Report states 70% of 

Belgium adult population is mildly 

hypercholesterolemic 

Belgium 

3 portions/d of test margarine eaten w/meals 

replaced habitual margarine use 

C = spread w/o added 

PS 

I = 2.1 g PS/d as plant 

sterol esters in PS-enriched spread 

Habitual diet ................... Total-C (mg/dL) After 4 

wk test period: 

C 248 

I 231 

Total-C% change compared to control: I ↓ 

6.9%* 

LDL–C (mg/dL) After 4 

wk test period: 

C 166 

I 150 

LDL–C % change compared to control: I ↓ 

9.6%* 

*p < 0.05 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
76564 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

TABLE 1—RANDOMIZED CLINICAL TRIALS OF PHYTOSTEROLS IN CONVENTIONAL FOODS AND TOTAL AND LDL 

CHOLESTEROL CONCENTRATION—Continued 

Study Design Population Intervention Diet Results 

Vanstone et al., 2002 

(Ref. 22).

Randomized doubleblind, crossover trial; 

no run-in period; four 

3-wk controlled test periods separated by 4- 

wk washout periods 

Primary familial 

hyperlipidemia adults 

16 enrolled, 15 completed 

Mean age ± sd 

47.8 ± 1.9 y 

n = 15 

Inclusion criteria: age 

35–58 y; Total-C 201– 

348 mg/dL, and TG < 

310 mg/dL 

Canada 

3 portions/d test butter 

eaten w/meals 

C = butter w/cornstarch 

added to mimic appearance of PS-enriched butter 

I1 =1.8 g PS/d as 

nonesterified soy 

sterols in PS-enriched 

butter 

I2 = 1.8 g PS/d as 

nonesterified soy 

stanols in PS-enriched 

butter 

I3 = 1.8 g PS/d as 50/50 

mix of nonesterified 

soy sterols/stanols in 

PS-enriched butter 

Controlled feeding of typical American diet, all 

food and beverage 

prepared/provided by 

study, 2 or more 

meals/d eaten onsite 

Total-C (mg/dL) At end of 

3 wk test period: 

C 238 

I1 214 

I2 215 

I3 216 

Total-C % change compared to control: 

I1 ↓ 7.8%* 

I2 ↓ 11.9%* 

I3 ↓ 13.1%* 

LDL–C (mg/dL) At end of 

three wk test period: 

C 155 

I1 139 

I2 139 

I3 137 

LDL–C % change at 3 

wk relative to placebo: 

I1↓11.3* 

I2↓13.4* 

I3↓16.0* 

*p < 0.05 

No significant difference 

between I1, I2 and I3

Christiansen et al., 2001 

(Ref. 24).

Randomized doubleblind, parallel design; 

three arm, 6-wk run-in, 

6-month test period 

Hypercholesterolemic 

adults 

155 enrolled, 134 completed 

Mean age 50.7 y 

n = about 45/group 

Inclusion criteria: total-C 

≥ 227 mg/dL, TG < 

266 mg/dL 

Finland 

2 servings/d of test 

spread (rapeseed oil 

margarine) in place of 

usual dietary fat 

C = spread w/o added 

PS 

I1 = 1.5g PS/d as microcrystalline wood-derived (tall oil) 

nonesterified sterol/ 

stanols in PS-enriched 

spread 

I2 = 3 g PS/d as microcrystalline wood-derived (tall oil) 

nonesterified sterol/ 

stanols in PS-enriched 

spread 

Habitual Finnish diet; 7- 

day food diaries ‘‘were 

kept by half of subjects.’’ 

Total-C (mg/dL) Baseline: 

257 

Total-C % change compared to control: 

I1 ↓ 9%* 

I2 ↓ 8.3%* 

*p=0.001 

LDL–C (mg/dL) Baseline: 

166 

LDL–C % change compared to control: 

I1 ↓ 11.3%* 

I2 ↓ 10.6%* 

*p=0.002 

Davidson et al., 2001 

(Ref. 55).

Randomized doubleblind, parallel trial; four 

arm, 8-wk test period 

Healthy adults 

84 randomized 77 completed 

Mean Age 46 y 

n = 19 (C) 

n = 19 (I1) 

n = 18 (I2) 

n = 21 (I3) 

Inclusion criteria: total-C 

< 300 mg/dL, TG < 

350 mg/dL, BMI < 35 

USA 

2 servings/d of reducedfat test spread, and 1 

serving/d of reducedfat test salad dressing 

C = spread + salad 

dressing 

I1 = 3 g PS/d as sterol 

esters in PS-enriched 

spread; placebo salad 

dressing 

I2 = 6 g PS/d as sterol 

esters in PS-enriched 

salad dressing; placebo spread 

I3 = 9 g PS/d as sterol 

esters in PS-enriched 

spread + PS-enriched 

salad dressing 

Habitual diet supplemented w/3 servings/d 

of test foods. 3-day 

diet records collected 

at wk 0, 4, and 8 

Total-C (mg/dL) Baseline: 

205 

Total-C % change compared to control: 

I1 ↓ 3.9% 

I2 ↓ 0.9% 

I3 ↓ 4.6% 

LDL–C (mg/dL) Baseline: 

130 

LDL–C % change compared to control: 

C ↓ 1.3% 

I1 ↓ 3.7% 

I2 ↓ 1.5% 

I3 ↓ 7.7% 

No significant treatment 

effects on total-C or 

LDL–C 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 76565 

TABLE 1—RANDOMIZED CLINICAL TRIALS OF PHYTOSTEROLS IN CONVENTIONAL FOODS AND TOTAL AND LDL 

CHOLESTEROL CONCENTRATION—Continued 

Study Design Population Intervention Diet Results 

Maki et al., 2001 (Ref. 

101).

Randomized doubleblind, placebo-controlled, parallel trial, 4- 

wk run-in; 5-wk test 

period 

Hypercholesterolemic 

adults 

224 enrolled, 192 included in analysis 

n = 83 (C) 

n = 75 (I1) 

n = 35 (I2) 

Mean age ± sd 

57.5 ± 10.8 y (C) 

58.7 ± 10.6 y (I1) 

60.4 ± 9.7 y (I2) 

Inclusion criteria: no RX

that affect lipids, BMI < 

35, LDL–C 130–200 

mg/dL, TG < 350 mg/ 

dL, BMI < 35 

USA 

2 servings/d of reducedfat test spread eaten 

w/meals 

C = spread with w/o 

added PS 

I1 = 1.1 g PS/d as soy 

sterol esters in PS-enriched spread 

I2 = 2.2 g PS/d as soy 

sterol esters in PS-enriched spread 

National Cholesterol Education Program Step I, 

supplemented w/reduced-fat test spread 

Total-C (mg/dL) Baseline: 

238 

Total-C % change compared to control: 

I1 ↓ 5.2%* 

I2 ¥ 6.6%* 

*p < 0.001 

LDL–C (mg/dL) Baseline: 

158 

LDL–C % change compared to control: 

I1 ↓ 7.6%* 

I2 ↓ 8.1%* 

*p < 0.001 

Nestel et al., 2001 (Ref. 

35).

Randomized single-blinded, crossover trial; 2- 

wk run-in, three 4-wk 

test periods w/o washout period 

Study 1 

Hypercholesterolemic 

adults 

22 enrolled, 22 completed 

Mean age ± sd 

60 ± 9 y 

n = 22 

Inclusion criteria: Total-C 

>213 mg/dL, TG < 266 

mg/dL 

Australia 

3 servings/d of test foods 

(low-fat wheat cereal, 

low-fat bread, spread), 

one serving eaten w/ 

each meal 

C = test foods, w/o 

added phytosterols 

I1 = 2.4 g PS/d as soy 

sterol esters in PS-enriched foods 

I2 = 2.4 g PS/d as 

nonesterified soy 

stanols in PS-enriched 

foods 

Habitual low sat fat, low 

cholesterol diet prescribed for cholesterol 

control; diet assessed 

by 3-day FFQ during 

run-in phase 

Median Total-C (mg/dL) 

at 4 wk: 

C 271 

I1 247* 

I2 261* 

*p < 0.001 compared to 

control 

Median LDL–C (mg/dL) 

at 4 wk: 

C 184 

I1 159* 

I2 169* 

*p < 0.05 compared to 

control 

I1 significantly lower than 

I2

Randomized single-blinded, crossover trial; 2- 

wk run-in followed by 

two 4-wk test periods 

w/o wash-out period 

Study 2 

Hypercholesterolemic 

adults (all Study 1 participants) 

15 enrolled, 15 completed 

Australia 

1 serving/d of test dairy 

spread (butter + margarine blend) eaten w/ 

a meal 

C = spread w/o added 

PS 

I3 = 2.4 g PS/d as soy 

sterol esters in PS-enriched dairy spread 

Habitual low sat fat, low 

cholesterol diet prescribed for cholesterol 

control 

Total-C (mg/dL) Baseline: 

257 

Total-C % change compared to control: I3 ↓ 

9.8%* 

*p < 0.001 

LDL–C (mg/dL) Baseline: 

178 

LDL–C % change compared to control: I3 ↓ 

13.0%* 

*p = 0.05 

Tikkanen 2001 (Ref. 25) .. Double-blind, placebocontrolled, parallel trial, 

two arms; 2-wk run-in 

period w/placebo 

foods, 3 consecutive 5- 

wk periods. PS dose 

doubled w/each successive test period 

Hypercholesterolemic 

adults 

78 enrolled, 71 completed 

Mean age ± sd 

54 ± 11 y (C) 

57 ± 8 y (I) 

n = 35 (C) 

n = 36 (I) 

Inclusion criteria: age 

25–75 y; no familial 

↑total-C, no HX of CAD 

previous 3 mos, no HX

of revascularization 

previous 4 mo, no RX

that affect lipids, totalC 232–310 mg/dL; TG 

< 355 mg/dL 

Finland 

3 servings/d of test 

foods/d (bread, meat, 

jam) 

C = test foods w/o added 

PS 

I=1.25 g PS/d for 5 wk, 

then 2.5 g PS/d for 

wks 6–10, then 5 g 

PS/d for wks 11–15. 

PS as nonesterified 

wood-derived sterol/ 

stanol mixture in PSenriched bread, meats, 

and jam 

Subjects received individual dietary advice 

and kept 3-d food diaries 5 times during the 

study 

Total-C (mg/dL) Baseline: 

C 253 

I 263 

Total-C % change compared to control: 

I wk5 ↓ 4.4% 

I wk10 ↓ 6.2% 

I wk15 ↓ 5.5% 

Significant difference between P and I by repeated measures 

ANOVA p < 0.05 

LDL–C (mg/dL) Baseline: 

C 166 

I 173 

LDL–C % change compared to control: 

I wk5 ↓ 5.4% 

I wk10 ↓ 7.9% 

I wk15 ↓ 8.9% 

Significant difference between C and I by repeated measures 

ANOVA p < 0.05 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
76566 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

TABLE 1—RANDOMIZED CLINICAL TRIALS OF PHYTOSTEROLS IN CONVENTIONAL FOODS AND TOTAL AND LDL 

CHOLESTEROL CONCENTRATION—Continued 

Study Design Population Intervention Diet Results 

Blair et al., 2000 (Ref. 

102).

Randomized doubleblind, placebo-controlled, parallel trial, 

two arms; 8-wk test 

period with additional 

6-wk follow-up 

Hypercholesterolemic 

adults on statin RX

167 randomized, 141 

completed 

Mean age ± sd 

56 ± 10 y 

n = 72 (C) 

n = 69 (I) 

Inclusion criteria: age 

≥20 y; LDL–C ≥130 

mg/dL, TG ≤350 mg/ 

dL, stable statin dose 

for >90d 

USA 

3 servings/d of test margarine in place of usual 

margarine consumptions 

C = margarine w/o added 

PS 

I = 3.0g PS/d as stanol 

esters in PS-enriched 

margarine 

Habitual diet. Diets assessed by 24-hr recalls Total-C (mg/dL) Baseline: 

231 

Total-C % change compared to control: I ↓ 

7% (p < 0.0001) 

LDL–C (mg/dL) Baseline: 

147 

LDL–C % change compared to control: I ↓ 

9.6% (p < 0.0001) 

Hallikainen et al., 2000B 

(Ref. 39).

Randomized doubleblind, crossover trial; 2- 

wk run-in period; three 

consecutive 4-wk test 

periods 

Mildly 

hypercholesterolemic 

adults 

42 enrolled, 34 completed 

Mean age ± sd 

48.8 ± 8.1 y 

n = 34 

Inclusion criteria: age 

30–65 y, Total-C 186– 

271 mg/dL, TG < 220 

mg/dL 

Finland 

2–3 portions/d of test 

margarines eaten with 

meals 

C = margarine w/o added 

PS 

I1 = 2 g PS/d as plant 

stanol ester in PS-enriched margarine 

I2 = 2 g PS/d as plant 

sterol ester in PS-enriched margarine 

Step I diet. Diet was assessed with 4-day food 

records at the end of 

each period 

Total-C (mg/dL) At end of 

4 wk: 

C 236 

I1 213 

I2 218 

Total-C % change compared to control: 

I1 ↓ 9.2%* 

I2 ↓ 7.3%* 

*p < 0.001 

LDL–C (mg/dL) At end of 

4 wk: 

C 162 

I1 141 

I2 145 

LDL–C % change compared to control: 

I1 ↓ 12.7%* 

I2 ↓ 10.4%* 

*p < 0.001 

I1 and I2 not significantly 

different 

Hallikainen et al., 2000a 

(Ref. 53).

Randomized single-blind 

crossover trial; 1-wk 

run-in period, five 3-wk 

test periods 

Hypercholsterolemic 

adults 

22 entolled, 22 completed 

Mean age 50.5 ± 11.7 

n = 22 

Inclusion criteria: Total-C 

194–329 mg/dL 

Finland 

2–3 portions of test margarine w/meals 

C = margarine w/out 

added PS 

I1 = 0.8 g PS/d as plant 

stanol esters 

I2 = 1.6 g/d PS/d as plant 

stanol esters 

I3 = 2.4 g PS/d as plant 

stanol esters 

I4 = 3.2 g PD/d as plant 

stanol esters 

Subjects consumed a 

standardized background diet 

Total-C (mg/dL) Baseline: 

266 ± 50 mg/dL0 

Total-C % change compared to control: 

I1 ↓ 2.8% 

I2 ↓ 6.8%* 

I3 ↓ 10.3%* 

I4 ↓ 11.3%* 

LDL–C % change compared to control: 

I1 ↓ 1.7% 

I2 ↓ 5.6% 

I3 ↓ 9.7%* 

I4 ↓ 10.4%* 

*p < 0.05 

Jones et al., 2000 (Ref. 

40).

Randomized doubleblind, crossover trial; 

no run-in period; three 

3-wk controlled feeding 

test periods separated 

by 5-wk washout periods 

Hyperlipidemic males 

18 enrolled, 15 included 

in analyses 

n = 15 

Inclusion criteria: Age 

37–61 y; Total-C 232– 

387 mg/dL, TG < 266 

mg/dL 

Canada 

3 servings/d of test margarine, eaten with 

meals 

C = margarine w/o added 

PS 

I1 = 1.84 g PS/d as plant 

sterol esters in PS-enriched margarine 

I2 = 1.84 g PS/d as plant 

stanol esters in PS-enriched margarine 

Controlled diet formulated to meet Canadian 

Recommended Nutrient Intakes. All food 

and beverage prepared/provided by 

study; at least 2 meals/ 

d eaten onsite 

Total-C (mg/dL) Baseline: 

C 250 

I1 247 

I2 246 

Total-C % change compared to control: 

I1 ↓ 9.1%* 

I2 ↓ 5.5% 

*p < 0.02 

LDL–C (mg/dL) Baseline: 

C 172 

I1 166 

I2 168 

LDL–C % change compared to control: 

I1 ↓ 13.2%* 

I2 ↓ 6.4%* * 

*p < 0.02 

I1 significantly lower than 

I2


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 76567 

TABLE 1—RANDOMIZED CLINICAL TRIALS OF PHYTOSTEROLS IN CONVENTIONAL FOODS AND TOTAL AND LDL 

CHOLESTEROL CONCENTRATION—Continued 

Study Design Population Intervention Diet Results 

Plat et al. 2000 (Ref. 87) Randomized doubleblind, placebo-controlled, crossover trial. 

Three consecutive 4- 

wk test periods, no 

washout periods 

Healthy, normal or mildly 

hypercholesterolemic 

subjects 

40 enrolled, 39 completed 

Mean age ± sd 

31 ± 14 y 

n = 39 

Inclusion criteria: age 

18–65 y; Total-C < 250 

mg/dL; TG < 266; BMI 

< 30, BP < 160/95, no 

RX or diet that affect 

lipids, no HX of CVD 

The Netherlands 

One serving/d of test 

margarine and 3 

servings/d of test 

shortening (in cookies/ 

cakes) with each 

meals 

C = margarine & shortening w/o added PS 

I1 = 2.5 g PS/d as stanol 

ester in PS-enriched 

margarine eaten w/ 

lunch 

I2 = 2.5 g PS/d as stanol 

ester in PS-enriched 

margarine and PS-enriched shortening divided over 3 servings 

w/meals 

Habitual diets supplemented w/test margarine and test cookies/cake. PS-free 

shortening was provided to subjects for 

baking and cooking 

Total-C (mg/dL) 

At end of 4 wk: 

C 194 

I1 182 

I2 181 

Total-C % change compared to control: 

I1 ↓ 6.4%* 

I2 ↓ 6.6%* 

*p < 0.001 

LDL–C (mg/dL) At end of 

4 wk 

C 118 

I1 106 

I2 106 

LDL–C % change compared to control: 

I1 ↓ 9.9%* 

I2 ↓ 10.2%* 

*p < 0.001 

Vissers et al., 2000 (Ref. 

36).

Double-blind, crossover 

trial; no run-in period; 

three consecutive 3-wk 

test periods 

Normal adults 

60 enrolled, 60 completed 

age range=18–59 y 

n = 60 

Inclusion criteria: age 

>17 y; no RX or prescribed diet that affect 

lipids, Total-C < 290 

mg/dL, TG < 204 mg/ 

dL 

The Netherlands 

Test margarine, divided 

over multiple portions, 

eaten with meals in 

place of usual margarine 

C = margarine without 

added PS 

I1 = 2.1 g PS/d as rice 

bran nonesterified oil 

sterols in PS-enriched 

margarine (∼1 g/d of 4- 

desmethylsterols) 

I2 = sheanut oil 

triterpenes in margarine 

Habitual diets. Diet assessed each period 

with 24-h diet recall 

Total-C (mg/dL) At end of 

3 wks: 

C 164 

I1 157 

I2 162 

Total-C % change compared to control: 

I1 ↓ 4.5%* 

I2 ↓ 1.2% 

*p < 0.05 

LDL–C (mg/dL) At end of 

3 wks: 

C 91 

I1 84 

I2 89 

LDL–C % change compared to control: 

I1 ↓ 8.5%* 

I2 ↓ 3.0% 

*p < 0.05 

Andersson et al., 1999 

(Ref. 103).

Randomized double blind 

controlled parallel trial; 

4-wk run-in period, 

three 8-wk test periods 

Moderately 

hypercholesterolemic 

adults 

Age ± sd 

55.1 ± 7.9 y 

n = 21 (C) 

n = 19 (I) 

Inclusion criteria: Total-C 

< 330 mg/dL, BMI >30 

Sweden 

25 g/d margarine provided as 3 single 

servings 

C = margarine w/o added 

PS 

I1 = 2 g PS/d as plant 

stanol esters in PS-enriched margarine 

Consumed a test diet ..... Total-C % change compared to baseline 

C ↓ 8.0% 

I1 ↓ 15%* 

*p = 0.0035 

LDL–C % change compared to baseline 

C ↓ 12% 

I1 ↓ 19%* 

*p = 0.0158 

Ayesh et al., 1999 (Ref. 

104).

Randomized placebocontrolled parallel trial; 

21 to 28 d run-in, 21– 

28 d test period 

Healthy adults 

24 enrolled, 21 completed 

Age 30–40 y 

n = 11 (C) 

n =10 (I) 

Inclusion criteria: Total-C 

158–255 mg/dL 

United Kingdom 

40 g/d margarine consumed at breakfast 

and dinner 

C = margarine w/o added 

PS 

I = 8.6 g PS/d as plant 

sterol esters in PS-enriched margarine 

Typical British diet, 

breakfast and dinner 

consumed under supervision 

Total-C % change compared to control: 

I ↓ 18%* 

LDL–C % change compared to control: 

I ↓ 23%* 

*p < 0.0001 

Gylling and Miettinen, 

1999 (Ref. 105).

Randomized double-blind 

crossover trial; 1-wk 

run-in period; two 5 wk 

test periods 

Moderately 

hypercholesterolemic, 

postmenopausal 

women; 24 enrolled 

Age 50–55 y 

n = 21 butter period 

Inclusion criteria: Total-C 

between 213 and 310 

mg/dL 

Finland 

25 g/d butter 

C = butter w/out added 

PS 

I = 2.4 g PS/d as wood 

sitostanol ester in PSenriched butter 

Subjects were advised to 

replace 25 g of their 

normal dietary fat with 

butter 

Total-C % change compared to control: 

I ↓ 8%* 

LDL–C % change compared to control: 

I ↓ 12%* 

*p < 0.05 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
76568 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

TABLE 1—RANDOMIZED CLINICAL TRIALS OF PHYTOSTEROLS IN CONVENTIONAL FOODS AND TOTAL AND LDL 

CHOLESTEROL CONCENTRATION—Continued 

Study Design Population Intervention Diet Results 

Hendriks et al., 1999 

(Ref. 51).

Randomized, doubleblind, crossover trial; 

no run-in period, four 

test periods of 3.5 wks 

Normocholesterolemic 

and mildly 

cholesterolemic adults, 

100 enrolled, 80 per 

test period 

Age 19–58 y 

n = 80 

Inclusion criteria: Total-C 

< 290 mg/dL 

The Netherlands 

25 g/d butter or spread 

consumed at lunch or 

dinner 

C1 = butter w/out added 

PS 

C2 = spread w/out added 

PS 

I1 = 0.8 g PS/d as plant 

sterol esters in PS-enriched spreads 

I2 = 1.6 g PS/d as plant 

sterol esters in PS-enriched spreads 

I3 = 3.2 g PS/d as plant 

sterol esters in PS-enriched spreads 

Habitual diets. Spreads 

replace an equivalent 

amount of spreads habitually used 

Total-C (mg/dL) Baseline: 

197 mg/dL 

Total-C % change compared to C2

I1 ↓ 4.9%* 

I2 ↓ 5.9%* 

I3 ↓ 6.8%* 

LDL–C % change compared to C2

I1 ↓ 6.7%* 

I2 ↓ 8.5%* 

I3 ↓ 9.9%* 

*p < 0.0001 

Jones et al., 1999 (Ref. 

21).

Randomized doubleblind, placebo-controlled, parallel trial 

with 2 groups; No runin period; 30-d test period; 20-d follow-up 

after test period 

Hypercholsterolemic 

adults, 32 enrolled, 32 

completed 

Age 25–60 y 

n = 16 (C) 

n = 16 (I) 

Inclusion criteria: Total-C 

252–387 mg/dL 

Canada 

30 g/d test margarine 

consumed with 3 

meals 

C = margarine w/o added 

PS 

I = 1.7 g PS/d 

sistostanol-containing 

phytosterols (20% 

sitostanol, remaining 

plant sterols are sitosterol, campesterol) as 

nonesterified tall oil 

Controlled feeding regimen; a prudent fixed 

North American diet 

formulated to meet Canadian recommended 

nutrient intakes 

Total-C (mg/dL) Baseline: 

C 263 

I 260 

LDL–C % change compared to control: I ↓ 

15.5% (p < 0.05) 

Nguyen et al., 1999 (Ref. 

106).

Multicenter randomized, 

double-blind, placebocontrolled parallel trial; 

4-wk run-in period, 8- 

wk test period 

Mildly 

hypercholesterolemic 

adults 

Age ± sd 

51.3 ± 12.0 to 54.5 ± 

11.3 y 

n = 76 (C) 

n = 71 (I1) 

n = 77 (I2) 

Inclusion criteria: 20 y, 

Total-C 200 and 280 

mg/dL 

USA 

24 g/d U.S. vegetable oil 

spread (three 8 g 

servings/d) 

C = U.S. vegetable oil 

spread w/out added 

PS 

I1 = 3 g PS/d as stanol 

esters in U.S. vegetable oil spread 

I2 = 2 g PS/d as stanol 

esters in U.S. vegetable oil spread 

Usual dietary habits 

maintained 

Total-C % change compared to control: 

I1 ↓ 6.4* 

I2 ↓ 4.1* 

*p < 0.001 

LDL–C % change compared to control: 

I1 ↓ 10.1* 

I2 ↓ 4.1* 

*p < 0.02 

Sierksma et al., 1999 

(Ref. 29).

Balanced, double-blind 

crossover trial; 1-wk 

run-in, 3-wk test period 

Healthy adults, 78 enrolled, 76 completed 

Age 18–62 y 

n = 75 

Inclusion criteria: < TotalC < 309 mg/dL 

The Netherlands 

25 g/d Flora spread, with 

meals 

C = Flora spread w/o 

added PS 

I1 = 0.8 g PS/d as 

nonesterified sterols in 

PS-enriched Flora 

spread 

I2 = 3.3 g PS/d as 

esterified sterols in PSenriched Flora spread 

Habitual diets. Phytosterol-containing spread 

replaced all or part of 

habitual spread or butter used for spreading 

Total-C (mg/dL) Baseline: 

310 mg/dL 

Total-C (mg/dL) 

C 196 

I1 188* 

I2 194 

LDL–C (mg/dL) 

C 122 

I1 114* 

I2 119 

Total-C % change compared to control: 

I1 ↓ 3.8%* 

LDL–C % change compared to control: 

I1 ↓ 6.0%* 

*p < 0.05 

Westrate and Meijer, 

1998 (Ref. 31).

Balanced, Randomized 

double-blind crossover 

trial; 5-d run-in, four 

test periods of 3.5 wks 

Normocholesterolemic 

and mildly 

hypercholesterolemic 

adults, 100 enrolled, 

95 completed 

Mean age ± sd 

45 ± 12.8 y 

n = 95 

Inclusion criteria: Total-C 

< 310 mg/dL 

The Netherlands 

30 g/d margarine consumed at lunch and 

dinner 

C = Flora spread w/o 

added PS 

I1 = 2.7 g PS/d as plant 

stanol esters (2.7 g/d 

I2 = 3.0 g PS/d as soybean sterol esters 

I3 = 1.6 g PS/d as rice 

bran nonesterified 

sterols 

I4 = 2.9 g PS/day as 

sheanut nonesterified 

sterols 

Stanol source: wood 

Test margarine replaced 

margarines habitually 

used 

Total-C (mg/dL) Baseline: 

207 

Total-C % change compared to control: 

I1 ↓ 7.3%* 

I2 ↓ 8.3%* 

I3 ↓ 1.1% 

I4 ↓ 0.7% 

LDL–C % change compared to control: 

I1 ↓ 13%* 

I2 ↓ 13%* 

I3 ↓ 1.5% 

I4 ↓ 0.9% 

*p < 0.05 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 76569 

TABLE 1—RANDOMIZED CLINICAL TRIALS OF PHYTOSTEROLS IN CONVENTIONAL FOODS AND TOTAL AND LDL 

CHOLESTEROL CONCENTRATION—Continued 

Study Design Population Intervention Diet Results 

Niinikoski et al., 1997 

(Ref. 107).

Randomized doubleblind, placebo-controlled parallel trial; no 

run-in period, 5-wk test 

period 

Normocholesterolemic 

adults, 24 enrolled 

Age 24–52 y 

n = 12 (C) 

n = 12 (I) 

Inclusion criteria: not provided 

Finland 

24 g margarine consumed in 3 portions 

C = margarine w/out 

added PS 

I = 3 g PS/day as 

esterified sitostanol 

Habitual diet. Replace 

normal dietary fat with 

test rapeseed oil margarine 

Total-C (mg/dL) Baseline: 

197 

Total C % compared to 

control 

C ↓ 11 

I ↓ 31* 

*p < 0.05 

Pelletier et al., 1995 (Ref. 

30).

Randomized, crossover 

trial; 1-wk run-in, two 

test periods of 4 wks 

Normolipidemic men 

Mean age ± sd 

22.7 ± 2.6 y 

n = 12 

Inclusion criteria: light 

smokers and normal 

physical activity 

France 

50 g/d butter as part of a 

normal diet 

C =butter w/out added 

PS 

I = 0.74 g PS/d as soybean nonesterified 

sterols 

Controlled but normal 

diet 

Total-C % change compared to control: 

I ↓ 10%* 

LDL–C % change compared to control: 

I ↓ 15%* 

*p < 0.05 

Miettinen et al., 1994 

(Ref. 28).

Randomized doubleblind, placebo-controlled parallel trial; 6- 

wk run-in, 9-wk test 

period 

Hypercholesterolemic 

adults, 31 enrolled 

Mean age ± sd 

45 ± 3 y 

n = 31 

Inclusion criteria: Total-C 

>232 mg/dL 

Finland 

50 g rapeseed oil mayonnaise, with meals 

C = mayonnaise w/out 

added PS 

I1 = 0.7 g PS/d as 

nonesterified sitosterol 

in mayonnaise 

I2 = 0.7 g PS/d as 

nonesterified sitostanol 

in mayonnaise 

I3 = 0.8 g PS/d as 

sitostanol ester in mayonnaise 

Habitual diets. Advised to 

replace 50 g of typical 

daily fat with mayonnaise containing 

rapeseed oil 

Total-C % change compared to control: 

I1 ↓ 7.7% 

I2 ↓ 0.4% 

I3 ↓ 7.4%* 

LDL–C % change compared to control: 

I1 ↓ 7.0% 

I2 ↓ 1.2% 

I3 ↓ 7.7%* 

*p < 0.05 

Blomqvist et al., 1993 

Vanhanen et al., 1993 

(Ref. 108).

Randomized double-blind 

placebo controlled parallel trial; 4-wk run-in, 

6-wk test period 

Hypercholesterolemic 

adults, 37 enrolled 

Mean age ± sd 

43–48 ± 2 y 

n = 33 (C) 

n =34 (I) 

Inclusion criteria: Total-C 

>232 mg/dL 

Finland 

50 g rapeseed oil mayonnaise, with meals 

C = mayonnaise w/out 

added PS 

I = 3.4 g PS/d as sitosterol ester in 

mayonniase 

Habitual diets. Advised to 

replace 50 g of daily 

fat intake with 50 of 

mayonnaise containing 

rapeseed oil 

Total-C % change compared to control: 

C ↓ 2.7 

I ↓ 17.0* 

LDL–C % change compared to control: 

C ↓ 1.5 

I ↓ 14.3* 

*p < 0.051 

1Weight 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-blinded, 3 sequential 3-mos 

trial periods separated 

by 3-mos washout periods.

Moderately 

hypercholesterolemic 

males.

33 enrolled, 33 completed 

Age range 31–70 y 

Subjects’ characteristics: 

mean LDL–C with Step 

I diet 175 mg/dL, TG < 

250 mg/dL, mean BMI 

26.2 

USA 

(1) Gelatin capsules containing tall oil sitostanol 

suspended in safflower 

oil; 3 doses/d of 4 capsules (total 12 capsules/d) taken with 

meals. (2) 

Cholestyramine supplied in flavored bars.

I1 = 3 g/d sitostanol1

I2 = cholestyramine 

I3 = sitostanol + 

cholestyramine 

Step I diet (control) during intervention and 

washout periods.

Total-C (mg/dL) Baseline: 

239 

Total-C % change compared to Step I diet: 

I1 ↓ 0.5% 

I2 ↓ 7.1%* 

I3 ↓ 8.9%* 

LDL–C (mg/dL) Baseline: 

175 

LDL–C % change from 

Sep 1 diet: 

I1 ↓ 1.8% 

I2 ↓ 12.6%* 

I3 ↓ 14.8%* 

*p < 0.001 compared 

to preceding and 

subsequent washout 

periods. 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
76570 Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 

TABLE 2—RANDOMIZED CLINICAL TRIALS OF PHYTOSTEROLS IN SUPPLEMENTS AND TOTAL AND LDL CHOLESTEROL

CONCENTRATION—Continued 

Study Design Population Intervention Diet Results 

McPherson et al., 2005 

(Ref. 66).

Randomized, double 

blind, placebo-controlled, parallel design; 

four arms; 6-wk trial 

period.

Healthy adults 52 enrolled, 52 completed.

Mean age ± sd 46.5 ± 

8.1 y (tablets) 

50.7 ± 12.5 y (capsules) 

tablet trial 

n = 13 (IT) 

n = 12 (PT) 

n = 27 (capsule trial) 

Inclusion criteria: LDL– 

C 70–190 mg/dL, TG 

< 300 mg/dL 

USA 

Dietary supplement of 

rapidly disintegrating 

tablets or slowly disintegrating capsules, 

twice/d with meals.

CT = lecithin-containing 

tablets w/o PS.

CC = lecithin-containing 

capsules w/o PS.

IT = 1.26 g PS/d as 

spray-dried plant 

stanol/lecithin emulsion 

in tablets.

IC = 1.26 g PS/d as 

spray-dried plant 

stanol/lecithin emulsion 

in gelatin capsules.

AHA heart healthy diet ... Total-C (mg/dL) Baseline: 

CT 195 

IT 186 

CC 198 

IC 203 

Total-C % change compared to control: 

IT ↓ 4.8% 

IC ↓ 1.9% 

No significant differences 

between IT and IC and 

control 

LDL–C (mg/dL) Baseline: 

CT 121 

IT 117 

CC 123 

IC 235 

LDL–C % change relative 

to placebo: 

IT ↓ 10.4%* 

IC ↓ 2.5% 

* p < 0.05 compared to 

placebo 

Goldberg et al., 2006 

(Ref. 67).

Randomized doubleblind, placebo-controlled, parallel trial, 1- 

wk run-in, 6-wk test 

period.

Hyperlipidemic adults 

taking statins 26 enrolled, 26 completed..

age range 40–78 y 

n = 13/group 

Inclusion criteria: Stable 

statin dose, LDL–C 

>100 mg/dL, TG < 300 

mg/dL 

USA 

Soy stanols as a tableted 

stanol/lecithin emulsion. 225 mg PS/tablet; 

4 tablets twice a day 

before meals. Starch 

replaced stanol/lecithin 

complex in placebo 

tablets.

C = placebo tablet 

I = 1.8 g PS/d as stanol/ 

lecithin emulsion in 

tablets 

American Heart Association Heart Healthy Diet.Total-C (mg/dL) Baseline: 

C 197 

I 193 

Total-C % change compared to control: 

I ↓ 5.7% (p < 0.05) 

LDL–C (mg/dL) Baseline: 

C 119 

I 112 

LDL–C % change compared to placebo: 

I ↓ 9.1% (p < 0.05) 

Esterified Phytosterols 

Woodgate et al., 2006 

(Ref. 64).

Randomized, doubleblind, placebo-controlled trial with 2 

groups; 4-wk test period.

Hyperchoelsterolemic 

adults, 30 enrolled, 29 

completed.

Age 33–70 y 

Inclusion criteria: no diabetes, no cholesterol 

lowering Rx, no prior 

myocardial infarction or 

heart surgery 

Total of 6 softgel 

(glyceron) capsules 

with breakfast and dinner.

C = corn oil 

I = 1.6 g PS/d as stanol 

esters 

Habitual diets Total-C (mg/dL) Baseline: 

C 266 

I 267 

Total-C % change compared to control 

I ↓ 8% (p < 0.05) 

LDL–C (mg/dL) Baseline: 

C 207 

I 201 

LDL–C % change compared to control 

I ↓ 9% (p < 0.05) 

Acuff et al., 2007 

(Ref. 62).

Randomized, doubleblind, placebo-controlled, sequential trial; 

two 4-wk test periods 

separated by 2-wk 

washout period.

Hypercholesterolemic 

adults, 20 enrolled, 16 

completed.

Mean age ± sd 

51 ± 13 y 

Inclusion criteria: 

hyperlipidemia, BMI < 

30, no lipid lowering 

RX, no diseases requiring tmt, no hypertension 

USA 

2 dietary supplement 

capsules/d, one capsule w/lunch, second 

capsule w/dinner.

C = soy oil capsules. 

I = 0.8 g PS/d as plant 

sterol esters divided 

between 2 capsules 

Habitual diets, diets not 

monitored.

Total-C (mg/dL) Baseline: 

256 

After 4 wk test period: 

C 242 

I 230 

Total-C % change compared to control: 

I ↓ 4.7% (not significant) 

LDL–C (mg/dL) Baseline: 

177 

After 4 wk test period: 

C 169 

I 163 

LDL–C % change compared to control: 

I ↓ 3.5% (p < 0.05) 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2
Federal Register / Vol. 75, No. 235 / Wednesday, December 8, 2010 / Proposed Rules 76571 

TABLE 2—RANDOMIZED CLINICAL TRIALS OF PHYTOSTEROLS IN SUPPLEMENTS AND TOTAL AND LDL CHOLESTEROL

CONCENTRATION—Continued 

Study Design Population Intervention Diet Results 

Earnest et al., 2007 

(Ref. 63).

Randomized doubleblind, placebo-controlled, parallel trial 

with 2 groups; 12-wk 

test period.

Mildly 

hypercholesterolemic 

adults.

54 enrolled, 54 completed 

Age 20–70 y 

Inclusion criteria: LDL–C 

≥130 mg/dL 

USA 

4 dietary supplement 

capsules/d; 2 capsules 

w/each of 2 meals.

C = capsule w/o PS 

I = 2.6 g PS/d as plant 

sterol esters divided 

among 4 capsules 

Habitual diets, diets not 

monitored.

Total-C (mg/dL) Baseline: 

C 232 

I 243 

After 4 wk test period: 

C 237 

I 234 

Total-C % change compared to control: 

I ↓ 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 ↓ 9.2% (p < 0.05) 

Rader and Nguyen, 2000 

(Ref. 61).

Randomized, doubleblind, placebo-controlled, parallel trial, 

two arm. 3-wk trial period.

Hypercholesterolemic 

adults; 160 enrolled, 

156 completed.

n = 156 

Inclusion criteria: Total-C 

220–300 mg/dL; TG 

≤350 mg/dL; good 

health 

USA 

3 dietary supplement test 

capsules/d with meals.

C = placebo capsules w/ 

o PS 

I = 1 g PS/d as plant 

stanol esters divided 

over 3 capsules 

Habitual diets Total-C (mg/dL) Baseline: 

P 245 

I 248 

Total-C % change compared to control: 

I ↓ 3.0% (p < 0.05) 

LDL–C (mg/dL) Baseline: 

C 154 

I 155 

LDL–C % change compared to control: 

I ↓ 5.2% (p < 0.05) 

1Weight 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 


jlentini on DSKJ8SOYB1PROD with PROPOSALS2