[Federal Register Volume 66, Number 194 (Friday, October 5, 2001)]
[Rules and Regulations]
[Pages 50824-50826]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-25106]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 101

[Docket Nos. 00P-1275 and 00P-1276]


Food Labeling: Health Claims; Plant Sterol/Stanol Esters and 
Coronary Heart Disease

AGENCY: Food and Drug Administration, HHS.

ACTION: Interim final rule; reopening of comment period.

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[[Page 50825]]

SUMMARY: The Food and Drug Administration (FDA) is reopening for 45 
days the comment period for the interim final rule authorizing a health 
claim on the association between plant sterol/stanol esters and reduced 
risk of coronary heart disease (CHD). This interim final rule appeared 
in the Federal Register of September 8, 2000 (65 FR 54686). Interested 
persons were given until November 22, 2000, to comment on the health 
claim. After the comment period closed, FDA received two requests to 
reopen the comment period; therefore, this reopening is in response to 
these requests.

DATES: Submit written or electronic comments by November 19, 2001.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments.

FOR FURTHER INFORMATION CONTACT: James Hoadley, Center for Food Safety 
and Applied Nutrition (HFS-832), Food and Drug Administration, 200 C 
St. SW., Washington, DC 20204, 202-205-5429.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of September 8, 2000 (65 FR 54686), FDA 
published an interim final rule authorizing the use, on food labels and 
in food labeling, of a health claim on the relationship between plant 
sterol/stanol esters and reduced risk of CHD (the interim final rule). 
In the interim final rule, FDA specified requirements for a health 
claim about the relationship, including types of food eligible to bear 
the claim, sources and nature of the plant sterol/stanol esters that 
are the subjects of the claim, daily intakes of these substances needed 
to reduce the risk of CHD, and analytical methods for assessing 
compliance with qualifying criteria for the claim. The 75-day comment 
period closed on November 22, 2000.
    After the comment period closed, FDA received comments from two 
companies, Unilever United States, Inc., and Raisio Benecol Ltd., which 
included requests for an extension of the comment period. Both comments 
requested more time for submission of data comparing the daily intake 
levels of plant sterol esters and plant stanol esters that are 
effective in reducing the risk of CHD. Because FDA cannot extend a 
comment period that has closed, the agency considers these as requests 
to reopen the comment period.
    Among the other comments received in response to the interim final 
rule were requests to expand the types of substances eligible for the 
health claim to include unesterified plant sterols/stanols and mixtures 
of plant sterols and plant stanols. We also received a comment 
advocating the use of serum apolipoprotein B level as a surrogate 
measure of CHD risk.
    Furthermore, in the past year, both the European Commission (EC) 
and the Australia New Zealand Food Standards Council (ANZFSC) have 
taken regulatory actions limiting food use of plant sterol esters and 
requiring advisory labeling statements on foods to which plant sterol 
esters have been added. Also, a recent publication from the American 
Heart Association (AHA) (Ref. 1) raised a concern about daily ingestion 
of plant sterol/stanol ester-containing foods among certain individuals 
who have abnormally high absorption of plant sterols.
    FDA believes that the issues raised by comments and recent events 
are significant and that thorough evaluation is needed before a final 
rule is issued. Accordingly, the agency is reopening the comment period 
for this rulemaking. Given the very tight timeframes that are 
established by the health claim provisions of the statute, however (see 
section 403(r)(4)(A)(i) of the Federal Food, Drug, and Cosmetic Act 
(the act) (21 U.S.C. 343(r)(4)(A)(i))), as well as the agency's 
interest in ensuring that scientifically valid claims are authorized as 
quickly as possible, the agency cautions that only on rare occasions 
might FDA be in a position to reopen the comment period in a health 
claim rulemaking. In this case, we believe that reopening the comment 
period to obtain public input on the new issues is important to help us 
make more informed decisions in the final rule. Although the statutory 
deadline for this final rule has passed, FDA intends to move as 
expeditiously as possible to complete this rulemaking.

II. Issues on Which FDA Is Requesting Comment

A. Eligibility of Unesterified Plant Sterols and Plant Stanols for the 
Health Claim

    In the interim final rule, FDA did not include unesterified plant 
sterols and plant stanols in the definition of substances eligible for 
the health claim. Several comments requested that the agency allow 
foods containing the unesterified form of these substances to bear the 
health claim. While some of the data in support of the interim final 
rule were from studies involving unesterified plant sterols or plant 
stanols, the agency requests submission of any additional data on the 
effectiveness, particularly at lower intake levels, of the unesterified 
forms in reducing the risk of CHD. FDA also requests data on the 
effects of various food matrices on the relationship of unesterified 
plant sterols/stanols and CHD risk.

B. Daily Intake Levels Necessary to Reduce the Risk of CHD

    In the interim final rule, FDA required health claims for plant 
sterol/stanol esters to specify the daily intake necessary to reduce 
the risk of CHD. The agency set different daily intake levels for plant 
sterol esters and plant stanol esters (1.3 grams/day (g/d) and 3.4 g/d, 
respectively), based on studies that showed differences in the levels 
of intake that were effective in reducing low-density lipoprotein (LDL) 
and blood total cholesterol levels. Many comments argued that one of 
the daily intake levels should be changed; several comments argued that 
the daily intake levels for plant sterol esters and plant stanol esters 
should be the same. FDA requests further comment on these issues, 
including supporting data on the daily intake levels of plant sterols 
and plant stanols (in either esterified or unesterified form) that are 
effective in reducing the risk of CHD.

C. Eligibility of Mixtures of Plant Sterols and Plant Stanols for the 
Health Claim

    In the interim final rule, FDA authorized separate health claims 
for plant sterol esters and plant stanol esters. One comment requested 
that FDA include mixtures of plant sterols and stanols in the 
definition of substances eligible to bear the health claim. FDA 
requests data on the daily intake levels of mixtures of plant sterol 
esters and plant stanol esters (or mixtures of the unesterified forms) 
that are effective in lowering CHD risk. If plant sterols and plant 
stanols (in either esterified or unesterified form) are not equally 
beneficial at the same levels of intake in reducing CHD risk (as 
evidenced by validated surrogate markers), FDA also requests data on 
the relative amounts of plant sterols and plant stanols (in either 
esterified or unesterified form) in the mixtures that should qualify a 
food to bear the health claim.

D. Significance of Apolipoprotein B Concentration as a Surrogate Marker 
for CHD Risk

    One comment seeking a lower daily effective intake level for plant 
stanol esters, argued that plasma apolipoprotein B level is a reliable 
marker of LDL cholesterol that can be measured precisely and directly, 
in

[[Page 50826]]

contrast to serum LDL cholesterol level, which usually is determined 
indirectly by calculation. The comment further argued that plasma 
apolipoprotein B level is a reliable marker in evaluating the risk of 
cardiovascular disease. These comments were discussed in relation to 
the study by Hallikainen et al. (Ref. 2). In the Hallikainen et al. 
study, the lowest intake of plant stanol esters that reduced serum LDL 
cholesterol was greater than the intake that reduced serum 
apolipoprotein B. Thus, the comment asserted these results support a 
lower daily effective intake level for plant stanol esters than that 
established in the interim final rule.
    FDA requests comment on use of serum apolipoprotein B as a 
validated surrogate marker for CHD and on the relative utilities of 
apolipoprotein B and LDL cholesterol in predicting CHD risk.

E. Issues Regarding Safe Use of Plant Sterol/Stanol Esters in Foods and 
Advisory Label Statements

    Since the issuance of the plant sterol/stanol esters interim final 
rule, FDA has become aware of pertinent regulations from other 
countries. The EC issued a regulation that requires the label of foods 
to which plant sterol esters have been added to include certain 
statements (Ref. 3). Such statements include: (1) The product is for 
people who want to lower their blood cholesterol levels; (2) patients 
on cholesterol lowering medication should consume the product only 
under medical supervision; (3) the product may not be appropriate 
nutritionally for certain segments of the population (pregnant and 
breast-feeding women, and children under the age of 5 years); and (4) 
the product should be used as part of a healthy diet, including regular 
consumption of fruit and vegetables. The EC explained that statements 
(3) and (4) were necessary to protect populations at risk (people whose 
vitamin A status was not optimal) since these products may cause a 
reduction in plasma beta-carotene (Ref. 3).
    The ANZFSC adopted the standard, recommended by the Australia New 
Zealand Food Authority (Ref. 4), that plant sterol esters should be 
allowed for use only in edible oil spreads, and that the product must 
carry an advisory label statement. The advisory label statement informs 
consumers that plant sterol ester-enriched edible oil spreads are not 
appropriate for infants, children and pregnant and lactating women, and 
that people using cholesterol-reducing medication should seek medical 
advice before using the spreads.
    The AHA (Ref. 1) recently published a statement for healthcare 
professionals on foods containing plant sterol/stanol esters. One of 
the issues that the AHA raised concerned individuals who have unusually 
high intestinal absorption of plant sterols. Plant sterols are poorly 
absorbed by the human intestine, but individuals who are homozygous for 
a rare genetic disease, sitosterolemia (also known as phytosterolemia), 
are high absorbers of plant sterols, resulting in tendon and 
subcutaneous xanthomas (skin lipid deposits). It is not known if 
individuals heterozygous for this condition absorb higher amounts of 
plant sterols than the normal population or if this would lead to 
adverse effects. In the absence of more data on the genetic mutation 
involved in sitosterolemia, the AHA recommends that individuals with 
this condition not use foods containing plant sterols/stanols.
    Section 201(n) of the the act (21 U.S.C. 321(n)) 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 or material with respect to consequences that may 
result from use of the product. The omission of material facts from the 
labeling of a food causes the product to be misbranded within the 
meaning of sections 201(n) and 403(a)(1) of the act. FDA may require 
disclosure of material facts in labeling by rulemaking or by direct 
enforcement action (see 21 CFR 1.21).
    In light of the issues raised by recent regulatory actions of other 
countries and by the AHA statement (i.e., whether foods containing 
plant sterol esters should be used under medical supervision, the 
appropriateness of consumption of such foods by some subpopulation 
groups, negative effect of such foods on plasma beta-carotene, and 
concerns about potential hyper-absorption of plant sterols by some 
individuals), FDA is considering whether changes to the health claim 
regulation (Sec. 101.83 (21 CFR 101.83)), advisory labeling, or other 
actions are needed to ensure the safe use of plant sterols and stanols 
(esterified or unesterified) in foods. The agency requests comment on 
whether the concerns summarized above are material facts and what 
action, if any, the agency should take to address them. Depending on 
the comments received and FDA's own evaluation of relevant data, the 
agency may consider issuing a proposal to amend Sec. 101.83 or 
initiating a separate rulemaking, as appropriate.

III. Comments

    Interested persons may submit to the Dockets Management Branch 
(address above) written or electronic comments by November 19, 2001. 
Two copies of any comments are to be submitted, except that individuals 
may submit one copy. Comments are to be identified with the docket 
number found in brackets in the heading of this document. The interim 
final rule and received comments may be seen in the Dockets Management 
Branch between 9 a.m. and 4 p.m., Monday through Friday. Submit 
electronic comments to http://www.fda.gov/dockets/ecomments.

IV. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. Lichtenstein, A. H. and R. J. Deckelbaum for the American 
Heart Association Nutrition Committee, ``Stanol/Sterol Ester-
Containing Foods and Blood Cholesterol Levels. A Statement for 
Healthcare Professionals From the Nutrition Committee of the Council 
on Nutrition, Physical Activity, and Metabolism of the American 
Heart Association,'' Circulation, vol. 103, pp. 1177-1179, 2001.
    2. 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,'' 
Journal of Nutrition, vol. 130, pp. 767-776, 2000.
    3. Commission Decision of July 24, 2000, on ``Authorizing the 
Placing on the Market of `Yellow Fat Spreads with Added Phytosterol 
Esters' as a Novel Food Ingredient under Regulation (EC) No 258/97 
of the European Parliament and of the Council,'' Official Journal L 
200, August 8, 2000, pp. 0059-0060.
    4. Australia New Zealand Food Authority (ANZFA), Food Standard 
Ministers Approve Plant Sterol Esters as a Novel Food Ingredient in 
Edible Oil Spreads, ANZFA Media Release, June 1, 2001, available at 
www.anzfa.gov.au.

    Dated: September 28, 2001.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 01-25106 Filed 10-2-01; 5:03 pm]
BILLING CODE 4160-01-S